Urology

ATLANTA – Interstitial cystitis and chronic pelvic pain may be more common in males than assumed.

A national telephone survey shows that about 2 million U.S. men may suffer from either of the disorders, Dr. Anne Suskind said during a poster session at the annual meeting of the American Urological Association.

"We found that anywhere from 1% to 2.5% of men report symptoms suggestive of interstitial cystitis and a similar number report symptoms suggestive of chronic prostatitis or chronic pelvic pain," said Dr. Suskind, a fellow at the University of Michigan, Ann Arbor. "The degree of overlap is less than 20%"

Dr. Suskind and her colleagues conducted a telephone survey similar to the RAND IC Epidemiology Study (RICE) survey of women. That study – the largest interstitial cystitis epidemiology study ever undertaken – found that up to 6.5% of U.S. women may have the disorder.

The male-targeted survey used versions of the RICE validated definitions to assess problems in men. Chronic prostatitis was considered a value of greater than 5 on the National Institute of Health Chronic Prostatitis Symptom Index, plus ejaculatory or perineal pain.

Researchers contacted 6,072 households, asking if the male resident would be willing to answer a survey about President Obama’s performance. If the answer was yes, the survey ensued, with questions about any urinary tract pain attached at the end of the political questions.

Initially, 296 men screened positive for the bladder symptoms; 149 of these men met inclusionary diagnostic criteria for interstitial cystitis or prostatitis. Of these, 52 were excluded from the final analysis.

Based on the remaining sample of 97 subjects, 23% met the high specificity definition of interstitial cystitis/ bladder pain syndrome, 16% met the case definition of chronic prostatitis/chronic pelvic pain syndrome, and 8% met both definitions.

By extrapolating the numbers to the entire U.S. adult male population, Dr. Suskind concluded that up to 2 million men would meet the diagnostic definition for either of the disorders. A further analysis showed that the overlap between the two conditions was small – about 17% – indicating that they could be easily diagnostically differentiated.

"These conditions appear to be more widespread in men than many of us have believed," she concluded.

Dr. Suskind reported having no financial disclosures.

ATLANTA – Interstitial cystitis and chronic pelvic pain may be more common in males than assumed.

A national telephone survey shows that about 2 million U.S. men may suffer from either of the disorders, Dr. Anne Suskind said during a poster session at the annual meeting of the American Urological Association.

"We found that anywhere from 1% to 2.5% of men report symptoms suggestive of interstitial cystitis and a similar number report symptoms suggestive of chronic prostatitis or chronic pelvic pain," said Dr. Suskind, a fellow at the University of Michigan, Ann Arbor. "The degree of overlap is less than 20%"

Dr. Suskind and her colleagues conducted a telephone survey similar to the RAND IC Epidemiology Study (RICE) survey of women. That study – the largest interstitial cystitis epidemiology study ever undertaken – found that up to 6.5% of U.S. women may have the disorder.

The male-targeted survey used versions of the RICE validated definitions to assess problems in men. Chronic prostatitis was considered a value of greater than 5 on the National Institute of Health Chronic Prostatitis Symptom Index, plus ejaculatory or perineal pain.

Researchers contacted 6,072 households, asking if the male resident would be willing to answer a survey about President Obama’s performance. If the answer was yes, the survey ensued, with questions about any urinary tract pain attached at the end of the political questions.

Initially, 296 men screened positive for the bladder symptoms; 149 of these men met inclusionary diagnostic criteria for interstitial cystitis or prostatitis. Of these, 52 were excluded from the final analysis.

Based on the remaining sample of 97 subjects, 23% met the high specificity definition of interstitial cystitis/ bladder pain syndrome, 16% met the case definition of chronic prostatitis/chronic pelvic pain syndrome, and 8% met both definitions.

By extrapolating the numbers to the entire U.S. adult male population, Dr. Suskind concluded that up to 2 million men would meet the diagnostic definition for either of the disorders. A further analysis showed that the overlap between the two conditions was small – about 17% – indicating that they could be easily diagnostically differentiated.

"These conditions appear to be more widespread in men than many of us have believed," she concluded.

Dr. Suskind reported having no financial disclosures.

ATLANTA – Interstitial cystitis and chronic pelvic pain may be more common in males than assumed.

A national telephone survey shows that about 2 million U.S. men may suffer from either of the disorders, Dr. Anne Suskind said during a poster session at the annual meeting of the American Urological Association.

"We found that anywhere from 1% to 2.5% of men report symptoms suggestive of interstitial cystitis and a similar number report symptoms suggestive of chronic prostatitis or chronic pelvic pain," said Dr. Suskind, a fellow at the University of Michigan, Ann Arbor. "The degree of overlap is less than 20%"

Dr. Suskind and her colleagues conducted a telephone survey similar to the RAND IC Epidemiology Study (RICE) survey of women. That study – the largest interstitial cystitis epidemiology study ever undertaken – found that up to 6.5% of U.S. women may have the disorder.

The male-targeted survey used versions of the RICE validated definitions to assess problems in men. Chronic prostatitis was considered a value of greater than 5 on the National Institute of Health Chronic Prostatitis Symptom Index, plus ejaculatory or perineal pain.

Researchers contacted 6,072 households, asking if the male resident would be willing to answer a survey about President Obama’s performance. If the answer was yes, the survey ensued, with questions about any urinary tract pain attached at the end of the political questions.

Initially, 296 men screened positive for the bladder symptoms; 149 of these men met inclusionary diagnostic criteria for interstitial cystitis or prostatitis. Of these, 52 were excluded from the final analysis.

Based on the remaining sample of 97 subjects, 23% met the high specificity definition of interstitial cystitis/ bladder pain syndrome, 16% met the case definition of chronic prostatitis/chronic pelvic pain syndrome, and 8% met both definitions.

By extrapolating the numbers to the entire U.S. adult male population, Dr. Suskind concluded that up to 2 million men would meet the diagnostic definition for either of the disorders. A further analysis showed that the overlap between the two conditions was small – about 17% – indicating that they could be easily diagnostically differentiated.

"These conditions appear to be more widespread in men than many of us have believed," she concluded.

Dr. Suskind reported having no financial disclosures.

"Do not use prostate-specific antigen (PSA)–based screening for prostate cancer."

With these words, the U.S. Preventive Services Task Force (USPSTF) finalized its stance against using this blood test to screen men universally in the United States for prostate cancer.

This firm position is unlikely to end the controversy that ensued after the task force released its draft recommendations in October 2011 ("U.S. Task Force: No PSA Testing for Healthy Men.") Editorials opposing and supporting universal prostate specific antigen (PSA) screening accompany publication early online of the final recommendations in the May 22 issue of Annals of Internal Medicine.

The 16-member task force gave population-based PSA screening a grade D recommendation, after a public comment period yielded no new, overwhelming evidence countering the draft recommendations against universal testing. This means the members believe there is moderate or high certainty that the harms of the intervention are equal to or outweigh the benefits.

"Science shows us the benefit is small and the harms significant," Dr. Virginia A. Moyer, the task force chair, said in an interview.

Fever, blood in the urine, transient urinary difficulties, and moderate-to-severe pain associated with biopsy are potential harms associated with screening cited in the recommendations. Risk for perioperative death, cardiovascular events, urinary incontinence, erectile dysfunction, and bowel dysfunction are some of the harms associated with treatment of prostate cancer.

The recommendation applies to "men in the general U.S. population, regardless of age." The new position replaces the 2008 recommendations, which cited insufficient evidence to support improved health outcomes associated with prostate cancer screening for men younger than 75 years and more conclusive evidence pointing to more harm than benefit for men aged 75 years or older.

The new literature-based recommendations leave room for physicians and patients particularly concerned about risk of prostate cancer to consider individual PSA testing. The USPSTF learned during the public comment period that it needed to emphasize that the recommendations do not preclude such discussions, said Dr. Moyer, professor of pediatrics at Baylor College of Medicine, Houston.

"One of the main things we clarified was ... that this is not a recommendation not to talk to patients about it or not to address the patient’s concerns," she said.

Opponents Step Forward

Coming out against the new recommendations is an ad hoc group of nine oncologists, primary care physicians, and preventive medicine specialists. In an accompanying editorial they argue against curtailment of PSA screening, criticize a lack of specialty physician involvement on the task force, and question the quality of evidence in two large trials heavily weighted in the task force’s decision making: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (N. Engl. J. Med. 2009;360:1310-9) and the European Randomized Study for Prostate Cancer (ERSCP) (N. Engl. J. Med. 2012;366:981-90).

"The most important flaws of the PLCO are the greater than 50% ‘contamination’ rate by nonprotocol PSA measurements in the control group, prescreening of 40% of study participants before enrollment in the trial, and the fact that two thirds of patients with abnormal screening tests did not have prompt biopsy," the ad hoc group wrote.

"The study has a known flaw – that a fair number in the control group got screened – which would tend to make the intervention and control groups look more alike," Dr. Moyer acknowledged.

The task force, however, offset this potential bias with inclusion of the European study, she said. The different methodologies used in the two studies provided balance.

The task force does not include urologists or cancer specialists, the ad hoc group also pointed out.

Dr. Moyer said that these specialty physicians were involved in the evidence report initially developed for review by the task force. The members of the task force have "precisely the expertise needed" to advise these doctors on management of asymptomatic men in the primary care setting, she added.

"We are experts in primary care and prevention, and we advise primary care physicians," Dr. Moyer said.

Dr. Otis Brawley Backs Task Force

Backing the task force’s recommendations is Dr. Otis Brawley, chief medical officer of the American Cancer Society. "What many people, doctors as well as lay people, have not truly appreciated is that there are significant harms associated with prostate cancer screening," he said in an interview. "Those harms are seen consistently in every clinical trial that has been done to assess screening."

Dr. Brawley supports individual PSA screening as long as it follows a thorough and balanced informed consent process. "I and the American Cancer Society hold out that there are some people at high risk and some people who are so concerned about prostate cancer that, if they understand the considerable harms and understand that the possibility of benefit is a possibility and not proven, and they want to be screened ... they should be allowed to get screened."

"Part of the reason the task force came down so hard is because this [informed consent] has not been happening," said Dr. Brawley, professor of hematology and oncology at the Emory Clinic in Atlanta.

Another reason, he said, is that "we have all these mass screening events going on. Not only is there no informed decision-making done and not only is there no information regarding harms, but men are being told screening can only benefit them."

Dr. Brawley outlined these and other considerations in a second editorial that accompanies the recommendations.

Going forward, Dr. Brawley recommends that physicians provide patients with a brief, written handout on prostate cancer that summarizes the task force recommendations, including potential benefits and harms of PSA screening. Patients could review the information prior to seeing their physician and then opt in or opt out of this screening, he said.

The American Cancer Society provides a patient handout on "Testing for Prostate Cancer" online. The USPSTF also is posting guidance for physicians on counseling patients in light of its new recommendations.

Dr. Moyer acknowledged that the issues surrounding PSA screening are emotionally charged. "Change is stunningly hard," she said. Our understanding of cancer dates back to the 1950s or earlier. Our thinking has been that you get one cancer cell in your body and then it’s a march to imminent death. We now recognize that cancer is not a monolithic thing."

Regarding prostate cancer, she added, "For the vast majority of men, it will not affect them in their lifetime."

"Unfortunately, at the moment, the PSA is the only test we have," Dr. Moyer said. "The test itself is not very good. The PSA test is too sensitive – it picks up almost anything that happens to the prostate." She added. "The dream is that a better test is developed."

Dr. Moyer and Dr. Brawley had no relevant financial disclosures.

"Do not use prostate-specific antigen (PSA)–based screening for prostate cancer."

With these words, the U.S. Preventive Services Task Force (USPSTF) finalized its stance against using this blood test to screen men universally in the United States for prostate cancer.

This firm position is unlikely to end the controversy that ensued after the task force released its draft recommendations in October 2011 ("U.S. Task Force: No PSA Testing for Healthy Men.") Editorials opposing and supporting universal prostate specific antigen (PSA) screening accompany publication early online of the final recommendations in the May 22 issue of Annals of Internal Medicine.

The 16-member task force gave population-based PSA screening a grade D recommendation, after a public comment period yielded no new, overwhelming evidence countering the draft recommendations against universal testing. This means the members believe there is moderate or high certainty that the harms of the intervention are equal to or outweigh the benefits.

"Science shows us the benefit is small and the harms significant," Dr. Virginia A. Moyer, the task force chair, said in an interview.

Fever, blood in the urine, transient urinary difficulties, and moderate-to-severe pain associated with biopsy are potential harms associated with screening cited in the recommendations. Risk for perioperative death, cardiovascular events, urinary incontinence, erectile dysfunction, and bowel dysfunction are some of the harms associated with treatment of prostate cancer.

The recommendation applies to "men in the general U.S. population, regardless of age." The new position replaces the 2008 recommendations, which cited insufficient evidence to support improved health outcomes associated with prostate cancer screening for men younger than 75 years and more conclusive evidence pointing to more harm than benefit for men aged 75 years or older.

The new literature-based recommendations leave room for physicians and patients particularly concerned about risk of prostate cancer to consider individual PSA testing. The USPSTF learned during the public comment period that it needed to emphasize that the recommendations do not preclude such discussions, said Dr. Moyer, professor of pediatrics at Baylor College of Medicine, Houston.

"One of the main things we clarified was ... that this is not a recommendation not to talk to patients about it or not to address the patient’s concerns," she said.

Opponents Step Forward

Coming out against the new recommendations is an ad hoc group of nine oncologists, primary care physicians, and preventive medicine specialists. In an accompanying editorial they argue against curtailment of PSA screening, criticize a lack of specialty physician involvement on the task force, and question the quality of evidence in two large trials heavily weighted in the task force’s decision making: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (N. Engl. J. Med. 2009;360:1310-9) and the European Randomized Study for Prostate Cancer (ERSCP) (N. Engl. J. Med. 2012;366:981-90).

"The most important flaws of the PLCO are the greater than 50% ‘contamination’ rate by nonprotocol PSA measurements in the control group, prescreening of 40% of study participants before enrollment in the trial, and the fact that two thirds of patients with abnormal screening tests did not have prompt biopsy," the ad hoc group wrote.

"The study has a known flaw – that a fair number in the control group got screened – which would tend to make the intervention and control groups look more alike," Dr. Moyer acknowledged.

The task force, however, offset this potential bias with inclusion of the European study, she said. The different methodologies used in the two studies provided balance.

The task force does not include urologists or cancer specialists, the ad hoc group also pointed out.

Dr. Moyer said that these specialty physicians were involved in the evidence report initially developed for review by the task force. The members of the task force have "precisely the expertise needed" to advise these doctors on management of asymptomatic men in the primary care setting, she added.

"We are experts in primary care and prevention, and we advise primary care physicians," Dr. Moyer said.

Dr. Otis Brawley Backs Task Force

Backing the task force’s recommendations is Dr. Otis Brawley, chief medical officer of the American Cancer Society. "What many people, doctors as well as lay people, have not truly appreciated is that there are significant harms associated with prostate cancer screening," he said in an interview. "Those harms are seen consistently in every clinical trial that has been done to assess screening."

Dr. Brawley supports individual PSA screening as long as it follows a thorough and balanced informed consent process. "I and the American Cancer Society hold out that there are some people at high risk and some people who are so concerned about prostate cancer that, if they understand the considerable harms and understand that the possibility of benefit is a possibility and not proven, and they want to be screened ... they should be allowed to get screened."

"Part of the reason the task force came down so hard is because this [informed consent] has not been happening," said Dr. Brawley, professor of hematology and oncology at the Emory Clinic in Atlanta.

Another reason, he said, is that "we have all these mass screening events going on. Not only is there no informed decision-making done and not only is there no information regarding harms, but men are being told screening can only benefit them."

Dr. Brawley outlined these and other considerations in a second editorial that accompanies the recommendations.

Going forward, Dr. Brawley recommends that physicians provide patients with a brief, written handout on prostate cancer that summarizes the task force recommendations, including potential benefits and harms of PSA screening. Patients could review the information prior to seeing their physician and then opt in or opt out of this screening, he said.

The American Cancer Society provides a patient handout on "Testing for Prostate Cancer" online. The USPSTF also is posting guidance for physicians on counseling patients in light of its new recommendations.

Dr. Moyer acknowledged that the issues surrounding PSA screening are emotionally charged. "Change is stunningly hard," she said. Our understanding of cancer dates back to the 1950s or earlier. Our thinking has been that you get one cancer cell in your body and then it’s a march to imminent death. We now recognize that cancer is not a monolithic thing."

Regarding prostate cancer, she added, "For the vast majority of men, it will not affect them in their lifetime."

"Unfortunately, at the moment, the PSA is the only test we have," Dr. Moyer said. "The test itself is not very good. The PSA test is too sensitive – it picks up almost anything that happens to the prostate." She added. "The dream is that a better test is developed."

Dr. Moyer and Dr. Brawley had no relevant financial disclosures.

"Do not use prostate-specific antigen (PSA)–based screening for prostate cancer."

With these words, the U.S. Preventive Services Task Force (USPSTF) finalized its stance against using this blood test to screen men universally in the United States for prostate cancer.

This firm position is unlikely to end the controversy that ensued after the task force released its draft recommendations in October 2011 ("U.S. Task Force: No PSA Testing for Healthy Men.") Editorials opposing and supporting universal prostate specific antigen (PSA) screening accompany publication early online of the final recommendations in the May 22 issue of Annals of Internal Medicine.

The 16-member task force gave population-based PSA screening a grade D recommendation, after a public comment period yielded no new, overwhelming evidence countering the draft recommendations against universal testing. This means the members believe there is moderate or high certainty that the harms of the intervention are equal to or outweigh the benefits.

"Science shows us the benefit is small and the harms significant," Dr. Virginia A. Moyer, the task force chair, said in an interview.

Fever, blood in the urine, transient urinary difficulties, and moderate-to-severe pain associated with biopsy are potential harms associated with screening cited in the recommendations. Risk for perioperative death, cardiovascular events, urinary incontinence, erectile dysfunction, and bowel dysfunction are some of the harms associated with treatment of prostate cancer.

The recommendation applies to "men in the general U.S. population, regardless of age." The new position replaces the 2008 recommendations, which cited insufficient evidence to support improved health outcomes associated with prostate cancer screening for men younger than 75 years and more conclusive evidence pointing to more harm than benefit for men aged 75 years or older.

The new literature-based recommendations leave room for physicians and patients particularly concerned about risk of prostate cancer to consider individual PSA testing. The USPSTF learned during the public comment period that it needed to emphasize that the recommendations do not preclude such discussions, said Dr. Moyer, professor of pediatrics at Baylor College of Medicine, Houston.

"One of the main things we clarified was ... that this is not a recommendation not to talk to patients about it or not to address the patient’s concerns," she said.

Opponents Step Forward

Coming out against the new recommendations is an ad hoc group of nine oncologists, primary care physicians, and preventive medicine specialists. In an accompanying editorial they argue against curtailment of PSA screening, criticize a lack of specialty physician involvement on the task force, and question the quality of evidence in two large trials heavily weighted in the task force’s decision making: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (N. Engl. J. Med. 2009;360:1310-9) and the European Randomized Study for Prostate Cancer (ERSCP) (N. Engl. J. Med. 2012;366:981-90).

"The most important flaws of the PLCO are the greater than 50% ‘contamination’ rate by nonprotocol PSA measurements in the control group, prescreening of 40% of study participants before enrollment in the trial, and the fact that two thirds of patients with abnormal screening tests did not have prompt biopsy," the ad hoc group wrote.

"The study has a known flaw – that a fair number in the control group got screened – which would tend to make the intervention and control groups look more alike," Dr. Moyer acknowledged.

The task force, however, offset this potential bias with inclusion of the European study, she said. The different methodologies used in the two studies provided balance.

The task force does not include urologists or cancer specialists, the ad hoc group also pointed out.

Dr. Moyer said that these specialty physicians were involved in the evidence report initially developed for review by the task force. The members of the task force have "precisely the expertise needed" to advise these doctors on management of asymptomatic men in the primary care setting, she added.

"We are experts in primary care and prevention, and we advise primary care physicians," Dr. Moyer said.

Dr. Otis Brawley Backs Task Force

Backing the task force’s recommendations is Dr. Otis Brawley, chief medical officer of the American Cancer Society. "What many people, doctors as well as lay people, have not truly appreciated is that there are significant harms associated with prostate cancer screening," he said in an interview. "Those harms are seen consistently in every clinical trial that has been done to assess screening."

Dr. Brawley supports individual PSA screening as long as it follows a thorough and balanced informed consent process. "I and the American Cancer Society hold out that there are some people at high risk and some people who are so concerned about prostate cancer that, if they understand the considerable harms and understand that the possibility of benefit is a possibility and not proven, and they want to be screened ... they should be allowed to get screened."

"Part of the reason the task force came down so hard is because this [informed consent] has not been happening," said Dr. Brawley, professor of hematology and oncology at the Emory Clinic in Atlanta.

Another reason, he said, is that "we have all these mass screening events going on. Not only is there no informed decision-making done and not only is there no information regarding harms, but men are being told screening can only benefit them."

Dr. Brawley outlined these and other considerations in a second editorial that accompanies the recommendations.

Going forward, Dr. Brawley recommends that physicians provide patients with a brief, written handout on prostate cancer that summarizes the task force recommendations, including potential benefits and harms of PSA screening. Patients could review the information prior to seeing their physician and then opt in or opt out of this screening, he said.

The American Cancer Society provides a patient handout on "Testing for Prostate Cancer" online. The USPSTF also is posting guidance for physicians on counseling patients in light of its new recommendations.

Dr. Moyer acknowledged that the issues surrounding PSA screening are emotionally charged. "Change is stunningly hard," she said. Our understanding of cancer dates back to the 1950s or earlier. Our thinking has been that you get one cancer cell in your body and then it’s a march to imminent death. We now recognize that cancer is not a monolithic thing."

Regarding prostate cancer, she added, "For the vast majority of men, it will not affect them in their lifetime."

"Unfortunately, at the moment, the PSA is the only test we have," Dr. Moyer said. "The test itself is not very good. The PSA test is too sensitive – it picks up almost anything that happens to the prostate." She added. "The dream is that a better test is developed."

Dr. Moyer and Dr. Brawley had no relevant financial disclosures.

After initially turning it down – and being pressured to reevaluate by the U.K. Department of Health – the clinical effectiveness agency for England and Wales has decided to recommend abiraterone, in combination with glucocorticoids, as a second-line treatment for metastatic prostate cancer.

The National Institute for Health and Clinical Excellence announced on May 16 that its new draft guidance recommending abiraterone (Zytiga, Janssen) for castration-resistant prostate cancer came in response to both a new manufacturer pricing agreement and additional information on how many patients were likely to be eligible for treatment.

In February, NICE had deemed abiraterone, which has been shown to prolong survival by a median 4.6 months, not cost-effective at an estimated £63,200 per quality-adjusted life year.

The following month, the U.K. Department of Health asked NICE to reevaluate its decision with regard to its estimates of the number of men eligible to be treated with abiraterone. NICE evaluates differently end-of-life treatments for patients with a life expectancy of less than 2 years, depending on the size of the population affected.

A revised pricing scheme in addition to revised estimates of the population eligible for abiraterone treatment lowered NICE’s estimates to £46,800 per QALY, just under its threshold for an end-of-life treatment in a small population.

Abiraterone works by blocking androgen synthesis in the adrenal glands, prostate tissue, and prostate tumors. It is indicated for men whose disease has progressed following docetaxel-containing chemotherapy regimens, and who have been deemed "castration resistant" because their tumors do not respond to androgen-deprivation treatments that may or may not include surgical castration.

The list price of abiraterone is £2,930 for a 30-day supply of 120 tablets; NICE did not disclose the new discounted price. It is taken as a single dose of 1,000 mg daily, in four tablets. In a manufacturer-sponsored randomized controlled trial (n = 1,195), subjects receiving abiraterone plus prednisone or prednisolone saw a median overall survival gain of 14.8 months compared with 10.9 months for those taking placebo plus either prednisone or prednisolone after 1 year follow-up (HR 0.65; 95% confidence interval, 0.54-0.77; P less than .001).

The trial (N. Engl. J. Med. 2011;364:1995-2005) was stopped due to significant evidence of benefit, but follow-up continued, and an updated analysis after 20.2 months showed that median survival continued to be significantly longer in the abiraterone group than the prednisolone group (15.8 months compared with 11.2 months; HR 0.74; 95% CI 0.64 to 0.86).

In its earlier draft guidance NICE had estimated the number of men eligible for second-line treatment with abiraterone to be at least 3,500 in 2011. The revised estimate suggests that only 2,500 would have been eligible – a small population, by NICE’s calculations, and therefore meeting its cost-effectiveness criteria for an end-of-life treatment.

After initially turning it down – and being pressured to reevaluate by the U.K. Department of Health – the clinical effectiveness agency for England and Wales has decided to recommend abiraterone, in combination with glucocorticoids, as a second-line treatment for metastatic prostate cancer.

The National Institute for Health and Clinical Excellence announced on May 16 that its new draft guidance recommending abiraterone (Zytiga, Janssen) for castration-resistant prostate cancer came in response to both a new manufacturer pricing agreement and additional information on how many patients were likely to be eligible for treatment.

In February, NICE had deemed abiraterone, which has been shown to prolong survival by a median 4.6 months, not cost-effective at an estimated £63,200 per quality-adjusted life year.

The following month, the U.K. Department of Health asked NICE to reevaluate its decision with regard to its estimates of the number of men eligible to be treated with abiraterone. NICE evaluates differently end-of-life treatments for patients with a life expectancy of less than 2 years, depending on the size of the population affected.

A revised pricing scheme in addition to revised estimates of the population eligible for abiraterone treatment lowered NICE’s estimates to £46,800 per QALY, just under its threshold for an end-of-life treatment in a small population.

Abiraterone works by blocking androgen synthesis in the adrenal glands, prostate tissue, and prostate tumors. It is indicated for men whose disease has progressed following docetaxel-containing chemotherapy regimens, and who have been deemed "castration resistant" because their tumors do not respond to androgen-deprivation treatments that may or may not include surgical castration.

The list price of abiraterone is £2,930 for a 30-day supply of 120 tablets; NICE did not disclose the new discounted price. It is taken as a single dose of 1,000 mg daily, in four tablets. In a manufacturer-sponsored randomized controlled trial (n = 1,195), subjects receiving abiraterone plus prednisone or prednisolone saw a median overall survival gain of 14.8 months compared with 10.9 months for those taking placebo plus either prednisone or prednisolone after 1 year follow-up (HR 0.65; 95% confidence interval, 0.54-0.77; P less than .001).

The trial (N. Engl. J. Med. 2011;364:1995-2005) was stopped due to significant evidence of benefit, but follow-up continued, and an updated analysis after 20.2 months showed that median survival continued to be significantly longer in the abiraterone group than the prednisolone group (15.8 months compared with 11.2 months; HR 0.74; 95% CI 0.64 to 0.86).

In its earlier draft guidance NICE had estimated the number of men eligible for second-line treatment with abiraterone to be at least 3,500 in 2011. The revised estimate suggests that only 2,500 would have been eligible – a small population, by NICE’s calculations, and therefore meeting its cost-effectiveness criteria for an end-of-life treatment.

After initially turning it down – and being pressured to reevaluate by the U.K. Department of Health – the clinical effectiveness agency for England and Wales has decided to recommend abiraterone, in combination with glucocorticoids, as a second-line treatment for metastatic prostate cancer.

The National Institute for Health and Clinical Excellence announced on May 16 that its new draft guidance recommending abiraterone (Zytiga, Janssen) for castration-resistant prostate cancer came in response to both a new manufacturer pricing agreement and additional information on how many patients were likely to be eligible for treatment.

In February, NICE had deemed abiraterone, which has been shown to prolong survival by a median 4.6 months, not cost-effective at an estimated £63,200 per quality-adjusted life year.

The following month, the U.K. Department of Health asked NICE to reevaluate its decision with regard to its estimates of the number of men eligible to be treated with abiraterone. NICE evaluates differently end-of-life treatments for patients with a life expectancy of less than 2 years, depending on the size of the population affected.

A revised pricing scheme in addition to revised estimates of the population eligible for abiraterone treatment lowered NICE’s estimates to £46,800 per QALY, just under its threshold for an end-of-life treatment in a small population.

Abiraterone works by blocking androgen synthesis in the adrenal glands, prostate tissue, and prostate tumors. It is indicated for men whose disease has progressed following docetaxel-containing chemotherapy regimens, and who have been deemed "castration resistant" because their tumors do not respond to androgen-deprivation treatments that may or may not include surgical castration.

The list price of abiraterone is £2,930 for a 30-day supply of 120 tablets; NICE did not disclose the new discounted price. It is taken as a single dose of 1,000 mg daily, in four tablets. In a manufacturer-sponsored randomized controlled trial (n = 1,195), subjects receiving abiraterone plus prednisone or prednisolone saw a median overall survival gain of 14.8 months compared with 10.9 months for those taking placebo plus either prednisone or prednisolone after 1 year follow-up (HR 0.65; 95% confidence interval, 0.54-0.77; P less than .001).

The trial (N. Engl. J. Med. 2011;364:1995-2005) was stopped due to significant evidence of benefit, but follow-up continued, and an updated analysis after 20.2 months showed that median survival continued to be significantly longer in the abiraterone group than the prednisolone group (15.8 months compared with 11.2 months; HR 0.74; 95% CI 0.64 to 0.86).

In its earlier draft guidance NICE had estimated the number of men eligible for second-line treatment with abiraterone to be at least 3,500 in 2011. The revised estimate suggests that only 2,500 would have been eligible – a small population, by NICE’s calculations, and therefore meeting its cost-effectiveness criteria for an end-of-life treatment.

NEW ORLEANS – Because of problems inherent in the "expert medical testimony" system for medical liability cases, some form of extrajudicial oversight is probably needed, according to Dr. Steve Waxman.

Dr. Waxman, a urologist and a lawyer who is an expert in medicolegal issues, spoke at the annual conference of the American College of Legal Medicine.

Medical experts play a crucial role in determining causation, whether a physician has met the standard of care, and whether a case should move forward. While they used to be given great deference by the court and enjoyed near-immunity, problems with expert testimony are now being acknowledged, Dr. Waxman said.

These include, in particular, the varying levels of expertise and the questionable impartiality of some medical experts and the fact that scientific support for testimony is often lacking. "Their opinions on causation are not always supported by facts," he observed. And while expert witnesses should see themselves as "educators," they often become "advocates," depending upon who is paying their fee, he said, noting they could be swayed by financial gain.

"There is a big difference in level 1 evidence and expert opinion, but to a jury those distinguishing characteristics are not so clear, especially when presented by a smooth-talking expert witness," he continued.

Medical experts should determine the standard of care based on several factors: scientific basis, method and testability; peer-reviewed literature; clinical practice guidelines; and majority or respected minority opinion. The standard of care upon which a physician defendant is judged "should not just be personal opinion or experience," he emphasized.

Such concerns raise the question of whether "extrajudicial oversight" is necessary. "If a judge, jury, or attorney cannot recognize and therefore challenge false or misleading testimony, can it or should it be challenged outside of the courtroom?" Dr. Waxman asked.

A Need for Extrajudicial Review of Experts?

There are Federal Rules of Evidence that give trial judges oversight of expert witness testimony, although the court is not inclined to impose punitive measures against experts who testify falsely, according to Dr. Waxman. "The view of the medical community is that the judicial oversight of medical expert testimony is incomplete," he said.

Extrajudicial oversight, therefore, has been advocated by a number of entities, including medical specialty organizations, state medical boards, and national and state medical associations. A number have instituted some means of peer review, evaluating medical experts with regard to ethics and bylaws violations, unprofessional behavior, and the "practice of medicine."

Some of the medical specialty organizations providing extrajudicial oversight include the American Association of Neurological Surgeons (Professional Conduct Committee and Procedural Guidelines), Society of Thoracic Surgeons (Expert Registry), American Academy of Emergency Medicine (Remarkable Testimony), and the American Urological Association (Judicial and Ethics Committee). The Society of Hospital Medicine does not have a policy statement on the issue.

The American Urological Association, of which Dr. Waxman is a member, lays out qualifications that must be met by medical. Members pay their dues and sign an affirmation statement agreeing to the guidelines. Members who violate this agreement can be disciplined.

But such extrajudicial oversight is not welcomed by the plaintiff bar, he said. The American Association for Justice maintains that cross-examination should uncover the truth; that peer-review programs may be "facially neutral," but their real purpose is suspect; that the threat of extrajudicial review will reduce the pool of available medical experts for plaintiffs; and that medical associations have a conflict of interest in participating (they want to protect their members).

Emerging Alternatives

Some specialty societies are developing their own expert registries, which are aimed at improving the availability of qualified medical expert witnesses for the plaintiff, to raise the bar for testimony, and to weed out frivolous suits and encourage settlement of meritorious suits. "The defense bar likes this idea, but the plaintiff bar is not very interested," Dr. Waxman said. "They have a stable of experts whose responses are predictable. If they use the registry, they may not like the answers they get. This is not a case of ‘if you build it, they will come,’ in terms of the plaintiff bar."

Physician panels are another emerging alternative and are in place in Indiana and Louisiana. These panels review all cases to determine merit, but plaintiff attorneys can proceed in spite of the outcome.

Dr. Waxman concluded that "the current system is working, most of the time," and that problematic medical experts are being weeded out of the system, though there is room for improvement. Peer oversight is "probably appropriate and necessary," he maintained, "because it usually takes a physician to spot a physician giving false or misleading testimony."

"Because of the esoteric nature of many specialties, judges and juries are not able to spot irresponsible, misleading, or even fraudulent testimony. Physicians are best suited to review the quality of medical expert testimony, but the current judicial system does not adequately allow for a critical objective review of this form of testimony," he said.

"My view is that physician panels or physician review of medical expert testimony, early on in the litigation process, is preferable to extrajudicial review by medical societies, associations, or boards after the fact. If there is a three-to-zero decision by the panel, and the plaintiff still wants to bring in the expert, this expert is on notice that he or she has three of their own who disagree. The expert better be able to back the testimony up with science."

American Urological Association Qualifications for Expert Witness Testimony

• Active in the practice of clinical urology with a current valid and unrestricted license at the time of the alleged occurrence.

• Current certification in urology from the American Board of Urology.

• At least 5 years of clinical practice after satisfactorily completing residency/fellowship training.

• Expertise with texts, journals, guidelines, and other sources of information that establish the applicable standard of care at the time of the alleged occurrence.

• Perform a complete and thorough review of all available medical and legal information, including other medical depositions, before rendering any opinion regarding the case.

• Identify personal opinions as such, particularly where these deviate from other urologic viewpoints.

• Proficiency and experience in the area of clinical practice that is the subject of the case.

• Willingness to serve for either defendant or plaintiff in a fair and impartial manner; refusal to be manipulated by an attorney into becoming an advocate or partisan for one side.

• Willingness to declare and document the particulars related to the expert witness practice, inclusive of the number of cases for the defense or plaintiff, percentage of time spent in expert witness testimony, fees and compensation; refusal to accept contingency fees.

• Willingness to sign the AUA Expert Witness Affirmation Statement.

NEW ORLEANS – Because of problems inherent in the "expert medical testimony" system for medical liability cases, some form of extrajudicial oversight is probably needed, according to Dr. Steve Waxman.

Dr. Waxman, a urologist and a lawyer who is an expert in medicolegal issues, spoke at the annual conference of the American College of Legal Medicine.

Medical experts play a crucial role in determining causation, whether a physician has met the standard of care, and whether a case should move forward. While they used to be given great deference by the court and enjoyed near-immunity, problems with expert testimony are now being acknowledged, Dr. Waxman said.

These include, in particular, the varying levels of expertise and the questionable impartiality of some medical experts and the fact that scientific support for testimony is often lacking. "Their opinions on causation are not always supported by facts," he observed. And while expert witnesses should see themselves as "educators," they often become "advocates," depending upon who is paying their fee, he said, noting they could be swayed by financial gain.

"There is a big difference in level 1 evidence and expert opinion, but to a jury those distinguishing characteristics are not so clear, especially when presented by a smooth-talking expert witness," he continued.

Medical experts should determine the standard of care based on several factors: scientific basis, method and testability; peer-reviewed literature; clinical practice guidelines; and majority or respected minority opinion. The standard of care upon which a physician defendant is judged "should not just be personal opinion or experience," he emphasized.

Such concerns raise the question of whether "extrajudicial oversight" is necessary. "If a judge, jury, or attorney cannot recognize and therefore challenge false or misleading testimony, can it or should it be challenged outside of the courtroom?" Dr. Waxman asked.

A Need for Extrajudicial Review of Experts?

There are Federal Rules of Evidence that give trial judges oversight of expert witness testimony, although the court is not inclined to impose punitive measures against experts who testify falsely, according to Dr. Waxman. "The view of the medical community is that the judicial oversight of medical expert testimony is incomplete," he said.

Extrajudicial oversight, therefore, has been advocated by a number of entities, including medical specialty organizations, state medical boards, and national and state medical associations. A number have instituted some means of peer review, evaluating medical experts with regard to ethics and bylaws violations, unprofessional behavior, and the "practice of medicine."

Some of the medical specialty organizations providing extrajudicial oversight include the American Association of Neurological Surgeons (Professional Conduct Committee and Procedural Guidelines), Society of Thoracic Surgeons (Expert Registry), American Academy of Emergency Medicine (Remarkable Testimony), and the American Urological Association (Judicial and Ethics Committee). The Society of Hospital Medicine does not have a policy statement on the issue.

The American Urological Association, of which Dr. Waxman is a member, lays out qualifications that must be met by medical. Members pay their dues and sign an affirmation statement agreeing to the guidelines. Members who violate this agreement can be disciplined.

But such extrajudicial oversight is not welcomed by the plaintiff bar, he said. The American Association for Justice maintains that cross-examination should uncover the truth; that peer-review programs may be "facially neutral," but their real purpose is suspect; that the threat of extrajudicial review will reduce the pool of available medical experts for plaintiffs; and that medical associations have a conflict of interest in participating (they want to protect their members).

Emerging Alternatives

Some specialty societies are developing their own expert registries, which are aimed at improving the availability of qualified medical expert witnesses for the plaintiff, to raise the bar for testimony, and to weed out frivolous suits and encourage settlement of meritorious suits. "The defense bar likes this idea, but the plaintiff bar is not very interested," Dr. Waxman said. "They have a stable of experts whose responses are predictable. If they use the registry, they may not like the answers they get. This is not a case of ‘if you build it, they will come,’ in terms of the plaintiff bar."

Physician panels are another emerging alternative and are in place in Indiana and Louisiana. These panels review all cases to determine merit, but plaintiff attorneys can proceed in spite of the outcome.

Dr. Waxman concluded that "the current system is working, most of the time," and that problematic medical experts are being weeded out of the system, though there is room for improvement. Peer oversight is "probably appropriate and necessary," he maintained, "because it usually takes a physician to spot a physician giving false or misleading testimony."

"Because of the esoteric nature of many specialties, judges and juries are not able to spot irresponsible, misleading, or even fraudulent testimony. Physicians are best suited to review the quality of medical expert testimony, but the current judicial system does not adequately allow for a critical objective review of this form of testimony," he said.

"My view is that physician panels or physician review of medical expert testimony, early on in the litigation process, is preferable to extrajudicial review by medical societies, associations, or boards after the fact. If there is a three-to-zero decision by the panel, and the plaintiff still wants to bring in the expert, this expert is on notice that he or she has three of their own who disagree. The expert better be able to back the testimony up with science."

American Urological Association Qualifications for Expert Witness Testimony

• Active in the practice of clinical urology with a current valid and unrestricted license at the time of the alleged occurrence.

• Current certification in urology from the American Board of Urology.

• At least 5 years of clinical practice after satisfactorily completing residency/fellowship training.

• Expertise with texts, journals, guidelines, and other sources of information that establish the applicable standard of care at the time of the alleged occurrence.

• Perform a complete and thorough review of all available medical and legal information, including other medical depositions, before rendering any opinion regarding the case.

• Identify personal opinions as such, particularly where these deviate from other urologic viewpoints.

• Proficiency and experience in the area of clinical practice that is the subject of the case.

• Willingness to serve for either defendant or plaintiff in a fair and impartial manner; refusal to be manipulated by an attorney into becoming an advocate or partisan for one side.

• Willingness to declare and document the particulars related to the expert witness practice, inclusive of the number of cases for the defense or plaintiff, percentage of time spent in expert witness testimony, fees and compensation; refusal to accept contingency fees.

• Willingness to sign the AUA Expert Witness Affirmation Statement.

NEW ORLEANS – Because of problems inherent in the "expert medical testimony" system for medical liability cases, some form of extrajudicial oversight is probably needed, according to Dr. Steve Waxman.

Dr. Waxman, a urologist and a lawyer who is an expert in medicolegal issues, spoke at the annual conference of the American College of Legal Medicine.

Medical experts play a crucial role in determining causation, whether a physician has met the standard of care, and whether a case should move forward. While they used to be given great deference by the court and enjoyed near-immunity, problems with expert testimony are now being acknowledged, Dr. Waxman said.

These include, in particular, the varying levels of expertise and the questionable impartiality of some medical experts and the fact that scientific support for testimony is often lacking. "Their opinions on causation are not always supported by facts," he observed. And while expert witnesses should see themselves as "educators," they often become "advocates," depending upon who is paying their fee, he said, noting they could be swayed by financial gain.

"There is a big difference in level 1 evidence and expert opinion, but to a jury those distinguishing characteristics are not so clear, especially when presented by a smooth-talking expert witness," he continued.

Medical experts should determine the standard of care based on several factors: scientific basis, method and testability; peer-reviewed literature; clinical practice guidelines; and majority or respected minority opinion. The standard of care upon which a physician defendant is judged "should not just be personal opinion or experience," he emphasized.

Such concerns raise the question of whether "extrajudicial oversight" is necessary. "If a judge, jury, or attorney cannot recognize and therefore challenge false or misleading testimony, can it or should it be challenged outside of the courtroom?" Dr. Waxman asked.

A Need for Extrajudicial Review of Experts?

There are Federal Rules of Evidence that give trial judges oversight of expert witness testimony, although the court is not inclined to impose punitive measures against experts who testify falsely, according to Dr. Waxman. "The view of the medical community is that the judicial oversight of medical expert testimony is incomplete," he said.

Extrajudicial oversight, therefore, has been advocated by a number of entities, including medical specialty organizations, state medical boards, and national and state medical associations. A number have instituted some means of peer review, evaluating medical experts with regard to ethics and bylaws violations, unprofessional behavior, and the "practice of medicine."

Some of the medical specialty organizations providing extrajudicial oversight include the American Association of Neurological Surgeons (Professional Conduct Committee and Procedural Guidelines), Society of Thoracic Surgeons (Expert Registry), American Academy of Emergency Medicine (Remarkable Testimony), and the American Urological Association (Judicial and Ethics Committee). The Society of Hospital Medicine does not have a policy statement on the issue.

The American Urological Association, of which Dr. Waxman is a member, lays out qualifications that must be met by medical. Members pay their dues and sign an affirmation statement agreeing to the guidelines. Members who violate this agreement can be disciplined.

But such extrajudicial oversight is not welcomed by the plaintiff bar, he said. The American Association for Justice maintains that cross-examination should uncover the truth; that peer-review programs may be "facially neutral," but their real purpose is suspect; that the threat of extrajudicial review will reduce the pool of available medical experts for plaintiffs; and that medical associations have a conflict of interest in participating (they want to protect their members).

Emerging Alternatives

Some specialty societies are developing their own expert registries, which are aimed at improving the availability of qualified medical expert witnesses for the plaintiff, to raise the bar for testimony, and to weed out frivolous suits and encourage settlement of meritorious suits. "The defense bar likes this idea, but the plaintiff bar is not very interested," Dr. Waxman said. "They have a stable of experts whose responses are predictable. If they use the registry, they may not like the answers they get. This is not a case of ‘if you build it, they will come,’ in terms of the plaintiff bar."

Physician panels are another emerging alternative and are in place in Indiana and Louisiana. These panels review all cases to determine merit, but plaintiff attorneys can proceed in spite of the outcome.

Dr. Waxman concluded that "the current system is working, most of the time," and that problematic medical experts are being weeded out of the system, though there is room for improvement. Peer oversight is "probably appropriate and necessary," he maintained, "because it usually takes a physician to spot a physician giving false or misleading testimony."

"Because of the esoteric nature of many specialties, judges and juries are not able to spot irresponsible, misleading, or even fraudulent testimony. Physicians are best suited to review the quality of medical expert testimony, but the current judicial system does not adequately allow for a critical objective review of this form of testimony," he said.

"My view is that physician panels or physician review of medical expert testimony, early on in the litigation process, is preferable to extrajudicial review by medical societies, associations, or boards after the fact. If there is a three-to-zero decision by the panel, and the plaintiff still wants to bring in the expert, this expert is on notice that he or she has three of their own who disagree. The expert better be able to back the testimony up with science."

American Urological Association Qualifications for Expert Witness Testimony

• Active in the practice of clinical urology with a current valid and unrestricted license at the time of the alleged occurrence.

• Current certification in urology from the American Board of Urology.

• At least 5 years of clinical practice after satisfactorily completing residency/fellowship training.

• Expertise with texts, journals, guidelines, and other sources of information that establish the applicable standard of care at the time of the alleged occurrence.

• Perform a complete and thorough review of all available medical and legal information, including other medical depositions, before rendering any opinion regarding the case.

• Identify personal opinions as such, particularly where these deviate from other urologic viewpoints.

• Proficiency and experience in the area of clinical practice that is the subject of the case.

• Willingness to serve for either defendant or plaintiff in a fair and impartial manner; refusal to be manipulated by an attorney into becoming an advocate or partisan for one side.

• Willingness to declare and document the particulars related to the expert witness practice, inclusive of the number of cases for the defense or plaintiff, percentage of time spent in expert witness testimony, fees and compensation; refusal to accept contingency fees.

• Willingness to sign the AUA Expert Witness Affirmation Statement.

The fast-acting erectile dysfunction medication avanafil was approved by the Food and Drug Administration April 30 on the basis of findings from multiple phase-III trials demonstrating the safety and efficacy of the phosphodiesterase type 5 inhibitor, according to a statement from the agency.

The first new entry in the erectile dysfunction (ED) marketplace in nearly 10 years, avanafil (Stendra) joins the ranks of other PDE5 inhibitors approved for the treatment of ED and is expected to be a formidable competitor in the marketplace because it is a faster-acting agent associated with fewer side effects than the currently available options, including sildenafil citrate (Viagra), vardenafil (Levitra), and tadalafil (Cialis), according to Dr. Irwin Goldstein, director of the sexual medicine program at Alvarado Hospital in San Diego.

Dr. Goldstein was the lead investigator of the pivotal phase-III Research Evaluating an Investigational Medication for Erectile Dysfunction (REVIVE) trial in which 646 men with a history of ED for at least 6 months were randomized to 50-mg, 100-mg, or 200-mg of avanafil or placebo (J. Sex. Med. 2012;9:1122-33).

"We observed significant improvements in erectile function and low rates of side effects common to [the PDE5] drug class," Dr. Goldstein said in an interview. "Importantly, the majority of patients who attempted intercourse within 15 minutes of dosing were successful at all dosage levels," he said, noting that successful attempts were reported 64%, 67%, and 71% of the time with 50-mg, 100-mg, and 200-mg doses, respectively, compared with 27% for placebo.

In addition to the REVIVE trial, the avanafil development program included the REVIVE-Diabetes trial comprising 390 men with ED and diabetes and the REVIVE-RP trial comprising 298 men with ED following radical prostatectomy, as well as a year-long safety study of 712 continuation patients from the REVIVE and REVIVE-Diabetes trials, according to a statement issued by Vivus, manufacturer of the drug.

The combined highlights of the various studies showed statistically significant improvements relative to placebo in measures of erectile function, vaginal penetration, and successful intercourse at all three dosages, according the FDA.

The most common side effects, reported in more than 2% of the patients, were headache, facial flushing, nasal congestion, and back pain; there were no drug-related serious adverse events reported, the FDA said.

In the continuation study of patients who received up to 40 additional weeks of treatment, initially at the 100-mg dose and eventually maintained, increased, or decreased based on individual patient response, the side effects did not appear to worsen over time.

Dr. Goldstein disclosed financial relationships with BioSante, Boehringer Ingelheim, Medtronic, Pfizer, VIVUS, Alagin, Shionogi, Slate, Abbott, Ascend, Auxilium, Coloplast, and Warner Chilcott.

The fast-acting erectile dysfunction medication avanafil was approved by the Food and Drug Administration April 30 on the basis of findings from multiple phase-III trials demonstrating the safety and efficacy of the phosphodiesterase type 5 inhibitor, according to a statement from the agency.

The first new entry in the erectile dysfunction (ED) marketplace in nearly 10 years, avanafil (Stendra) joins the ranks of other PDE5 inhibitors approved for the treatment of ED and is expected to be a formidable competitor in the marketplace because it is a faster-acting agent associated with fewer side effects than the currently available options, including sildenafil citrate (Viagra), vardenafil (Levitra), and tadalafil (Cialis), according to Dr. Irwin Goldstein, director of the sexual medicine program at Alvarado Hospital in San Diego.

Dr. Goldstein was the lead investigator of the pivotal phase-III Research Evaluating an Investigational Medication for Erectile Dysfunction (REVIVE) trial in which 646 men with a history of ED for at least 6 months were randomized to 50-mg, 100-mg, or 200-mg of avanafil or placebo (J. Sex. Med. 2012;9:1122-33).

"We observed significant improvements in erectile function and low rates of side effects common to [the PDE5] drug class," Dr. Goldstein said in an interview. "Importantly, the majority of patients who attempted intercourse within 15 minutes of dosing were successful at all dosage levels," he said, noting that successful attempts were reported 64%, 67%, and 71% of the time with 50-mg, 100-mg, and 200-mg doses, respectively, compared with 27% for placebo.

In addition to the REVIVE trial, the avanafil development program included the REVIVE-Diabetes trial comprising 390 men with ED and diabetes and the REVIVE-RP trial comprising 298 men with ED following radical prostatectomy, as well as a year-long safety study of 712 continuation patients from the REVIVE and REVIVE-Diabetes trials, according to a statement issued by Vivus, manufacturer of the drug.

The combined highlights of the various studies showed statistically significant improvements relative to placebo in measures of erectile function, vaginal penetration, and successful intercourse at all three dosages, according the FDA.

The most common side effects, reported in more than 2% of the patients, were headache, facial flushing, nasal congestion, and back pain; there were no drug-related serious adverse events reported, the FDA said.

In the continuation study of patients who received up to 40 additional weeks of treatment, initially at the 100-mg dose and eventually maintained, increased, or decreased based on individual patient response, the side effects did not appear to worsen over time.

Dr. Goldstein disclosed financial relationships with BioSante, Boehringer Ingelheim, Medtronic, Pfizer, VIVUS, Alagin, Shionogi, Slate, Abbott, Ascend, Auxilium, Coloplast, and Warner Chilcott.

The fast-acting erectile dysfunction medication avanafil was approved by the Food and Drug Administration April 30 on the basis of findings from multiple phase-III trials demonstrating the safety and efficacy of the phosphodiesterase type 5 inhibitor, according to a statement from the agency.

The first new entry in the erectile dysfunction (ED) marketplace in nearly 10 years, avanafil (Stendra) joins the ranks of other PDE5 inhibitors approved for the treatment of ED and is expected to be a formidable competitor in the marketplace because it is a faster-acting agent associated with fewer side effects than the currently available options, including sildenafil citrate (Viagra), vardenafil (Levitra), and tadalafil (Cialis), according to Dr. Irwin Goldstein, director of the sexual medicine program at Alvarado Hospital in San Diego.

Dr. Goldstein was the lead investigator of the pivotal phase-III Research Evaluating an Investigational Medication for Erectile Dysfunction (REVIVE) trial in which 646 men with a history of ED for at least 6 months were randomized to 50-mg, 100-mg, or 200-mg of avanafil or placebo (J. Sex. Med. 2012;9:1122-33).

"We observed significant improvements in erectile function and low rates of side effects common to [the PDE5] drug class," Dr. Goldstein said in an interview. "Importantly, the majority of patients who attempted intercourse within 15 minutes of dosing were successful at all dosage levels," he said, noting that successful attempts were reported 64%, 67%, and 71% of the time with 50-mg, 100-mg, and 200-mg doses, respectively, compared with 27% for placebo.

In addition to the REVIVE trial, the avanafil development program included the REVIVE-Diabetes trial comprising 390 men with ED and diabetes and the REVIVE-RP trial comprising 298 men with ED following radical prostatectomy, as well as a year-long safety study of 712 continuation patients from the REVIVE and REVIVE-Diabetes trials, according to a statement issued by Vivus, manufacturer of the drug.

The combined highlights of the various studies showed statistically significant improvements relative to placebo in measures of erectile function, vaginal penetration, and successful intercourse at all three dosages, according the FDA.

The most common side effects, reported in more than 2% of the patients, were headache, facial flushing, nasal congestion, and back pain; there were no drug-related serious adverse events reported, the FDA said.

In the continuation study of patients who received up to 40 additional weeks of treatment, initially at the 100-mg dose and eventually maintained, increased, or decreased based on individual patient response, the side effects did not appear to worsen over time.

Dr. Goldstein disclosed financial relationships with BioSante, Boehringer Ingelheim, Medtronic, Pfizer, VIVUS, Alagin, Shionogi, Slate, Abbott, Ascend, Auxilium, Coloplast, and Warner Chilcott.

MIAMI – Faced with erectile dysfunction following prostate cancer surgery, many men adopt an avoidant coping style that inadvertently interferes with rehabilitation efforts to spare them long-term sexual side effects.

"We have ways of helping men to get their erections back; that isn’t the issue," Christian J. Nelson, Ph.D., said at the annual conference of the American Psychosocial Oncology Society.

"The issue is, men avoid and drop out of rehabilitation programs."

Avoidance was one key theme raised by 35 men who had undergone radical prostatectomy for prostate cancer 2-3 years prior to being recruited into focus groups by Dr. Nelson and his colleagues as an initial step in devising a more effective approach to erectile dysfunction (ED) rehabilitation. He presented results of a systematic analysis of those themes at the meeting, and offered a preview of the ongoing study that resulted.

Dr. Nelson described a cycle in which men experienced frustration, shame, and embarrassment over ED during a sexual experience following surgery, then began avoiding intimate contact due to anxiety. Relationship issues, depression, and increased frustration often followed.

"It’s absolutely devastating," one focus group participant told him.

Another remarked, "It’s like the ground you walked on since you were a teenager is gone."

Rather than seek help, many men acknowledged that they dealt with ED by withdrawing emotionally, sidestepping the potential for intimacy.

"Doc, it’s fear. It’s fear, Doc," another participant told Dr. Nelson.

"Men are struggling [on average] for about 2 years before they actually pursue treatment," said Dr. Nelson, a psychologist at Memorial Sloan-Kettering Cancer Center in New York.

Ideally, he explained, ED rehabilitation should begin as soon as possible after surgery to maintain blood flow and muscle tone, and "biology dictates the best treatment."

A common, but temporary, effect of nerve-sparing surgery is not only ED, but also stretching of the nerves responsible for the nitric oxide release triggered by oral phosphodiesterase inhibitor drugs. Pills such as sildenafil (Viagra) and taldenafil (Cialis) are effective in only about 20% of men following surgery, so after a brief trial injection therapy is recommended for the maintenance of erections over the 18-24 months that it may take to recover what erectile function remains.

In addition to the barrier of avoidance, men adamantly complained to focus group researchers that they were not properly told before surgery about postsurgical side effects, including ED and its treatments.

"It was ... Theme One ... and clearly the most predominant theme [in the focus groups]," said Dr. Nelson. "We don’t know if surgeons are telling patients about side effects, and they [patients] are thinking about the surgery and just not hearing the information – or whether the surgeons are not giving the information. But clearly, there was a lot of frustration and anger."

While men said they found the idea of penile injections "freakish and barbaric," they did not find them as painful as they had feared. Some saw the long-term benefits of injection therapy to be worth their initial reluctance, but one remarked, "This is the most humiliating thing I’ve ever done in my life."

Considering the trend to diagnose and treat earlier-stage prostate cancer in younger men, combined with an 85% prevalence of ED 4 years post surgery, "it’s an important survivorship issue," Dr. Nelson said.

Drawing from focus group findings, he and his team were encouraged by men’s humor in discussing difficult and awkward topics, offering a potential guidepost for future interventions. He also said men were "not overly enthusiastic" about the proposed idea of psychological interventions during rehabilitation, but advised that such efforts might be better accepted if they were characterized as "coaching."

Indeed, Dr. Nelson and his colleagues drew on the focus group findings to launch a randomized controlled trial of an intervention based on Acceptance and Commitment Therapy, a psychological orientation that encourages participants to define values that are important to them. Over time, the goal is to learn to tolerate distress and overcome barriers in order to achieve goals associated with those prized values, Dr. Nelson explained.

Enrollment in the trial has commenced, and a handful of participants in each group have completed the intervention (or a control condition) during injection training for ED.

"An initial peek at the data looks promising," he said.

Funding for the study was provided through a grant from the National Cancer Institute.

MIAMI – Faced with erectile dysfunction following prostate cancer surgery, many men adopt an avoidant coping style that inadvertently interferes with rehabilitation efforts to spare them long-term sexual side effects.

"We have ways of helping men to get their erections back; that isn’t the issue," Christian J. Nelson, Ph.D., said at the annual conference of the American Psychosocial Oncology Society.

"The issue is, men avoid and drop out of rehabilitation programs."

Avoidance was one key theme raised by 35 men who had undergone radical prostatectomy for prostate cancer 2-3 years prior to being recruited into focus groups by Dr. Nelson and his colleagues as an initial step in devising a more effective approach to erectile dysfunction (ED) rehabilitation. He presented results of a systematic analysis of those themes at the meeting, and offered a preview of the ongoing study that resulted.

Dr. Nelson described a cycle in which men experienced frustration, shame, and embarrassment over ED during a sexual experience following surgery, then began avoiding intimate contact due to anxiety. Relationship issues, depression, and increased frustration often followed.

"It’s absolutely devastating," one focus group participant told him.

Another remarked, "It’s like the ground you walked on since you were a teenager is gone."

Rather than seek help, many men acknowledged that they dealt with ED by withdrawing emotionally, sidestepping the potential for intimacy.

"Doc, it’s fear. It’s fear, Doc," another participant told Dr. Nelson.

"Men are struggling [on average] for about 2 years before they actually pursue treatment," said Dr. Nelson, a psychologist at Memorial Sloan-Kettering Cancer Center in New York.

Ideally, he explained, ED rehabilitation should begin as soon as possible after surgery to maintain blood flow and muscle tone, and "biology dictates the best treatment."

A common, but temporary, effect of nerve-sparing surgery is not only ED, but also stretching of the nerves responsible for the nitric oxide release triggered by oral phosphodiesterase inhibitor drugs. Pills such as sildenafil (Viagra) and taldenafil (Cialis) are effective in only about 20% of men following surgery, so after a brief trial injection therapy is recommended for the maintenance of erections over the 18-24 months that it may take to recover what erectile function remains.

In addition to the barrier of avoidance, men adamantly complained to focus group researchers that they were not properly told before surgery about postsurgical side effects, including ED and its treatments.

"It was ... Theme One ... and clearly the most predominant theme [in the focus groups]," said Dr. Nelson. "We don’t know if surgeons are telling patients about side effects, and they [patients] are thinking about the surgery and just not hearing the information – or whether the surgeons are not giving the information. But clearly, there was a lot of frustration and anger."

While men said they found the idea of penile injections "freakish and barbaric," they did not find them as painful as they had feared. Some saw the long-term benefits of injection therapy to be worth their initial reluctance, but one remarked, "This is the most humiliating thing I’ve ever done in my life."

Considering the trend to diagnose and treat earlier-stage prostate cancer in younger men, combined with an 85% prevalence of ED 4 years post surgery, "it’s an important survivorship issue," Dr. Nelson said.

Drawing from focus group findings, he and his team were encouraged by men’s humor in discussing difficult and awkward topics, offering a potential guidepost for future interventions. He also said men were "not overly enthusiastic" about the proposed idea of psychological interventions during rehabilitation, but advised that such efforts might be better accepted if they were characterized as "coaching."

Indeed, Dr. Nelson and his colleagues drew on the focus group findings to launch a randomized controlled trial of an intervention based on Acceptance and Commitment Therapy, a psychological orientation that encourages participants to define values that are important to them. Over time, the goal is to learn to tolerate distress and overcome barriers in order to achieve goals associated with those prized values, Dr. Nelson explained.

Enrollment in the trial has commenced, and a handful of participants in each group have completed the intervention (or a control condition) during injection training for ED.

"An initial peek at the data looks promising," he said.

Funding for the study was provided through a grant from the National Cancer Institute.

MIAMI – Faced with erectile dysfunction following prostate cancer surgery, many men adopt an avoidant coping style that inadvertently interferes with rehabilitation efforts to spare them long-term sexual side effects.

"We have ways of helping men to get their erections back; that isn’t the issue," Christian J. Nelson, Ph.D., said at the annual conference of the American Psychosocial Oncology Society.

"The issue is, men avoid and drop out of rehabilitation programs."

Avoidance was one key theme raised by 35 men who had undergone radical prostatectomy for prostate cancer 2-3 years prior to being recruited into focus groups by Dr. Nelson and his colleagues as an initial step in devising a more effective approach to erectile dysfunction (ED) rehabilitation. He presented results of a systematic analysis of those themes at the meeting, and offered a preview of the ongoing study that resulted.

Dr. Nelson described a cycle in which men experienced frustration, shame, and embarrassment over ED during a sexual experience following surgery, then began avoiding intimate contact due to anxiety. Relationship issues, depression, and increased frustration often followed.

"It’s absolutely devastating," one focus group participant told him.

Another remarked, "It’s like the ground you walked on since you were a teenager is gone."

Rather than seek help, many men acknowledged that they dealt with ED by withdrawing emotionally, sidestepping the potential for intimacy.

"Doc, it’s fear. It’s fear, Doc," another participant told Dr. Nelson.

"Men are struggling [on average] for about 2 years before they actually pursue treatment," said Dr. Nelson, a psychologist at Memorial Sloan-Kettering Cancer Center in New York.

Ideally, he explained, ED rehabilitation should begin as soon as possible after surgery to maintain blood flow and muscle tone, and "biology dictates the best treatment."

A common, but temporary, effect of nerve-sparing surgery is not only ED, but also stretching of the nerves responsible for the nitric oxide release triggered by oral phosphodiesterase inhibitor drugs. Pills such as sildenafil (Viagra) and taldenafil (Cialis) are effective in only about 20% of men following surgery, so after a brief trial injection therapy is recommended for the maintenance of erections over the 18-24 months that it may take to recover what erectile function remains.

In addition to the barrier of avoidance, men adamantly complained to focus group researchers that they were not properly told before surgery about postsurgical side effects, including ED and its treatments.

"It was ... Theme One ... and clearly the most predominant theme [in the focus groups]," said Dr. Nelson. "We don’t know if surgeons are telling patients about side effects, and they [patients] are thinking about the surgery and just not hearing the information – or whether the surgeons are not giving the information. But clearly, there was a lot of frustration and anger."

While men said they found the idea of penile injections "freakish and barbaric," they did not find them as painful as they had feared. Some saw the long-term benefits of injection therapy to be worth their initial reluctance, but one remarked, "This is the most humiliating thing I’ve ever done in my life."

Considering the trend to diagnose and treat earlier-stage prostate cancer in younger men, combined with an 85% prevalence of ED 4 years post surgery, "it’s an important survivorship issue," Dr. Nelson said.

Drawing from focus group findings, he and his team were encouraged by men’s humor in discussing difficult and awkward topics, offering a potential guidepost for future interventions. He also said men were "not overly enthusiastic" about the proposed idea of psychological interventions during rehabilitation, but advised that such efforts might be better accepted if they were characterized as "coaching."

Indeed, Dr. Nelson and his colleagues drew on the focus group findings to launch a randomized controlled trial of an intervention based on Acceptance and Commitment Therapy, a psychological orientation that encourages participants to define values that are important to them. Over time, the goal is to learn to tolerate distress and overcome barriers in order to achieve goals associated with those prized values, Dr. Nelson explained.

Enrollment in the trial has commenced, and a handful of participants in each group have completed the intervention (or a control condition) during injection training for ED.

"An initial peek at the data looks promising," he said.

Funding for the study was provided through a grant from the National Cancer Institute.

A comparison of three radiotherapies for nonmetastatic prostate cancer supports the widespread use of intensity-modulated radiation treatment, though it leads to more erectile dysfunction than occurs with conformal radiation therapy, according to a report published April 17 in JAMA.

Proton therapy, the newest and most expensive option for these patients, fared poorly in the comparison. It had more GI side effects than intensity-modulated radiation treatment (IMRT) but was not more effective, investigators found.

Related Video >>

"Overall, our results do not clearly demonstrate a clinical benefit to support the recent increase in proton therapy use for prostate cancer," wrote Dr. Nathan C. Sheets of the University of North Carolina, Chapel Hill, and his coauthors (JAMA 2012;307:1611-20).

Dr. Sheets presented the study in February at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

This study and another comparing external beam radiation therapy, prostatectomy, and brachytherapy provoked discussion of whether outcomes justified the costs of newer technologies.

IMRT, a more expensive, more targeted form of radiotherapy, has gradually replaced conformal radiation therapy (CRT), with its use surging from 0.15% in 2000 to 95.9% in 2008, according to Dr. Sheets and his coauthors. In turn, IMRT is facing increasing competition from proton therapy, which they describe as "a high-profile, high-cost prostate cancer treatment."

"Since 2007, multiple proton facilities have been built, and direct-to-consumer advertising is likely to lead to a substantial increase in use," they observed, noting that comparative effectiveness research on these treatments is lacking.

To that end, the investigators used a propensity scoring method to analyze data on 12,976 men who were identified in the Surveillance, Epidemiology, and End Results program registry and had been treated between 2002 and 2006: 6,666 with IMRT and 6,310 with CRT.

The investigators found that men who received IMRT were about 20% less likely to receive additional cancer therapy, with an absolute risk of 2.5 vs. 3.1 per 100 person years (P less than .001).

The IMRT cohort also was significantly less likely to be diagnosed with GI morbidities (absolute risk, 13.4 vs. 14.7 per 100 person-years) and hip fractures (absolute risk, 0.8 vs. 1.0 per 100 person-years), but more likely to be diagnosed with erectile dysfunction than those who received CRT (absolute risk, 5.9 vs. 5.3 per 100 person-years).

In a smaller propensity-score matched comparison of 1,368 men treated with IMRT or proton therapy, the investigators found less GI morbidity with IMRT (absolute risk, 12.2 vs. 17.8 per 100 person-years) and no difference in efficacy.

"This population-based study suggests that IMRT may be associated with improved disease control without compromising morbidity compared with conformal radiation therapy, although proton therapy does not appear to provide additional benefit," they concluded.

The research was supported by the Agency for Healthcare Research and Quality. A grant from the National Institute of Nursing Research enabled publication. Two coauthors reported relationship with pharmaceutical companies.

A comparison of three radiotherapies for nonmetastatic prostate cancer supports the widespread use of intensity-modulated radiation treatment, though it leads to more erectile dysfunction than occurs with conformal radiation therapy, according to a report published April 17 in JAMA.

Proton therapy, the newest and most expensive option for these patients, fared poorly in the comparison. It had more GI side effects than intensity-modulated radiation treatment (IMRT) but was not more effective, investigators found.

Related Video >>

"Overall, our results do not clearly demonstrate a clinical benefit to support the recent increase in proton therapy use for prostate cancer," wrote Dr. Nathan C. Sheets of the University of North Carolina, Chapel Hill, and his coauthors (JAMA 2012;307:1611-20).

Dr. Sheets presented the study in February at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

This study and another comparing external beam radiation therapy, prostatectomy, and brachytherapy provoked discussion of whether outcomes justified the costs of newer technologies.

IMRT, a more expensive, more targeted form of radiotherapy, has gradually replaced conformal radiation therapy (CRT), with its use surging from 0.15% in 2000 to 95.9% in 2008, according to Dr. Sheets and his coauthors. In turn, IMRT is facing increasing competition from proton therapy, which they describe as "a high-profile, high-cost prostate cancer treatment."

"Since 2007, multiple proton facilities have been built, and direct-to-consumer advertising is likely to lead to a substantial increase in use," they observed, noting that comparative effectiveness research on these treatments is lacking.

To that end, the investigators used a propensity scoring method to analyze data on 12,976 men who were identified in the Surveillance, Epidemiology, and End Results program registry and had been treated between 2002 and 2006: 6,666 with IMRT and 6,310 with CRT.

The investigators found that men who received IMRT were about 20% less likely to receive additional cancer therapy, with an absolute risk of 2.5 vs. 3.1 per 100 person years (P less than .001).

The IMRT cohort also was significantly less likely to be diagnosed with GI morbidities (absolute risk, 13.4 vs. 14.7 per 100 person-years) and hip fractures (absolute risk, 0.8 vs. 1.0 per 100 person-years), but more likely to be diagnosed with erectile dysfunction than those who received CRT (absolute risk, 5.9 vs. 5.3 per 100 person-years).

In a smaller propensity-score matched comparison of 1,368 men treated with IMRT or proton therapy, the investigators found less GI morbidity with IMRT (absolute risk, 12.2 vs. 17.8 per 100 person-years) and no difference in efficacy.

"This population-based study suggests that IMRT may be associated with improved disease control without compromising morbidity compared with conformal radiation therapy, although proton therapy does not appear to provide additional benefit," they concluded.

The research was supported by the Agency for Healthcare Research and Quality. A grant from the National Institute of Nursing Research enabled publication. Two coauthors reported relationship with pharmaceutical companies.

A comparison of three radiotherapies for nonmetastatic prostate cancer supports the widespread use of intensity-modulated radiation treatment, though it leads to more erectile dysfunction than occurs with conformal radiation therapy, according to a report published April 17 in JAMA.

Proton therapy, the newest and most expensive option for these patients, fared poorly in the comparison. It had more GI side effects than intensity-modulated radiation treatment (IMRT) but was not more effective, investigators found.

Related Video >>

"Overall, our results do not clearly demonstrate a clinical benefit to support the recent increase in proton therapy use for prostate cancer," wrote Dr. Nathan C. Sheets of the University of North Carolina, Chapel Hill, and his coauthors (JAMA 2012;307:1611-20).

Dr. Sheets presented the study in February at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

This study and another comparing external beam radiation therapy, prostatectomy, and brachytherapy provoked discussion of whether outcomes justified the costs of newer technologies.

IMRT, a more expensive, more targeted form of radiotherapy, has gradually replaced conformal radiation therapy (CRT), with its use surging from 0.15% in 2000 to 95.9% in 2008, according to Dr. Sheets and his coauthors. In turn, IMRT is facing increasing competition from proton therapy, which they describe as "a high-profile, high-cost prostate cancer treatment."

"Since 2007, multiple proton facilities have been built, and direct-to-consumer advertising is likely to lead to a substantial increase in use," they observed, noting that comparative effectiveness research on these treatments is lacking.

To that end, the investigators used a propensity scoring method to analyze data on 12,976 men who were identified in the Surveillance, Epidemiology, and End Results program registry and had been treated between 2002 and 2006: 6,666 with IMRT and 6,310 with CRT.

The investigators found that men who received IMRT were about 20% less likely to receive additional cancer therapy, with an absolute risk of 2.5 vs. 3.1 per 100 person years (P less than .001).

The IMRT cohort also was significantly less likely to be diagnosed with GI morbidities (absolute risk, 13.4 vs. 14.7 per 100 person-years) and hip fractures (absolute risk, 0.8 vs. 1.0 per 100 person-years), but more likely to be diagnosed with erectile dysfunction than those who received CRT (absolute risk, 5.9 vs. 5.3 per 100 person-years).

In a smaller propensity-score matched comparison of 1,368 men treated with IMRT or proton therapy, the investigators found less GI morbidity with IMRT (absolute risk, 12.2 vs. 17.8 per 100 person-years) and no difference in efficacy.

"This population-based study suggests that IMRT may be associated with improved disease control without compromising morbidity compared with conformal radiation therapy, although proton therapy does not appear to provide additional benefit," they concluded.

The research was supported by the Agency for Healthcare Research and Quality. A grant from the National Institute of Nursing Research enabled publication. Two coauthors reported relationship with pharmaceutical companies.

SILVER SPRING, MD. – Physicians may soon have a first-in-class alternative to current treatments for overactive bladder, which may not always work and can have unpleasant side effects.

A Food and Drug Administration panel on April 5 voted 7-4 with 1 abstention that the overall benefit-risk assessment supports the approval of mirabegron for the treatment of overactive bladder.

Pharmacologic treatment options to date include muscarinic receptor antagonists, which can affect the salivary glands, intestines, and eyes, resulting in side effects such as dry mouth, constipation, and blurred vision, respectively.

Mirabegron is a first-in-class agonist of beta 3-adrenoceptors. Astellas Pharma developed the drug for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. In the United States, the proposed dose is 50 mg once daily with or without food. However, a dose of 25 mg is reserved for patients with severe renal or moderate hepatic impairment. The formulation is an oral controlled-absorption system (extended-release) tablets. The drug is already approved in Japan.

"The committee has a sense that there is marginal efficacy, but overall the majority feels that the benefits outweigh the risks. This is seen as a new agent, which can potentially be used for individuals who have not had success with other available agents," summarized Dr. Julia V. Johnson, who is the chair of the advisory committee for reproductive health drugs. "With some caution and with some reservation the overall approval of the medication comes from this committee."

The committee also voted 8-4 that the data do provide substantial evidence of benefit for mirabegron in the treatment of overactive bladder. However, many members agreed that there was statistically-significant improvement in symptoms but questioned whether this would translate to a meaningful clinical difference.

The committee also voted 9-3 that adequate safety had been demonstrated for the drug. Committee members did express reservations about the paucity of data with regard to neoplasms, hepatotoxicity events, and hypersensitivity reactions.

The primary sources of data for the evaluation are three randomized placebo-controlled phase III trials. Supportive data included data from a single long-term (active-controlled) study, three phase II studies, and a phase II study in patients with symptomatic benign prostatic hyperplasia.

The three phase III trials lasted for 12 weeks with individuals randomized to receive mirabegron either 25 mg daily, or 50 mg daily, or placebo. Coprimary end points included change from baseline in the average number of micturitions in 24 hours and the change from baseline in the average number of incontinence episodes in 24 hours.

Mirabegron at a dose of 50 mg achieved the primary efficacy objectives in three phase III studies. Treatment with 50 mg mirabegron reduced the mean number of micturitions by 0.55/day, compared with placebo. Likewise, mirabegron reduced the mean number of incontinence episodes per day by 0.40, compared with placebo. Lastly, the mean volume per void increased by 11.9 mL with the drug, compared with placebo.

Committee members expressed some concern about increases in both blood pressure and pulse rate associated with the drug. There was also an increased incidence of urologic adverse events, particularly urinary tract infections of mild severity. The committee members were particularly concerned about an increased incidence of neoplasm serious adverse events – new malignant events – in the group on 100 mg mirabegron in the 1-year study, as well as hepatotoxicity events and hypersensitivity reactions. However, they noted that there was insufficient data to draw firm conclusions about these serious adverse events.

SILVER SPRING, MD. – Physicians may soon have a first-in-class alternative to current treatments for overactive bladder, which may not always work and can have unpleasant side effects.

A Food and Drug Administration panel on April 5 voted 7-4 with 1 abstention that the overall benefit-risk assessment supports the approval of mirabegron for the treatment of overactive bladder.

Pharmacologic treatment options to date include muscarinic receptor antagonists, which can affect the salivary glands, intestines, and eyes, resulting in side effects such as dry mouth, constipation, and blurred vision, respectively.

Mirabegron is a first-in-class agonist of beta 3-adrenoceptors. Astellas Pharma developed the drug for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. In the United States, the proposed dose is 50 mg once daily with or without food. However, a dose of 25 mg is reserved for patients with severe renal or moderate hepatic impairment. The formulation is an oral controlled-absorption system (extended-release) tablets. The drug is already approved in Japan.

"The committee has a sense that there is marginal efficacy, but overall the majority feels that the benefits outweigh the risks. This is seen as a new agent, which can potentially be used for individuals who have not had success with other available agents," summarized Dr. Julia V. Johnson, who is the chair of the advisory committee for reproductive health drugs. "With some caution and with some reservation the overall approval of the medication comes from this committee."

The committee also voted 8-4 that the data do provide substantial evidence of benefit for mirabegron in the treatment of overactive bladder. However, many members agreed that there was statistically-significant improvement in symptoms but questioned whether this would translate to a meaningful clinical difference.

The committee also voted 9-3 that adequate safety had been demonstrated for the drug. Committee members did express reservations about the paucity of data with regard to neoplasms, hepatotoxicity events, and hypersensitivity reactions.

The primary sources of data for the evaluation are three randomized placebo-controlled phase III trials. Supportive data included data from a single long-term (active-controlled) study, three phase II studies, and a phase II study in patients with symptomatic benign prostatic hyperplasia.

The three phase III trials lasted for 12 weeks with individuals randomized to receive mirabegron either 25 mg daily, or 50 mg daily, or placebo. Coprimary end points included change from baseline in the average number of micturitions in 24 hours and the change from baseline in the average number of incontinence episodes in 24 hours.

Mirabegron at a dose of 50 mg achieved the primary efficacy objectives in three phase III studies. Treatment with 50 mg mirabegron reduced the mean number of micturitions by 0.55/day, compared with placebo. Likewise, mirabegron reduced the mean number of incontinence episodes per day by 0.40, compared with placebo. Lastly, the mean volume per void increased by 11.9 mL with the drug, compared with placebo.

Committee members expressed some concern about increases in both blood pressure and pulse rate associated with the drug. There was also an increased incidence of urologic adverse events, particularly urinary tract infections of mild severity. The committee members were particularly concerned about an increased incidence of neoplasm serious adverse events – new malignant events – in the group on 100 mg mirabegron in the 1-year study, as well as hepatotoxicity events and hypersensitivity reactions. However, they noted that there was insufficient data to draw firm conclusions about these serious adverse events.

SILVER SPRING, MD. – Physicians may soon have a first-in-class alternative to current treatments for overactive bladder, which may not always work and can have unpleasant side effects.

A Food and Drug Administration panel on April 5 voted 7-4 with 1 abstention that the overall benefit-risk assessment supports the approval of mirabegron for the treatment of overactive bladder.

Pharmacologic treatment options to date include muscarinic receptor antagonists, which can affect the salivary glands, intestines, and eyes, resulting in side effects such as dry mouth, constipation, and blurred vision, respectively.

Mirabegron is a first-in-class agonist of beta 3-adrenoceptors. Astellas Pharma developed the drug for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. In the United States, the proposed dose is 50 mg once daily with or without food. However, a dose of 25 mg is reserved for patients with severe renal or moderate hepatic impairment. The formulation is an oral controlled-absorption system (extended-release) tablets. The drug is already approved in Japan.

"The committee has a sense that there is marginal efficacy, but overall the majority feels that the benefits outweigh the risks. This is seen as a new agent, which can potentially be used for individuals who have not had success with other available agents," summarized Dr. Julia V. Johnson, who is the chair of the advisory committee for reproductive health drugs. "With some caution and with some reservation the overall approval of the medication comes from this committee."

The committee also voted 8-4 that the data do provide substantial evidence of benefit for mirabegron in the treatment of overactive bladder. However, many members agreed that there was statistically-significant improvement in symptoms but questioned whether this would translate to a meaningful clinical difference.

The committee also voted 9-3 that adequate safety had been demonstrated for the drug. Committee members did express reservations about the paucity of data with regard to neoplasms, hepatotoxicity events, and hypersensitivity reactions.

The primary sources of data for the evaluation are three randomized placebo-controlled phase III trials. Supportive data included data from a single long-term (active-controlled) study, three phase II studies, and a phase II study in patients with symptomatic benign prostatic hyperplasia.

The three phase III trials lasted for 12 weeks with individuals randomized to receive mirabegron either 25 mg daily, or 50 mg daily, or placebo. Coprimary end points included change from baseline in the average number of micturitions in 24 hours and the change from baseline in the average number of incontinence episodes in 24 hours.

Mirabegron at a dose of 50 mg achieved the primary efficacy objectives in three phase III studies. Treatment with 50 mg mirabegron reduced the mean number of micturitions by 0.55/day, compared with placebo. Likewise, mirabegron reduced the mean number of incontinence episodes per day by 0.40, compared with placebo. Lastly, the mean volume per void increased by 11.9 mL with the drug, compared with placebo.

Committee members expressed some concern about increases in both blood pressure and pulse rate associated with the drug. There was also an increased incidence of urologic adverse events, particularly urinary tract infections of mild severity. The committee members were particularly concerned about an increased incidence of neoplasm serious adverse events – new malignant events – in the group on 100 mg mirabegron in the 1-year study, as well as hepatotoxicity events and hypersensitivity reactions. However, they noted that there was insufficient data to draw firm conclusions about these serious adverse events.

SAN FRANCISCO – Healthy middle-aged and older men who take vitamin E supplements have an increased risk of prostate cancer, although the risk takes some time to emerge, suggests an update of the randomized SELECT prevention trial.

At a median follow-up of 7 years – or 1.5 years after the trial had been closed early for futility and men had been told to stop taking supplements – those who had taken vitamin E had a significant 17% greater risk of prostate cancer than those who had taken a placebo. The risk had been increased, although not significantly so, at the time of trial closure.

Photo credit: Juanmonino/iStockphoto

In absolute terms, the elevated risk from taking vitamin E translated to 11 more cancers for every 1,000 men over a 7-year period, Dr. Eric A. Klein said at the Genitourinary Cancers Symposium.

The findings serve as a cautionary tale, he said. "Nutritional supplements are biologically active and may in fact be harmful, and importantly, the effect may continue after the intervention stops," Dr. Klein commented.

More than half of U.S. men over age 60 take vitamin E, with about one-quarter taking at least 400 IU daily (Ann. Intern. Med. 2005;143:116-20), the dose used in the trial. "Consumers should be skeptical about health claims for unregulated over-the-counter products in the absence of strong evidence of benefit from clinical trials," said Dr. Klein at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

In other updated results, men who took selenium with vitamin E and men who took selenium alone did not have any significant increase in the risk of prostate cancer. And baseline plasma levels of various tocopherols (forms of vitamin E) modified prostate cancer risk: Within the vitamin E group, for example, higher levels of alpha-tocopherol were protective, whereas higher levels of gamma-tocopherol were deleterious.

The obvious question now is, how does vitamin E increase prostate cancer risk? said Dr. Klein, who is chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic. Theories that have been advanced include the possibility that antioxidants become carcinogenic pro-oxidants at high doses; there may be interplay between the different types of tocopherols; high doses of vitamin E may inhibit absorption of other, protective fat-soluble vitamins; and genetic susceptibility may affect the actions of antioxidants. A related, as yet unanswered question is why adding selenium to vitamin E abolishes the excess risk.

"We need to sort all of this out," Dr. Klein said, pointing to the SELECT (Selenium and Vitamin E Cancer Prevention Trial) Biorepository, which contains a wealth of information about the men studied and is being offered as a resource. "I invite anybody in the scientific community to float a hypothesis. If it passes scientific muster, we will give you access to the Biorepository to help us answer [these questions]." More than a half dozen studies have already been approved, he said.

In SELECT, 35,533 healthy North American men aged 50 years or older if black or 55 years or older if of other races/ethnicities who had an average risk of prostate cancer were randomized to four groups: vitamin E (400 IU/day, all rac-alpha-tocopherol acetate), selenium (200 mcg/day from l-selenomethionine), the combination, or a placebo.

"It was recommended, but not required in this trial, unlike in the PCPT [Prostate Cancer Prevention Trial], that men be screened yearly with PSA and digital rectal exam," Dr. Klein noted. "One of the strengths of the trial is that the screening interval and the trigger for biopsy were not prescribed by the trial; they were left to local community standards at these 400-plus sites."

At the time that the trial was halted early, men in the vitamin E group had a marginally increased risk of prostate cancer compared with men in the placebo group (hazard ratio, 1.13; P = .06) (JAMA 2009;301:39-51). But with the additional follow-up, despite cessation of supplement use, the trend continued and became significant (hazard ratio, 1.17; P = .008) (JAMA 2011;306:1549-56).

"There was no difference in tumor aggressiveness across the four arms as assessed by tumor stage and grade," Dr. Klein reported. "And the increased risk of being diagnosed with prostate cancer in the vitamin E arm was not accounted for by more intense screening or an increasing rate of biopsy."

In the vitamin E group, the risk of prostate cancer generally decreased with each additional quintile of alpha-tocopherol at baseline. In contrast, within the selenium and combination groups, the risk increased with quintile, and within the placebo group, risk was unaffected.

The results were "somewhat opposite" for plasma gamma-tocopherol levels at baseline. In the vitamin E group, the risk generally increased with quintile. In contrast, within all the other groups, the risk decreased with quintile.

The findings have noteworthy implications for the design of clinical trials, said Dr. Klein.

"There were interactions between selenium and vitamin E with respect to risk, and a factorial design would not have captured that. So it’s important that these be powered to allow for these interactions to be tested for," he explained. "And maybe most importantly, for agents whose biology we don’t really understand and don’t really understand what the time line of the effect is, that postintervention follow-up is critical: If we had not continued to follow these men beyond the 5.5 years that they took the supplements, we would not have discovered [the elevated risk with vitamin E]".

Dr. Klein disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – Healthy middle-aged and older men who take vitamin E supplements have an increased risk of prostate cancer, although the risk takes some time to emerge, suggests an update of the randomized SELECT prevention trial.

At a median follow-up of 7 years – or 1.5 years after the trial had been closed early for futility and men had been told to stop taking supplements – those who had taken vitamin E had a significant 17% greater risk of prostate cancer than those who had taken a placebo. The risk had been increased, although not significantly so, at the time of trial closure.

Photo credit: Juanmonino/iStockphoto

In absolute terms, the elevated risk from taking vitamin E translated to 11 more cancers for every 1,000 men over a 7-year period, Dr. Eric A. Klein said at the Genitourinary Cancers Symposium.

The findings serve as a cautionary tale, he said. "Nutritional supplements are biologically active and may in fact be harmful, and importantly, the effect may continue after the intervention stops," Dr. Klein commented.

More than half of U.S. men over age 60 take vitamin E, with about one-quarter taking at least 400 IU daily (Ann. Intern. Med. 2005;143:116-20), the dose used in the trial. "Consumers should be skeptical about health claims for unregulated over-the-counter products in the absence of strong evidence of benefit from clinical trials," said Dr. Klein at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

In other updated results, men who took selenium with vitamin E and men who took selenium alone did not have any significant increase in the risk of prostate cancer. And baseline plasma levels of various tocopherols (forms of vitamin E) modified prostate cancer risk: Within the vitamin E group, for example, higher levels of alpha-tocopherol were protective, whereas higher levels of gamma-tocopherol were deleterious.

The obvious question now is, how does vitamin E increase prostate cancer risk? said Dr. Klein, who is chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic. Theories that have been advanced include the possibility that antioxidants become carcinogenic pro-oxidants at high doses; there may be interplay between the different types of tocopherols; high doses of vitamin E may inhibit absorption of other, protective fat-soluble vitamins; and genetic susceptibility may affect the actions of antioxidants. A related, as yet unanswered question is why adding selenium to vitamin E abolishes the excess risk.

"We need to sort all of this out," Dr. Klein said, pointing to the SELECT (Selenium and Vitamin E Cancer Prevention Trial) Biorepository, which contains a wealth of information about the men studied and is being offered as a resource. "I invite anybody in the scientific community to float a hypothesis. If it passes scientific muster, we will give you access to the Biorepository to help us answer [these questions]." More than a half dozen studies have already been approved, he said.

In SELECT, 35,533 healthy North American men aged 50 years or older if black or 55 years or older if of other races/ethnicities who had an average risk of prostate cancer were randomized to four groups: vitamin E (400 IU/day, all rac-alpha-tocopherol acetate), selenium (200 mcg/day from l-selenomethionine), the combination, or a placebo.

"It was recommended, but not required in this trial, unlike in the PCPT [Prostate Cancer Prevention Trial], that men be screened yearly with PSA and digital rectal exam," Dr. Klein noted. "One of the strengths of the trial is that the screening interval and the trigger for biopsy were not prescribed by the trial; they were left to local community standards at these 400-plus sites."

At the time that the trial was halted early, men in the vitamin E group had a marginally increased risk of prostate cancer compared with men in the placebo group (hazard ratio, 1.13; P = .06) (JAMA 2009;301:39-51). But with the additional follow-up, despite cessation of supplement use, the trend continued and became significant (hazard ratio, 1.17; P = .008) (JAMA 2011;306:1549-56).

"There was no difference in tumor aggressiveness across the four arms as assessed by tumor stage and grade," Dr. Klein reported. "And the increased risk of being diagnosed with prostate cancer in the vitamin E arm was not accounted for by more intense screening or an increasing rate of biopsy."

In the vitamin E group, the risk of prostate cancer generally decreased with each additional quintile of alpha-tocopherol at baseline. In contrast, within the selenium and combination groups, the risk increased with quintile, and within the placebo group, risk was unaffected.

The results were "somewhat opposite" for plasma gamma-tocopherol levels at baseline. In the vitamin E group, the risk generally increased with quintile. In contrast, within all the other groups, the risk decreased with quintile.

The findings have noteworthy implications for the design of clinical trials, said Dr. Klein.

"There were interactions between selenium and vitamin E with respect to risk, and a factorial design would not have captured that. So it’s important that these be powered to allow for these interactions to be tested for," he explained. "And maybe most importantly, for agents whose biology we don’t really understand and don’t really understand what the time line of the effect is, that postintervention follow-up is critical: If we had not continued to follow these men beyond the 5.5 years that they took the supplements, we would not have discovered [the elevated risk with vitamin E]".

Dr. Klein disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – Healthy middle-aged and older men who take vitamin E supplements have an increased risk of prostate cancer, although the risk takes some time to emerge, suggests an update of the randomized SELECT prevention trial.

At a median follow-up of 7 years – or 1.5 years after the trial had been closed early for futility and men had been told to stop taking supplements – those who had taken vitamin E had a significant 17% greater risk of prostate cancer than those who had taken a placebo. The risk had been increased, although not significantly so, at the time of trial closure.

Photo credit: Juanmonino/iStockphoto

In absolute terms, the elevated risk from taking vitamin E translated to 11 more cancers for every 1,000 men over a 7-year period, Dr. Eric A. Klein said at the Genitourinary Cancers Symposium.

The findings serve as a cautionary tale, he said. "Nutritional supplements are biologically active and may in fact be harmful, and importantly, the effect may continue after the intervention stops," Dr. Klein commented.

More than half of U.S. men over age 60 take vitamin E, with about one-quarter taking at least 400 IU daily (Ann. Intern. Med. 2005;143:116-20), the dose used in the trial. "Consumers should be skeptical about health claims for unregulated over-the-counter products in the absence of strong evidence of benefit from clinical trials," said Dr. Klein at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

In other updated results, men who took selenium with vitamin E and men who took selenium alone did not have any significant increase in the risk of prostate cancer. And baseline plasma levels of various tocopherols (forms of vitamin E) modified prostate cancer risk: Within the vitamin E group, for example, higher levels of alpha-tocopherol were protective, whereas higher levels of gamma-tocopherol were deleterious.

The obvious question now is, how does vitamin E increase prostate cancer risk? said Dr. Klein, who is chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic. Theories that have been advanced include the possibility that antioxidants become carcinogenic pro-oxidants at high doses; there may be interplay between the different types of tocopherols; high doses of vitamin E may inhibit absorption of other, protective fat-soluble vitamins; and genetic susceptibility may affect the actions of antioxidants. A related, as yet unanswered question is why adding selenium to vitamin E abolishes the excess risk.

"We need to sort all of this out," Dr. Klein said, pointing to the SELECT (Selenium and Vitamin E Cancer Prevention Trial) Biorepository, which contains a wealth of information about the men studied and is being offered as a resource. "I invite anybody in the scientific community to float a hypothesis. If it passes scientific muster, we will give you access to the Biorepository to help us answer [these questions]." More than a half dozen studies have already been approved, he said.

In SELECT, 35,533 healthy North American men aged 50 years or older if black or 55 years or older if of other races/ethnicities who had an average risk of prostate cancer were randomized to four groups: vitamin E (400 IU/day, all rac-alpha-tocopherol acetate), selenium (200 mcg/day from l-selenomethionine), the combination, or a placebo.

"It was recommended, but not required in this trial, unlike in the PCPT [Prostate Cancer Prevention Trial], that men be screened yearly with PSA and digital rectal exam," Dr. Klein noted. "One of the strengths of the trial is that the screening interval and the trigger for biopsy were not prescribed by the trial; they were left to local community standards at these 400-plus sites."

At the time that the trial was halted early, men in the vitamin E group had a marginally increased risk of prostate cancer compared with men in the placebo group (hazard ratio, 1.13; P = .06) (JAMA 2009;301:39-51). But with the additional follow-up, despite cessation of supplement use, the trend continued and became significant (hazard ratio, 1.17; P = .008) (JAMA 2011;306:1549-56).

"There was no difference in tumor aggressiveness across the four arms as assessed by tumor stage and grade," Dr. Klein reported. "And the increased risk of being diagnosed with prostate cancer in the vitamin E arm was not accounted for by more intense screening or an increasing rate of biopsy."

In the vitamin E group, the risk of prostate cancer generally decreased with each additional quintile of alpha-tocopherol at baseline. In contrast, within the selenium and combination groups, the risk increased with quintile, and within the placebo group, risk was unaffected.

The results were "somewhat opposite" for plasma gamma-tocopherol levels at baseline. In the vitamin E group, the risk generally increased with quintile. In contrast, within all the other groups, the risk decreased with quintile.

The findings have noteworthy implications for the design of clinical trials, said Dr. Klein.

"There were interactions between selenium and vitamin E with respect to risk, and a factorial design would not have captured that. So it’s important that these be powered to allow for these interactions to be tested for," he explained. "And maybe most importantly, for agents whose biology we don’t really understand and don’t really understand what the time line of the effect is, that postintervention follow-up is critical: If we had not continued to follow these men beyond the 5.5 years that they took the supplements, we would not have discovered [the elevated risk with vitamin E]".

Dr. Klein disclosed that he had no relevant conflicts of interest.