AVAHO

Academic cancer centers around the United States continue to get caught up in an ever-evolving investigation into researchers – American and Chinese – who did not disclose payments from or the work they did for Chinese institutions while simultaneously accepting taxpayer money through U.S. government grants.

The U.S. Federal Bureau of Investigation has been ferreting out researchers it says have acted illegally.

On Jan. 28, the agency arrested Charles Lieber, a chemist from Harvard University, Cambridge, Mass., and also unveiled charges against Zheng Zaosong, a cancer researcher who is in the United States on a Harvard-sponsored visa.

The FBI said Mr. Zheng, who worked at the Harvard-affiliated Beth Israel Deaconess Medical Center, Boston, tried to smuggle 21 vials of biological material and research to China. Mr. Zheng was arrested in December at Boston’s Logan Airport. He admitted he planned to conduct and publish research in China using the stolen samples, said the FBI.

“All of the individuals charged today were either directly or indirectly working for the Chinese government, at our country’s expense,” said the agent in charge of the FBI’s Boston office, Joseph R. Bonavolonta.

Sen. Charles Grassley (R-IA), who has been pushing for more government action against foreign theft of U.S. research, said in a statement, “I’m glad the FBI appears to be taking foreign threats to taxpayer-funded research seriously, but I fear that this case is only the tip of the iceberg.”

The FBI said it is investigating China-related cases in all 50 states.

Ross McKinney, MD, the chief scientific officer at the Association of American Medical Colleges (AAMC), said he is aware of some 200 investigations, not all of which are cancer related, at 70-75 institutions.

“It’s a very ubiquitous problem,” Dr. McKinney said in an interview.

He also pointed out that some 6,000 National Institutes of Health–funded principal investigators are of Asian background. “So that 200 is a pretty small proportion,” said Dr. McKinney.

The NIH warned some 10,000 institutions in August 2018 that it had uncovered Chinese manipulation of peer review and a lack of disclosure of work for Chinese institutions. It urged the institutions to report irregularities.

For universities, “the trouble is sorting out who is the violator from who is not,” said Dr. McKinney. He noted that they are not set up to investigate whether someone has a laboratory in China.

“The fact that the Chinese government exploited the fact that universities are typically fairly trusting is extremely disappointing,” he said.
 

Moffitt story still unfolding

The most serious allegations have been leveled against six former employees of the Moffitt Cancer Center and Research Institute in Tampa, Florida.

In December 2019, Moffitt announced that the six – including President and CEO Alan List, MD, and the center director, Thomas Sellers, PhD – had left Moffitt as a result of “violations of conflict of interest rules through their work in China.”

New details have emerged, thanks to a new investigative report from a committee of the Florida House of Representatives.

The report said that Sheng Wei, a naturalized U.S. citizen who had worked at Moffitt since 2008 – when Moffitt began its affiliation with the Tianjin Medical University Cancer Institute and Hospital – was instrumental in recruiting top executives into the Thousand Talents program, which Wei had joined in 2010, according to the report. These executives included Dr. List, Dr. Sellers, and also Daniel Sullivan, head of Moffitt’s clinical science program, and cancer biologist Pearlie Epling-Burnette, it noted.

Begun in 2008, China’s Thousand Talents Plan gave salaries, funding, laboratory space, and other incentives to researchers who promised to bring U.S.-gained knowledge and research to China.

All information about this program has been removed from the Internet, but the program may still be active, Dr. McKinney commented.

According to the report, Dr. List pledged to work for the Tianjin cancer center 9 months a year for $71,000 annually. He was appointed head of the hematology department ($85,300 a year) in 2016. He opened a bank account in China to receive that salary and other Thousand Talents payments, the report found. The report notes that the exact amount Dr. List was paid is still not known.

Initially, Dr. Sellers, who was the principal investigator for Moffitt’s National Cancer Institute core grant, said he had not been involved in the Thousand Talents program. He later admitted that he had pledged to work in China 2 months a year for the program and that he’d opened a Chinese bank account and had deposited at least $35,000 into the account, the report notes.

The others pledged to work for the Thousand Talents program and also opened bank accounts in China and received money in those accounts.

Another Moffitt employee, Howard McLeod, MD, had worked for Thousand Talents before he joined Moffitt but did not disclose his China work. Dr. McLeod also supervised and had a close relationship with another researcher, Yijing (Bob) He, MD, who was employed by Moffitt but who lived in China, unbeknownst to Moffitt. “Dr. He appears to have functioned as an agent of Dr. McLeod in China,” said the report.

The report concluded that “none of the Moffitt faculty who were Talents program participants properly or timely disclosed their Talents program involvement to Moffitt, and none disclosed the full extent of their Talents program activities prior to Moffitt’s internal investigation.”

No charges have been filed against any of the former Moffitt employees.

However, the Cancer Letter has reported that Dr. Sellers is claiming he was not involved in the program and that he is preparing to sue Moffitt.

AAMC’s Dr. McKinney notes that it is illegal for researchers to take U.S. government grant money and pledge a certain amount of time but not deliver on that commitment because they are working for someone else – in this case, China. They also lied about not having any other research support, which is also illegal, he said.

The researchers received Chinese money and deposited it in Chinese accounts, which was never reported to the U.S. Internal Revenue Service.

“One of the hallmarks of the Chinese recruitment program was that people were instructed to not tell their normal U.S. host institution and not tell any U.S. government agency about their relationship with China,” Dr. McKinney said. “It was creating a culture where dishonesty in this situation was norm,” he added.

The lack of honesty brings up bigger questions for the field, he said. “Once you start lying about one thing, do you lie about your science, too?”
 

Lack of oversight?

Dr. McKinney said the NIH, as well as universities and hospitals, had a long and trusting relationship with China and should not be blamed for falling prey to the Chinese government’s concerted effort to steal intellectual property.

But some government watchdog groups have chided the NIH for lax oversight. In February 2019, the federal Health & Human Services’ Office of Inspector General found that “NIH has not assessed the risks to national security when permitting data access to foreign [principal investigators].”

Federal investigators have said that Thousand Talents has been one of the biggest threats.

The U.S. Senate Permanent Subcommittee on Investigations reported in November 2019 that “the federal government’s grant-making agencies did little to prevent this from happening, nor did the FBI and other federal agencies develop a coordinated response to mitigate the threat.”

The NIH invests $31 billion a year in medical research through 50,000 competitive grants to more than 300,000 researchers, according to that report. Even after uncovering grant fraud and peer-review manipulation that benefited China, “significant gaps in NIH’s grant integrity process remain,” the report states. Site visits by the NIH’s Division of Grants Compliance and Oversight dropped from 28 in 2012 to just 3 in 2018, the report noted.
 

Widening dragnet

In April 2019, Science reported that the NIH identified five researchers at MD Anderson Cancer Center in Houston who had failed to disclose their ties to Chinese enterprises and who had failed to keep peer review confidential.

Two resigned before they could be fired, one was fired, another eventually left the institution, and the fifth was found to have not willfully engaged in subterfuge.

Just a month later, Emory University in Atlanta announced that it had fired a husband and wife research team. The neuroscientists were known for their studies of Huntington disease. Both were U.S. citizens and had worked at Emory for more than 2 decades, according to the Science report.

The Moffitt situation led to the Florida legislature’s investigation, and also prompted some soul searching. The Tampa Bay Times reported that U.S. Senator Rick Scott (R-FL) asked state universities to provide information on what they are doing to stop foreign influence. The University of Florida then acknowledged that four faculty members resigned or were terminated because of ties to a foreign recruitment program.
 

This article first appeared on Medscape.com.

Academic cancer centers around the United States continue to get caught up in an ever-evolving investigation into researchers – American and Chinese – who did not disclose payments from or the work they did for Chinese institutions while simultaneously accepting taxpayer money through U.S. government grants.

The U.S. Federal Bureau of Investigation has been ferreting out researchers it says have acted illegally.

On Jan. 28, the agency arrested Charles Lieber, a chemist from Harvard University, Cambridge, Mass., and also unveiled charges against Zheng Zaosong, a cancer researcher who is in the United States on a Harvard-sponsored visa.

The FBI said Mr. Zheng, who worked at the Harvard-affiliated Beth Israel Deaconess Medical Center, Boston, tried to smuggle 21 vials of biological material and research to China. Mr. Zheng was arrested in December at Boston’s Logan Airport. He admitted he planned to conduct and publish research in China using the stolen samples, said the FBI.

“All of the individuals charged today were either directly or indirectly working for the Chinese government, at our country’s expense,” said the agent in charge of the FBI’s Boston office, Joseph R. Bonavolonta.

Sen. Charles Grassley (R-IA), who has been pushing for more government action against foreign theft of U.S. research, said in a statement, “I’m glad the FBI appears to be taking foreign threats to taxpayer-funded research seriously, but I fear that this case is only the tip of the iceberg.”

The FBI said it is investigating China-related cases in all 50 states.

Ross McKinney, MD, the chief scientific officer at the Association of American Medical Colleges (AAMC), said he is aware of some 200 investigations, not all of which are cancer related, at 70-75 institutions.

“It’s a very ubiquitous problem,” Dr. McKinney said in an interview.

He also pointed out that some 6,000 National Institutes of Health–funded principal investigators are of Asian background. “So that 200 is a pretty small proportion,” said Dr. McKinney.

The NIH warned some 10,000 institutions in August 2018 that it had uncovered Chinese manipulation of peer review and a lack of disclosure of work for Chinese institutions. It urged the institutions to report irregularities.

For universities, “the trouble is sorting out who is the violator from who is not,” said Dr. McKinney. He noted that they are not set up to investigate whether someone has a laboratory in China.

“The fact that the Chinese government exploited the fact that universities are typically fairly trusting is extremely disappointing,” he said.
 

Moffitt story still unfolding

The most serious allegations have been leveled against six former employees of the Moffitt Cancer Center and Research Institute in Tampa, Florida.

In December 2019, Moffitt announced that the six – including President and CEO Alan List, MD, and the center director, Thomas Sellers, PhD – had left Moffitt as a result of “violations of conflict of interest rules through their work in China.”

New details have emerged, thanks to a new investigative report from a committee of the Florida House of Representatives.

The report said that Sheng Wei, a naturalized U.S. citizen who had worked at Moffitt since 2008 – when Moffitt began its affiliation with the Tianjin Medical University Cancer Institute and Hospital – was instrumental in recruiting top executives into the Thousand Talents program, which Wei had joined in 2010, according to the report. These executives included Dr. List, Dr. Sellers, and also Daniel Sullivan, head of Moffitt’s clinical science program, and cancer biologist Pearlie Epling-Burnette, it noted.

Begun in 2008, China’s Thousand Talents Plan gave salaries, funding, laboratory space, and other incentives to researchers who promised to bring U.S.-gained knowledge and research to China.

All information about this program has been removed from the Internet, but the program may still be active, Dr. McKinney commented.

According to the report, Dr. List pledged to work for the Tianjin cancer center 9 months a year for $71,000 annually. He was appointed head of the hematology department ($85,300 a year) in 2016. He opened a bank account in China to receive that salary and other Thousand Talents payments, the report found. The report notes that the exact amount Dr. List was paid is still not known.

Initially, Dr. Sellers, who was the principal investigator for Moffitt’s National Cancer Institute core grant, said he had not been involved in the Thousand Talents program. He later admitted that he had pledged to work in China 2 months a year for the program and that he’d opened a Chinese bank account and had deposited at least $35,000 into the account, the report notes.

The others pledged to work for the Thousand Talents program and also opened bank accounts in China and received money in those accounts.

Another Moffitt employee, Howard McLeod, MD, had worked for Thousand Talents before he joined Moffitt but did not disclose his China work. Dr. McLeod also supervised and had a close relationship with another researcher, Yijing (Bob) He, MD, who was employed by Moffitt but who lived in China, unbeknownst to Moffitt. “Dr. He appears to have functioned as an agent of Dr. McLeod in China,” said the report.

The report concluded that “none of the Moffitt faculty who were Talents program participants properly or timely disclosed their Talents program involvement to Moffitt, and none disclosed the full extent of their Talents program activities prior to Moffitt’s internal investigation.”

No charges have been filed against any of the former Moffitt employees.

However, the Cancer Letter has reported that Dr. Sellers is claiming he was not involved in the program and that he is preparing to sue Moffitt.

AAMC’s Dr. McKinney notes that it is illegal for researchers to take U.S. government grant money and pledge a certain amount of time but not deliver on that commitment because they are working for someone else – in this case, China. They also lied about not having any other research support, which is also illegal, he said.

The researchers received Chinese money and deposited it in Chinese accounts, which was never reported to the U.S. Internal Revenue Service.

“One of the hallmarks of the Chinese recruitment program was that people were instructed to not tell their normal U.S. host institution and not tell any U.S. government agency about their relationship with China,” Dr. McKinney said. “It was creating a culture where dishonesty in this situation was norm,” he added.

The lack of honesty brings up bigger questions for the field, he said. “Once you start lying about one thing, do you lie about your science, too?”
 

Lack of oversight?

Dr. McKinney said the NIH, as well as universities and hospitals, had a long and trusting relationship with China and should not be blamed for falling prey to the Chinese government’s concerted effort to steal intellectual property.

But some government watchdog groups have chided the NIH for lax oversight. In February 2019, the federal Health & Human Services’ Office of Inspector General found that “NIH has not assessed the risks to national security when permitting data access to foreign [principal investigators].”

Federal investigators have said that Thousand Talents has been one of the biggest threats.

The U.S. Senate Permanent Subcommittee on Investigations reported in November 2019 that “the federal government’s grant-making agencies did little to prevent this from happening, nor did the FBI and other federal agencies develop a coordinated response to mitigate the threat.”

The NIH invests $31 billion a year in medical research through 50,000 competitive grants to more than 300,000 researchers, according to that report. Even after uncovering grant fraud and peer-review manipulation that benefited China, “significant gaps in NIH’s grant integrity process remain,” the report states. Site visits by the NIH’s Division of Grants Compliance and Oversight dropped from 28 in 2012 to just 3 in 2018, the report noted.
 

Widening dragnet

In April 2019, Science reported that the NIH identified five researchers at MD Anderson Cancer Center in Houston who had failed to disclose their ties to Chinese enterprises and who had failed to keep peer review confidential.

Two resigned before they could be fired, one was fired, another eventually left the institution, and the fifth was found to have not willfully engaged in subterfuge.

Just a month later, Emory University in Atlanta announced that it had fired a husband and wife research team. The neuroscientists were known for their studies of Huntington disease. Both were U.S. citizens and had worked at Emory for more than 2 decades, according to the Science report.

The Moffitt situation led to the Florida legislature’s investigation, and also prompted some soul searching. The Tampa Bay Times reported that U.S. Senator Rick Scott (R-FL) asked state universities to provide information on what they are doing to stop foreign influence. The University of Florida then acknowledged that four faculty members resigned or were terminated because of ties to a foreign recruitment program.
 

This article first appeared on Medscape.com.

Academic cancer centers around the United States continue to get caught up in an ever-evolving investigation into researchers – American and Chinese – who did not disclose payments from or the work they did for Chinese institutions while simultaneously accepting taxpayer money through U.S. government grants.

The U.S. Federal Bureau of Investigation has been ferreting out researchers it says have acted illegally.

On Jan. 28, the agency arrested Charles Lieber, a chemist from Harvard University, Cambridge, Mass., and also unveiled charges against Zheng Zaosong, a cancer researcher who is in the United States on a Harvard-sponsored visa.

The FBI said Mr. Zheng, who worked at the Harvard-affiliated Beth Israel Deaconess Medical Center, Boston, tried to smuggle 21 vials of biological material and research to China. Mr. Zheng was arrested in December at Boston’s Logan Airport. He admitted he planned to conduct and publish research in China using the stolen samples, said the FBI.

“All of the individuals charged today were either directly or indirectly working for the Chinese government, at our country’s expense,” said the agent in charge of the FBI’s Boston office, Joseph R. Bonavolonta.

Sen. Charles Grassley (R-IA), who has been pushing for more government action against foreign theft of U.S. research, said in a statement, “I’m glad the FBI appears to be taking foreign threats to taxpayer-funded research seriously, but I fear that this case is only the tip of the iceberg.”

The FBI said it is investigating China-related cases in all 50 states.

Ross McKinney, MD, the chief scientific officer at the Association of American Medical Colleges (AAMC), said he is aware of some 200 investigations, not all of which are cancer related, at 70-75 institutions.

“It’s a very ubiquitous problem,” Dr. McKinney said in an interview.

He also pointed out that some 6,000 National Institutes of Health–funded principal investigators are of Asian background. “So that 200 is a pretty small proportion,” said Dr. McKinney.

The NIH warned some 10,000 institutions in August 2018 that it had uncovered Chinese manipulation of peer review and a lack of disclosure of work for Chinese institutions. It urged the institutions to report irregularities.

For universities, “the trouble is sorting out who is the violator from who is not,” said Dr. McKinney. He noted that they are not set up to investigate whether someone has a laboratory in China.

“The fact that the Chinese government exploited the fact that universities are typically fairly trusting is extremely disappointing,” he said.
 

Moffitt story still unfolding

The most serious allegations have been leveled against six former employees of the Moffitt Cancer Center and Research Institute in Tampa, Florida.

In December 2019, Moffitt announced that the six – including President and CEO Alan List, MD, and the center director, Thomas Sellers, PhD – had left Moffitt as a result of “violations of conflict of interest rules through their work in China.”

New details have emerged, thanks to a new investigative report from a committee of the Florida House of Representatives.

The report said that Sheng Wei, a naturalized U.S. citizen who had worked at Moffitt since 2008 – when Moffitt began its affiliation with the Tianjin Medical University Cancer Institute and Hospital – was instrumental in recruiting top executives into the Thousand Talents program, which Wei had joined in 2010, according to the report. These executives included Dr. List, Dr. Sellers, and also Daniel Sullivan, head of Moffitt’s clinical science program, and cancer biologist Pearlie Epling-Burnette, it noted.

Begun in 2008, China’s Thousand Talents Plan gave salaries, funding, laboratory space, and other incentives to researchers who promised to bring U.S.-gained knowledge and research to China.

All information about this program has been removed from the Internet, but the program may still be active, Dr. McKinney commented.

According to the report, Dr. List pledged to work for the Tianjin cancer center 9 months a year for $71,000 annually. He was appointed head of the hematology department ($85,300 a year) in 2016. He opened a bank account in China to receive that salary and other Thousand Talents payments, the report found. The report notes that the exact amount Dr. List was paid is still not known.

Initially, Dr. Sellers, who was the principal investigator for Moffitt’s National Cancer Institute core grant, said he had not been involved in the Thousand Talents program. He later admitted that he had pledged to work in China 2 months a year for the program and that he’d opened a Chinese bank account and had deposited at least $35,000 into the account, the report notes.

The others pledged to work for the Thousand Talents program and also opened bank accounts in China and received money in those accounts.

Another Moffitt employee, Howard McLeod, MD, had worked for Thousand Talents before he joined Moffitt but did not disclose his China work. Dr. McLeod also supervised and had a close relationship with another researcher, Yijing (Bob) He, MD, who was employed by Moffitt but who lived in China, unbeknownst to Moffitt. “Dr. He appears to have functioned as an agent of Dr. McLeod in China,” said the report.

The report concluded that “none of the Moffitt faculty who were Talents program participants properly or timely disclosed their Talents program involvement to Moffitt, and none disclosed the full extent of their Talents program activities prior to Moffitt’s internal investigation.”

No charges have been filed against any of the former Moffitt employees.

However, the Cancer Letter has reported that Dr. Sellers is claiming he was not involved in the program and that he is preparing to sue Moffitt.

AAMC’s Dr. McKinney notes that it is illegal for researchers to take U.S. government grant money and pledge a certain amount of time but not deliver on that commitment because they are working for someone else – in this case, China. They also lied about not having any other research support, which is also illegal, he said.

The researchers received Chinese money and deposited it in Chinese accounts, which was never reported to the U.S. Internal Revenue Service.

“One of the hallmarks of the Chinese recruitment program was that people were instructed to not tell their normal U.S. host institution and not tell any U.S. government agency about their relationship with China,” Dr. McKinney said. “It was creating a culture where dishonesty in this situation was norm,” he added.

The lack of honesty brings up bigger questions for the field, he said. “Once you start lying about one thing, do you lie about your science, too?”
 

Lack of oversight?

Dr. McKinney said the NIH, as well as universities and hospitals, had a long and trusting relationship with China and should not be blamed for falling prey to the Chinese government’s concerted effort to steal intellectual property.

But some government watchdog groups have chided the NIH for lax oversight. In February 2019, the federal Health & Human Services’ Office of Inspector General found that “NIH has not assessed the risks to national security when permitting data access to foreign [principal investigators].”

Federal investigators have said that Thousand Talents has been one of the biggest threats.

The U.S. Senate Permanent Subcommittee on Investigations reported in November 2019 that “the federal government’s grant-making agencies did little to prevent this from happening, nor did the FBI and other federal agencies develop a coordinated response to mitigate the threat.”

The NIH invests $31 billion a year in medical research through 50,000 competitive grants to more than 300,000 researchers, according to that report. Even after uncovering grant fraud and peer-review manipulation that benefited China, “significant gaps in NIH’s grant integrity process remain,” the report states. Site visits by the NIH’s Division of Grants Compliance and Oversight dropped from 28 in 2012 to just 3 in 2018, the report noted.
 

Widening dragnet

In April 2019, Science reported that the NIH identified five researchers at MD Anderson Cancer Center in Houston who had failed to disclose their ties to Chinese enterprises and who had failed to keep peer review confidential.

Two resigned before they could be fired, one was fired, another eventually left the institution, and the fifth was found to have not willfully engaged in subterfuge.

Just a month later, Emory University in Atlanta announced that it had fired a husband and wife research team. The neuroscientists were known for their studies of Huntington disease. Both were U.S. citizens and had worked at Emory for more than 2 decades, according to the Science report.

The Moffitt situation led to the Florida legislature’s investigation, and also prompted some soul searching. The Tampa Bay Times reported that U.S. Senator Rick Scott (R-FL) asked state universities to provide information on what they are doing to stop foreign influence. The University of Florida then acknowledged that four faculty members resigned or were terminated because of ties to a foreign recruitment program.
 

This article first appeared on Medscape.com.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Sequencing Therapies

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patients With Rising PSAs

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

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

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

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

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

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

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

Adverse Effects

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

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

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

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

Julie Graff. I agree.

Patient Education

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

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

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

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

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

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

Imaging Modalities

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

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

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

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

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

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

Treatment Options for Patients With Adverse Events

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Clinical Trials

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

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

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

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

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

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

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

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

Immunotherapies

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

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

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

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

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

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

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

Pharmacy

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

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

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

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

Sequencing Therapies

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patients With Rising PSAs

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

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

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

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

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

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

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

Adverse Effects

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

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

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

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

Julie Graff. I agree.

Patient Education

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

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

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

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

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

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

Imaging Modalities

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

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

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

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

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

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

Treatment Options for Patients With Adverse Events

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Clinical Trials

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

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

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

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

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

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

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

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

Immunotherapies

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

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

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

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

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

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

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

Pharmacy

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

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

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

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

Sequencing Therapies

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patients With Rising PSAs

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

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

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

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

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

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

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

Adverse Effects

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

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

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

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

Julie Graff. I agree.

Patient Education

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

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

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

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

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

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

Imaging Modalities

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

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

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

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

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

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

Treatment Options for Patients With Adverse Events

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Clinical Trials

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

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

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

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

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

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

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

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

Immunotherapies

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

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

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

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

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

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

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

Pharmacy

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

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

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

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

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

Case Presentation

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

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

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

Discussion

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

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

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

Diagnosis

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

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

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

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

Treatment

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

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

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

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

Conclusion

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

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

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

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

Case Presentation

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

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

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

Discussion

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

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

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

Diagnosis

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

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

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

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

Treatment

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

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

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

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

Conclusion

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

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

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

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

Case Presentation

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

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

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

Discussion

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

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

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

Diagnosis

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

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

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

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

Treatment

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

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

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

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

Conclusion

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

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

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

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

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

Case Presentation

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

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

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

Discussion

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

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

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

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

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

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

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

Conclusion

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

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

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

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

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

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

Case Presentation

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

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

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

Discussion

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

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

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

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

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

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

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

Conclusion

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

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

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

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

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

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

Case Presentation

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

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

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

Discussion

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

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

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

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

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

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

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

Conclusion

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

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

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

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

Bone pain is one of the most common causes of morbidity in multiple myeloma (MM) and metastatic prostate cancer (CaP). This pain originates with the underlying pathologic processes of the cancer and with downstream skeletal-related events (SREs). SREs—fractures, spinal cord compression, and irradiation or surgery performed in ≥ 1 bone sites—represent a significant health care burden, particularly given the incidence of the underlying malignancies. According to American Cancer Society statistics, CaP is the second most common cancer in American men, and MM the second most common hematologic malignancy, despite its relatively low overall lifetime risk.^1,2 Regardless of the underlying malignancy, bisphosphonates are the cornerstone of SRE prevention, though the optimal dosing strategy is the subject of clinical debate.

Although similar in SRE incidence, MM and CaP have distinct pathophysiologic processes in the dysregulation of bone resorption. MM is a hematologic malignancy that increases the risk of SREs by osteoclast up-regulation, primarily through the RANK (receptor activator of nuclear factor α-B) signaling pathway.³ CaP is a solid tumor malignancy that metastasizes to bone. Dysregulation of the bone resorption or formation cycle and net bone loss are a result of endogenous osteoclast up-regulation in response to abnormal bone formation in osteoblastic bone metastases.⁴ Androgen-deprivation therapy, the cornerstone of CaP treatment, further predisposes CaP patients to osteoporosis and SREs.

Prevention of SREs is pharmacologically driven by bisphosphonates, which have antiresorptive effects on bone through promotion of osteoclast apoptosis.⁵ Two IV formulations, pamidronate and zoledronic acid (ZA), are US Food and Drug Administration approved for use in bone metastases from MM or solid tumors.^6-10 Although generally well tolerated, bisphosphonates can cause osteonecrosis of the jaw (ONJ), an avascular death of bone tissue, particularly with prolonged use.¹¹ With its documented incidence of 5% to 6.7% in bone metastasis, ONJ represents a significant morbidity risk in patients with MM and CaP who are treated with IV bisphosphonates.¹²

Investigators are exploring bisphosphonate dosing intervals to determine which is most appropriate in mitigating the risk of ONJ. Before 2006, bisphosphonates were consistently dosed once monthly in patients with MM or metastatic bone disease—a standard derived empirically rather than from comparative studies or compelling pharmacodynamic data.^13-15 In a 2006 consensus statement, the Mayo Clinic issued an expert opinion recommendation for increasing the bisphosphonate dosing interval to every 3 months in patients with MM.¹⁶ The first objective evidence for the clinical applicability of extending the ZA dosing interval was reported by Himelstein and colleagues in 2017.¹⁷ The randomized clinical trial found no differences in SRE rates when ZA was dosed every 12 weeks,¹⁷ prompting a conditional recommendation for dosing interval extension in the American Society of Clinical Oncology MM treatment guidelines (2018).¹³ Because of the age and racial demographics of the patients in these studies, many questions remain unanswered.

For the US Department of Veterans Affairs (VA) population, the pharmacokinetic and dynamic differences imposed by age and race limit the applicability of the available data. However, in veterans with MM or CaP, extending the bisphosphonate dosing interval may help decrease medication-related morbidity (eg, ONJ, nephrotoxicity) without compromising therapeutic benefit. To this end at the Memphis VA Medical Center (VAMC), we assessed for differences in SRE rates by comparing outcomes of patients who received ZA in standard- vs extended-interval dosing.

Methods

We retrospectively reviewed the Computerized Patient Record System for veterans with MM or metastatic CaP treated with ZA at the Memphis VAMC. Study inclusion criteria were aged > 18 years and care provided by a Memphis VAMC oncologist between January 2003 and January 2018. The study was approved by the Memphis VAMC’s Institutional Review Board, and procedures were followed in accordance with the ethical standards of its committee on human experimentation.

Using Microsoft SQL 2016 (Redmond, WA), we performed a query to identify patients who were prescribed ZA during the study period. Exclusion criteria were ZA prescribed for an indication other than MM or CaP (ie, osteoporosis) and receipt of ≤ 1 dose of ZA. Once a list was compiled, patients were stratified by ZA dosing interval: standard (mean, every month) or extended (mean, every 3 months). Patients whose ZA dosing interval was changed during treatment were included as independent data points in each group.

Skeletal-related events included fractures, spinal compression, irradiation, and surgery. Fractures and spinal compression were pertinent in the presence of radiographic documentation (eg, X-ray, magnetic resonance imaging scan) during the period the patient received ZA or within 1 dosing interval of the last recorded ZA dose. Irradiation was defined as documented application of radiation therapy to ≥ 1 bone sites for palliation of pain or as an intervention in the setting of spinal compression. Surgery was defined as any procedure performed to correct a fracture or spinal compression. Each SRE was counted as a single occurrence.

Osteonecrosis of the jaw was defined as radiographically documented necrosis of the mandible or associated structures with assessment by a VA dentist. Records from non-VA dental practices were not available for assessment. Documentation of dental assessment before the first dose of ZA and any assessments during treatment were recorded.

Medication use was assessed before and during ZA treatment. Number of ZA doses and reasons for any discontinuations were documented, as was concomitant use of calcium supplements, vitamin D supplements, calcitriol, paricalcitol, calcitonin, cinacalcet, and pamidronate.

The primary study outcome was observed difference in incidence of SREs between standard- and extended-interval dosing of ZA. Secondary outcomes included difference in incidence of ONJ as well as incidence of SREs and ONJ by disease subtype (MM, CaP).

Descriptive statistics were used to summarize demographic data and assess prespecified outcomes. Differences in rates of SREs and ONJ between dosing interval groups were analyzed with the Pearson χ² test. The predetermined a priori level of significance was .05.

Results

Of the 300 patients prescribed ZA at the Memphis VAMC, 177 were excluded (96 for indication,78 for receiving only 1 dose of ZA, 3 for not receiving any doses of ZA). The remaining 123 patients were stratified into a standard-interval dosing group (121) and an extended-interval dosing group (35). Of the 123 patients, 33 received both standard- and extended-interval dosing of ZA over the course of the study period and were included discretely in each group for the duration of each dosing strategy. 

Pre-ZA dental screenings were documented in 14% of standard-interval patients and 17% of extended-interval patients, and during-ZA screenings were documented in 17% of standard-interval patients and 20% of extended-interval patients. Chi-square analysis revealed no significant difference in rates of dental screening before or during use of ZA.

Standard-interval patients received a mean (SD) 11.4 (13.5) doses of ZA (range, 2-124). Extended-interval patients received a mean (SD) of 5.9 (3.18) doses (range, 2-14). All standard-interval patients had discontinued treatment at the time of the study, most commonly because of death or for an unknown reason. Sixty percent of extended-interval patients had discontinued treatment, most commonly because of patient/physician choice or for an unknown reason (Table 2). 

Skeletal-related events were observed in 31% of standard-interval patients and 23% of extended-interval patients. There were no statistically significant differences in SRE rates between groups (P = .374). The most common SRE in both groups was bone irradiation (42% and 60%, respectively), with no statistically significant difference in proportion between groups (Table 4). 

Discussion

This retrospective review of patients with MM and CaP receiving ZA for bone metastasesfound no differences in the rates of SREs when ZA was dosed monthly vs every 3 months. 

Earlier studies found that ZA can decrease SRE rates, but a major concern is that frequent, prolonged exposure to IV bisphosphonates may increase the risk of ONJ. No significant differences in ONJ rates existed between dosing groups, but all documented cases of ONJ occurred in the standard-interval group, suggesting a trend toward decreased incidence with an extension of the dosing interval.

Limitations

This study had several limitations. Geriatric African American men comprised the majority of the study population, and patients with MM accounted for only 22% of included regimens, limiting external validity. Patient overlap between groups may have confounded the results. The retrospective design precluded the ability to control for confounding variables, such as concomitant medication use and medication adherence, and significant heterogeneity was noted in rates of adherence with ZA infusion schedules regardless of dosing group. Use of medications associated with increased risk of osteoporosis—including corticosteroids and proton pump inhibitors—was not assessed.

Assessment of ONJ incidence was limited by the lack of access to dental records from providers outside the VA. Many patients in this review were not eligible for VA dental benefits because of requirements involving time and service connection, a reimbursement measurement that reflects health conditions “incurred or aggravated during active military service.”¹⁸

The results of this study provide further support for extended-interval dosing of ZA as a potential method of increasing patient adherence and decreasing the possibility of adverse drug reactions without compromising therapeutic benefit. Further randomized controlled trials are needed to define the potential decrease in ONJ incidence.

Conclusion

In comparisons of standard- and extended-interval dosing of ZA, there was no difference in the incidence of skeletal-related events in veteran patients with bone metastases from MM or CaP.

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

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

Bone pain is one of the most common causes of morbidity in multiple myeloma (MM) and metastatic prostate cancer (CaP). This pain originates with the underlying pathologic processes of the cancer and with downstream skeletal-related events (SREs). SREs—fractures, spinal cord compression, and irradiation or surgery performed in ≥ 1 bone sites—represent a significant health care burden, particularly given the incidence of the underlying malignancies. According to American Cancer Society statistics, CaP is the second most common cancer in American men, and MM the second most common hematologic malignancy, despite its relatively low overall lifetime risk.^1,2 Regardless of the underlying malignancy, bisphosphonates are the cornerstone of SRE prevention, though the optimal dosing strategy is the subject of clinical debate.

Although similar in SRE incidence, MM and CaP have distinct pathophysiologic processes in the dysregulation of bone resorption. MM is a hematologic malignancy that increases the risk of SREs by osteoclast up-regulation, primarily through the RANK (receptor activator of nuclear factor α-B) signaling pathway.³ CaP is a solid tumor malignancy that metastasizes to bone. Dysregulation of the bone resorption or formation cycle and net bone loss are a result of endogenous osteoclast up-regulation in response to abnormal bone formation in osteoblastic bone metastases.⁴ Androgen-deprivation therapy, the cornerstone of CaP treatment, further predisposes CaP patients to osteoporosis and SREs.

Prevention of SREs is pharmacologically driven by bisphosphonates, which have antiresorptive effects on bone through promotion of osteoclast apoptosis.⁵ Two IV formulations, pamidronate and zoledronic acid (ZA), are US Food and Drug Administration approved for use in bone metastases from MM or solid tumors.^6-10 Although generally well tolerated, bisphosphonates can cause osteonecrosis of the jaw (ONJ), an avascular death of bone tissue, particularly with prolonged use.¹¹ With its documented incidence of 5% to 6.7% in bone metastasis, ONJ represents a significant morbidity risk in patients with MM and CaP who are treated with IV bisphosphonates.¹²

Investigators are exploring bisphosphonate dosing intervals to determine which is most appropriate in mitigating the risk of ONJ. Before 2006, bisphosphonates were consistently dosed once monthly in patients with MM or metastatic bone disease—a standard derived empirically rather than from comparative studies or compelling pharmacodynamic data.^13-15 In a 2006 consensus statement, the Mayo Clinic issued an expert opinion recommendation for increasing the bisphosphonate dosing interval to every 3 months in patients with MM.¹⁶ The first objective evidence for the clinical applicability of extending the ZA dosing interval was reported by Himelstein and colleagues in 2017.¹⁷ The randomized clinical trial found no differences in SRE rates when ZA was dosed every 12 weeks,¹⁷ prompting a conditional recommendation for dosing interval extension in the American Society of Clinical Oncology MM treatment guidelines (2018).¹³ Because of the age and racial demographics of the patients in these studies, many questions remain unanswered.

For the US Department of Veterans Affairs (VA) population, the pharmacokinetic and dynamic differences imposed by age and race limit the applicability of the available data. However, in veterans with MM or CaP, extending the bisphosphonate dosing interval may help decrease medication-related morbidity (eg, ONJ, nephrotoxicity) without compromising therapeutic benefit. To this end at the Memphis VA Medical Center (VAMC), we assessed for differences in SRE rates by comparing outcomes of patients who received ZA in standard- vs extended-interval dosing.

Methods

We retrospectively reviewed the Computerized Patient Record System for veterans with MM or metastatic CaP treated with ZA at the Memphis VAMC. Study inclusion criteria were aged > 18 years and care provided by a Memphis VAMC oncologist between January 2003 and January 2018. The study was approved by the Memphis VAMC’s Institutional Review Board, and procedures were followed in accordance with the ethical standards of its committee on human experimentation.

Using Microsoft SQL 2016 (Redmond, WA), we performed a query to identify patients who were prescribed ZA during the study period. Exclusion criteria were ZA prescribed for an indication other than MM or CaP (ie, osteoporosis) and receipt of ≤ 1 dose of ZA. Once a list was compiled, patients were stratified by ZA dosing interval: standard (mean, every month) or extended (mean, every 3 months). Patients whose ZA dosing interval was changed during treatment were included as independent data points in each group.

Skeletal-related events included fractures, spinal compression, irradiation, and surgery. Fractures and spinal compression were pertinent in the presence of radiographic documentation (eg, X-ray, magnetic resonance imaging scan) during the period the patient received ZA or within 1 dosing interval of the last recorded ZA dose. Irradiation was defined as documented application of radiation therapy to ≥ 1 bone sites for palliation of pain or as an intervention in the setting of spinal compression. Surgery was defined as any procedure performed to correct a fracture or spinal compression. Each SRE was counted as a single occurrence.

Osteonecrosis of the jaw was defined as radiographically documented necrosis of the mandible or associated structures with assessment by a VA dentist. Records from non-VA dental practices were not available for assessment. Documentation of dental assessment before the first dose of ZA and any assessments during treatment were recorded.

Medication use was assessed before and during ZA treatment. Number of ZA doses and reasons for any discontinuations were documented, as was concomitant use of calcium supplements, vitamin D supplements, calcitriol, paricalcitol, calcitonin, cinacalcet, and pamidronate.

The primary study outcome was observed difference in incidence of SREs between standard- and extended-interval dosing of ZA. Secondary outcomes included difference in incidence of ONJ as well as incidence of SREs and ONJ by disease subtype (MM, CaP).

Descriptive statistics were used to summarize demographic data and assess prespecified outcomes. Differences in rates of SREs and ONJ between dosing interval groups were analyzed with the Pearson χ² test. The predetermined a priori level of significance was .05.

Results

Of the 300 patients prescribed ZA at the Memphis VAMC, 177 were excluded (96 for indication,78 for receiving only 1 dose of ZA, 3 for not receiving any doses of ZA). The remaining 123 patients were stratified into a standard-interval dosing group (121) and an extended-interval dosing group (35). Of the 123 patients, 33 received both standard- and extended-interval dosing of ZA over the course of the study period and were included discretely in each group for the duration of each dosing strategy. 

Pre-ZA dental screenings were documented in 14% of standard-interval patients and 17% of extended-interval patients, and during-ZA screenings were documented in 17% of standard-interval patients and 20% of extended-interval patients. Chi-square analysis revealed no significant difference in rates of dental screening before or during use of ZA.

Standard-interval patients received a mean (SD) 11.4 (13.5) doses of ZA (range, 2-124). Extended-interval patients received a mean (SD) of 5.9 (3.18) doses (range, 2-14). All standard-interval patients had discontinued treatment at the time of the study, most commonly because of death or for an unknown reason. Sixty percent of extended-interval patients had discontinued treatment, most commonly because of patient/physician choice or for an unknown reason (Table 2). 

Skeletal-related events were observed in 31% of standard-interval patients and 23% of extended-interval patients. There were no statistically significant differences in SRE rates between groups (P = .374). The most common SRE in both groups was bone irradiation (42% and 60%, respectively), with no statistically significant difference in proportion between groups (Table 4). 

Discussion

This retrospective review of patients with MM and CaP receiving ZA for bone metastasesfound no differences in the rates of SREs when ZA was dosed monthly vs every 3 months. 

Earlier studies found that ZA can decrease SRE rates, but a major concern is that frequent, prolonged exposure to IV bisphosphonates may increase the risk of ONJ. No significant differences in ONJ rates existed between dosing groups, but all documented cases of ONJ occurred in the standard-interval group, suggesting a trend toward decreased incidence with an extension of the dosing interval.

Limitations

This study had several limitations. Geriatric African American men comprised the majority of the study population, and patients with MM accounted for only 22% of included regimens, limiting external validity. Patient overlap between groups may have confounded the results. The retrospective design precluded the ability to control for confounding variables, such as concomitant medication use and medication adherence, and significant heterogeneity was noted in rates of adherence with ZA infusion schedules regardless of dosing group. Use of medications associated with increased risk of osteoporosis—including corticosteroids and proton pump inhibitors—was not assessed.

Assessment of ONJ incidence was limited by the lack of access to dental records from providers outside the VA. Many patients in this review were not eligible for VA dental benefits because of requirements involving time and service connection, a reimbursement measurement that reflects health conditions “incurred or aggravated during active military service.”¹⁸

The results of this study provide further support for extended-interval dosing of ZA as a potential method of increasing patient adherence and decreasing the possibility of adverse drug reactions without compromising therapeutic benefit. Further randomized controlled trials are needed to define the potential decrease in ONJ incidence.

Conclusion

In comparisons of standard- and extended-interval dosing of ZA, there was no difference in the incidence of skeletal-related events in veteran patients with bone metastases from MM or CaP.

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

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

Bone pain is one of the most common causes of morbidity in multiple myeloma (MM) and metastatic prostate cancer (CaP). This pain originates with the underlying pathologic processes of the cancer and with downstream skeletal-related events (SREs). SREs—fractures, spinal cord compression, and irradiation or surgery performed in ≥ 1 bone sites—represent a significant health care burden, particularly given the incidence of the underlying malignancies. According to American Cancer Society statistics, CaP is the second most common cancer in American men, and MM the second most common hematologic malignancy, despite its relatively low overall lifetime risk.^1,2 Regardless of the underlying malignancy, bisphosphonates are the cornerstone of SRE prevention, though the optimal dosing strategy is the subject of clinical debate.

Although similar in SRE incidence, MM and CaP have distinct pathophysiologic processes in the dysregulation of bone resorption. MM is a hematologic malignancy that increases the risk of SREs by osteoclast up-regulation, primarily through the RANK (receptor activator of nuclear factor α-B) signaling pathway.³ CaP is a solid tumor malignancy that metastasizes to bone. Dysregulation of the bone resorption or formation cycle and net bone loss are a result of endogenous osteoclast up-regulation in response to abnormal bone formation in osteoblastic bone metastases.⁴ Androgen-deprivation therapy, the cornerstone of CaP treatment, further predisposes CaP patients to osteoporosis and SREs.

Prevention of SREs is pharmacologically driven by bisphosphonates, which have antiresorptive effects on bone through promotion of osteoclast apoptosis.⁵ Two IV formulations, pamidronate and zoledronic acid (ZA), are US Food and Drug Administration approved for use in bone metastases from MM or solid tumors.^6-10 Although generally well tolerated, bisphosphonates can cause osteonecrosis of the jaw (ONJ), an avascular death of bone tissue, particularly with prolonged use.¹¹ With its documented incidence of 5% to 6.7% in bone metastasis, ONJ represents a significant morbidity risk in patients with MM and CaP who are treated with IV bisphosphonates.¹²

Investigators are exploring bisphosphonate dosing intervals to determine which is most appropriate in mitigating the risk of ONJ. Before 2006, bisphosphonates were consistently dosed once monthly in patients with MM or metastatic bone disease—a standard derived empirically rather than from comparative studies or compelling pharmacodynamic data.^13-15 In a 2006 consensus statement, the Mayo Clinic issued an expert opinion recommendation for increasing the bisphosphonate dosing interval to every 3 months in patients with MM.¹⁶ The first objective evidence for the clinical applicability of extending the ZA dosing interval was reported by Himelstein and colleagues in 2017.¹⁷ The randomized clinical trial found no differences in SRE rates when ZA was dosed every 12 weeks,¹⁷ prompting a conditional recommendation for dosing interval extension in the American Society of Clinical Oncology MM treatment guidelines (2018).¹³ Because of the age and racial demographics of the patients in these studies, many questions remain unanswered.

For the US Department of Veterans Affairs (VA) population, the pharmacokinetic and dynamic differences imposed by age and race limit the applicability of the available data. However, in veterans with MM or CaP, extending the bisphosphonate dosing interval may help decrease medication-related morbidity (eg, ONJ, nephrotoxicity) without compromising therapeutic benefit. To this end at the Memphis VA Medical Center (VAMC), we assessed for differences in SRE rates by comparing outcomes of patients who received ZA in standard- vs extended-interval dosing.

Methods

We retrospectively reviewed the Computerized Patient Record System for veterans with MM or metastatic CaP treated with ZA at the Memphis VAMC. Study inclusion criteria were aged > 18 years and care provided by a Memphis VAMC oncologist between January 2003 and January 2018. The study was approved by the Memphis VAMC’s Institutional Review Board, and procedures were followed in accordance with the ethical standards of its committee on human experimentation.

Using Microsoft SQL 2016 (Redmond, WA), we performed a query to identify patients who were prescribed ZA during the study period. Exclusion criteria were ZA prescribed for an indication other than MM or CaP (ie, osteoporosis) and receipt of ≤ 1 dose of ZA. Once a list was compiled, patients were stratified by ZA dosing interval: standard (mean, every month) or extended (mean, every 3 months). Patients whose ZA dosing interval was changed during treatment were included as independent data points in each group.

Skeletal-related events included fractures, spinal compression, irradiation, and surgery. Fractures and spinal compression were pertinent in the presence of radiographic documentation (eg, X-ray, magnetic resonance imaging scan) during the period the patient received ZA or within 1 dosing interval of the last recorded ZA dose. Irradiation was defined as documented application of radiation therapy to ≥ 1 bone sites for palliation of pain or as an intervention in the setting of spinal compression. Surgery was defined as any procedure performed to correct a fracture or spinal compression. Each SRE was counted as a single occurrence.

Osteonecrosis of the jaw was defined as radiographically documented necrosis of the mandible or associated structures with assessment by a VA dentist. Records from non-VA dental practices were not available for assessment. Documentation of dental assessment before the first dose of ZA and any assessments during treatment were recorded.

Medication use was assessed before and during ZA treatment. Number of ZA doses and reasons for any discontinuations were documented, as was concomitant use of calcium supplements, vitamin D supplements, calcitriol, paricalcitol, calcitonin, cinacalcet, and pamidronate.

The primary study outcome was observed difference in incidence of SREs between standard- and extended-interval dosing of ZA. Secondary outcomes included difference in incidence of ONJ as well as incidence of SREs and ONJ by disease subtype (MM, CaP).

Descriptive statistics were used to summarize demographic data and assess prespecified outcomes. Differences in rates of SREs and ONJ between dosing interval groups were analyzed with the Pearson χ² test. The predetermined a priori level of significance was .05.

Results

Of the 300 patients prescribed ZA at the Memphis VAMC, 177 were excluded (96 for indication,78 for receiving only 1 dose of ZA, 3 for not receiving any doses of ZA). The remaining 123 patients were stratified into a standard-interval dosing group (121) and an extended-interval dosing group (35). Of the 123 patients, 33 received both standard- and extended-interval dosing of ZA over the course of the study period and were included discretely in each group for the duration of each dosing strategy. 

Pre-ZA dental screenings were documented in 14% of standard-interval patients and 17% of extended-interval patients, and during-ZA screenings were documented in 17% of standard-interval patients and 20% of extended-interval patients. Chi-square analysis revealed no significant difference in rates of dental screening before or during use of ZA.

Standard-interval patients received a mean (SD) 11.4 (13.5) doses of ZA (range, 2-124). Extended-interval patients received a mean (SD) of 5.9 (3.18) doses (range, 2-14). All standard-interval patients had discontinued treatment at the time of the study, most commonly because of death or for an unknown reason. Sixty percent of extended-interval patients had discontinued treatment, most commonly because of patient/physician choice or for an unknown reason (Table 2). 

Skeletal-related events were observed in 31% of standard-interval patients and 23% of extended-interval patients. There were no statistically significant differences in SRE rates between groups (P = .374). The most common SRE in both groups was bone irradiation (42% and 60%, respectively), with no statistically significant difference in proportion between groups (Table 4). 

Discussion

This retrospective review of patients with MM and CaP receiving ZA for bone metastasesfound no differences in the rates of SREs when ZA was dosed monthly vs every 3 months. 

Earlier studies found that ZA can decrease SRE rates, but a major concern is that frequent, prolonged exposure to IV bisphosphonates may increase the risk of ONJ. No significant differences in ONJ rates existed between dosing groups, but all documented cases of ONJ occurred in the standard-interval group, suggesting a trend toward decreased incidence with an extension of the dosing interval.

Limitations

This study had several limitations. Geriatric African American men comprised the majority of the study population, and patients with MM accounted for only 22% of included regimens, limiting external validity. Patient overlap between groups may have confounded the results. The retrospective design precluded the ability to control for confounding variables, such as concomitant medication use and medication adherence, and significant heterogeneity was noted in rates of adherence with ZA infusion schedules regardless of dosing group. Use of medications associated with increased risk of osteoporosis—including corticosteroids and proton pump inhibitors—was not assessed.

Assessment of ONJ incidence was limited by the lack of access to dental records from providers outside the VA. Many patients in this review were not eligible for VA dental benefits because of requirements involving time and service connection, a reimbursement measurement that reflects health conditions “incurred or aggravated during active military service.”¹⁸

The results of this study provide further support for extended-interval dosing of ZA as a potential method of increasing patient adherence and decreasing the possibility of adverse drug reactions without compromising therapeutic benefit. Further randomized controlled trials are needed to define the potential decrease in ONJ incidence.

Conclusion

In comparisons of standard- and extended-interval dosing of ZA, there was no difference in the incidence of skeletal-related events in veteran patients with bone metastases from MM or CaP.

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

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

Newly discovered gene mutations in the progression of venetoclax-treated relapsed chronic lymphocytic leukemia (CLL) may improve understanding of clinical resistance mechanisms underlying the disease, according to recent research.

“We investigated patients with progressive CLL on venetoclax harboring subclonal BCL2 Gly101Val mutations for the presence of additional acquired BCL2 resistance mutations,” wrote Piers Blombery, MBBS, of the University of Melbourne in Victoria, Australia, and his colleagues in Blood.

Among 67 patients with relapsed disease treated with the BCL2 inhibitor venetoclax, the researchers identified a total of 11 patients with co-occurring BCL2 Gly101Val mutations. Each patient was enrolled in an early phase clinical trial at an institution in Australia.

With respect to testing methods, next-generation sequencing (NGS) and hybridization-based target enrichment technologies were used to detect novel acquired mutations in the BCL2 coding region.

Among those harboring the Gly101Val mutation, additional BCL2 mutations were identified in 10 patients (91%), with a median of three mutations detected per patient (range, 1-7). Previously undescribed mutations included an in-frame insertion mutation (Arg107_Arg110dup), and other substitutions (Asp103/Val156) in the BCL2 gene.

“As with the Gly101Val, these observations support the specificity of these mutations for the context of venetoclax resistance,” they wrote.

The investigators further explained that the BCL2 Asp103Glu mutation could have particular significance in the context of venetoclax sensitivity because of selective targeting of the BCL2 gene.

In comparison to wild-type aspartic acid, the BCL2 Asp103Glu substitution was linked to an approximate 20-fold reduction in affinity for venetoclax, they reported.

“[Our findings] consolidate the paradigm emerging across hematological malignancies of multiple independent molecular mechanisms underpinning an ‘oligoclonal’ pattern of clinical relapse on targeted therapies,” they concluded.

Further studies are needed to fully characterize the relationship between acquired BCL2 mutations and venetoclax resistance.

The study was funded by the Snowdome Foundation, Vision Super and the Wilson Centre for Lymphoma Genomics, the Leukemia and Lymphoma Society, the National Health and Medical Research Council of Australia, and other grant funding sources provided to the study authors. The authors reported financial affiliations with AbbVie, Genentech, and the Walter and Eliza Hall Institute.

Newly discovered gene mutations in the progression of venetoclax-treated relapsed chronic lymphocytic leukemia (CLL) may improve understanding of clinical resistance mechanisms underlying the disease, according to recent research.

“We investigated patients with progressive CLL on venetoclax harboring subclonal BCL2 Gly101Val mutations for the presence of additional acquired BCL2 resistance mutations,” wrote Piers Blombery, MBBS, of the University of Melbourne in Victoria, Australia, and his colleagues in Blood.

Among 67 patients with relapsed disease treated with the BCL2 inhibitor venetoclax, the researchers identified a total of 11 patients with co-occurring BCL2 Gly101Val mutations. Each patient was enrolled in an early phase clinical trial at an institution in Australia.

With respect to testing methods, next-generation sequencing (NGS) and hybridization-based target enrichment technologies were used to detect novel acquired mutations in the BCL2 coding region.

Among those harboring the Gly101Val mutation, additional BCL2 mutations were identified in 10 patients (91%), with a median of three mutations detected per patient (range, 1-7). Previously undescribed mutations included an in-frame insertion mutation (Arg107_Arg110dup), and other substitutions (Asp103/Val156) in the BCL2 gene.

“As with the Gly101Val, these observations support the specificity of these mutations for the context of venetoclax resistance,” they wrote.

The investigators further explained that the BCL2 Asp103Glu mutation could have particular significance in the context of venetoclax sensitivity because of selective targeting of the BCL2 gene.

In comparison to wild-type aspartic acid, the BCL2 Asp103Glu substitution was linked to an approximate 20-fold reduction in affinity for venetoclax, they reported.

“[Our findings] consolidate the paradigm emerging across hematological malignancies of multiple independent molecular mechanisms underpinning an ‘oligoclonal’ pattern of clinical relapse on targeted therapies,” they concluded.

Further studies are needed to fully characterize the relationship between acquired BCL2 mutations and venetoclax resistance.

The study was funded by the Snowdome Foundation, Vision Super and the Wilson Centre for Lymphoma Genomics, the Leukemia and Lymphoma Society, the National Health and Medical Research Council of Australia, and other grant funding sources provided to the study authors. The authors reported financial affiliations with AbbVie, Genentech, and the Walter and Eliza Hall Institute.

Newly discovered gene mutations in the progression of venetoclax-treated relapsed chronic lymphocytic leukemia (CLL) may improve understanding of clinical resistance mechanisms underlying the disease, according to recent research.

“We investigated patients with progressive CLL on venetoclax harboring subclonal BCL2 Gly101Val mutations for the presence of additional acquired BCL2 resistance mutations,” wrote Piers Blombery, MBBS, of the University of Melbourne in Victoria, Australia, and his colleagues in Blood.

Among 67 patients with relapsed disease treated with the BCL2 inhibitor venetoclax, the researchers identified a total of 11 patients with co-occurring BCL2 Gly101Val mutations. Each patient was enrolled in an early phase clinical trial at an institution in Australia.

With respect to testing methods, next-generation sequencing (NGS) and hybridization-based target enrichment technologies were used to detect novel acquired mutations in the BCL2 coding region.

Among those harboring the Gly101Val mutation, additional BCL2 mutations were identified in 10 patients (91%), with a median of three mutations detected per patient (range, 1-7). Previously undescribed mutations included an in-frame insertion mutation (Arg107_Arg110dup), and other substitutions (Asp103/Val156) in the BCL2 gene.

“As with the Gly101Val, these observations support the specificity of these mutations for the context of venetoclax resistance,” they wrote.

The investigators further explained that the BCL2 Asp103Glu mutation could have particular significance in the context of venetoclax sensitivity because of selective targeting of the BCL2 gene.

In comparison to wild-type aspartic acid, the BCL2 Asp103Glu substitution was linked to an approximate 20-fold reduction in affinity for venetoclax, they reported.

“[Our findings] consolidate the paradigm emerging across hematological malignancies of multiple independent molecular mechanisms underpinning an ‘oligoclonal’ pattern of clinical relapse on targeted therapies,” they concluded.

Further studies are needed to fully characterize the relationship between acquired BCL2 mutations and venetoclax resistance.

The study was funded by the Snowdome Foundation, Vision Super and the Wilson Centre for Lymphoma Genomics, the Leukemia and Lymphoma Society, the National Health and Medical Research Council of Australia, and other grant funding sources provided to the study authors. The authors reported financial affiliations with AbbVie, Genentech, and the Walter and Eliza Hall Institute.

The incorporation of medical scribes into an outpatient oncology setting may lower physician burnout and improve patient care, according to a retrospective study.

“The objective of this study was to determine the effect of scribe integration on clinic workflow efficiency and physician satisfaction and quality of life in outpatient oncology clinics,” wrote Rebecca W. Gao, MD, of Stanford (Calif.) Medicine, and colleagues in the Journal of Oncology Practice.

The researchers retrospectively analyzed patient and survey data from 129 physicians connected with a tertiary care academic medical center during 2017-2019. In the study, 33 physicians were paired with a scribe, while 96 others were not.

During each patient encounter, visit duration times were recorded into an electronic medical record by a medical scribe. The scribes also performed a variety of other tasks, including collating lab results, documenting medical history, and completing postvisit summaries.

In the analysis, the team compared average visit duration times between physicians with and without a scribe. The effects of scribe integration on individual physician’s visit times were also assessed.

After analysis, the researchers found that physicians with a scribe experienced a 12.1% reduction in overall average patient visit duration, compared with visit times before scribe integration (P less than .0001). They also reported that less time was spent charting at the end of the day (P = .04).

“Compared with their peers, oncologists with scribes showed a 10%-20% decrease in the duration of all patient visits,” they explained.

With respect to patient care, survey results revealed that 90% of physicians strongly agreed they spent additional time with patients, and less time at the computer. “100% of physicians surveyed ‘strongly agreed’ that scribes improved their quality of life,” they added.

The researchers acknowledged that a key limitation of the study was the single-center design. As a result, these findings may not be applicable to physicians practicing in community-based settings.

Further studies could include financial analyses to evaluate the cost-effectiveness of medical scribe use in oncology practices, they noted.

“Our study suggests that scribes can be successfully integrated into oncology clinics and may benefit physician quality of life, clinic workflow efficiency, and the quality of physician-patient interactions,” they concluded.

The study was funded by the Stanford Cancer Center. One study author reported financial affiliations with SurgVision, Vergent Biotechnology, Novadaq Technologies, and LI-COR Biosciences.

SOURCE: Gao RW et al. J Oncol Pract. 2019 Dec 5. doi: 10.1200/JOP.19.00307.

The incorporation of medical scribes into an outpatient oncology setting may lower physician burnout and improve patient care, according to a retrospective study.

“The objective of this study was to determine the effect of scribe integration on clinic workflow efficiency and physician satisfaction and quality of life in outpatient oncology clinics,” wrote Rebecca W. Gao, MD, of Stanford (Calif.) Medicine, and colleagues in the Journal of Oncology Practice.

The researchers retrospectively analyzed patient and survey data from 129 physicians connected with a tertiary care academic medical center during 2017-2019. In the study, 33 physicians were paired with a scribe, while 96 others were not.

During each patient encounter, visit duration times were recorded into an electronic medical record by a medical scribe. The scribes also performed a variety of other tasks, including collating lab results, documenting medical history, and completing postvisit summaries.

In the analysis, the team compared average visit duration times between physicians with and without a scribe. The effects of scribe integration on individual physician’s visit times were also assessed.

After analysis, the researchers found that physicians with a scribe experienced a 12.1% reduction in overall average patient visit duration, compared with visit times before scribe integration (P less than .0001). They also reported that less time was spent charting at the end of the day (P = .04).

“Compared with their peers, oncologists with scribes showed a 10%-20% decrease in the duration of all patient visits,” they explained.

With respect to patient care, survey results revealed that 90% of physicians strongly agreed they spent additional time with patients, and less time at the computer. “100% of physicians surveyed ‘strongly agreed’ that scribes improved their quality of life,” they added.

The researchers acknowledged that a key limitation of the study was the single-center design. As a result, these findings may not be applicable to physicians practicing in community-based settings.

Further studies could include financial analyses to evaluate the cost-effectiveness of medical scribe use in oncology practices, they noted.

“Our study suggests that scribes can be successfully integrated into oncology clinics and may benefit physician quality of life, clinic workflow efficiency, and the quality of physician-patient interactions,” they concluded.

The study was funded by the Stanford Cancer Center. One study author reported financial affiliations with SurgVision, Vergent Biotechnology, Novadaq Technologies, and LI-COR Biosciences.

SOURCE: Gao RW et al. J Oncol Pract. 2019 Dec 5. doi: 10.1200/JOP.19.00307.

The incorporation of medical scribes into an outpatient oncology setting may lower physician burnout and improve patient care, according to a retrospective study.

“The objective of this study was to determine the effect of scribe integration on clinic workflow efficiency and physician satisfaction and quality of life in outpatient oncology clinics,” wrote Rebecca W. Gao, MD, of Stanford (Calif.) Medicine, and colleagues in the Journal of Oncology Practice.

The researchers retrospectively analyzed patient and survey data from 129 physicians connected with a tertiary care academic medical center during 2017-2019. In the study, 33 physicians were paired with a scribe, while 96 others were not.

During each patient encounter, visit duration times were recorded into an electronic medical record by a medical scribe. The scribes also performed a variety of other tasks, including collating lab results, documenting medical history, and completing postvisit summaries.

In the analysis, the team compared average visit duration times between physicians with and without a scribe. The effects of scribe integration on individual physician’s visit times were also assessed.

After analysis, the researchers found that physicians with a scribe experienced a 12.1% reduction in overall average patient visit duration, compared with visit times before scribe integration (P less than .0001). They also reported that less time was spent charting at the end of the day (P = .04).

“Compared with their peers, oncologists with scribes showed a 10%-20% decrease in the duration of all patient visits,” they explained.

With respect to patient care, survey results revealed that 90% of physicians strongly agreed they spent additional time with patients, and less time at the computer. “100% of physicians surveyed ‘strongly agreed’ that scribes improved their quality of life,” they added.

The researchers acknowledged that a key limitation of the study was the single-center design. As a result, these findings may not be applicable to physicians practicing in community-based settings.

Further studies could include financial analyses to evaluate the cost-effectiveness of medical scribe use in oncology practices, they noted.

“Our study suggests that scribes can be successfully integrated into oncology clinics and may benefit physician quality of life, clinic workflow efficiency, and the quality of physician-patient interactions,” they concluded.

The study was funded by the Stanford Cancer Center. One study author reported financial affiliations with SurgVision, Vergent Biotechnology, Novadaq Technologies, and LI-COR Biosciences.

SOURCE: Gao RW et al. J Oncol Pract. 2019 Dec 5. doi: 10.1200/JOP.19.00307.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.