Urology

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.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said 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.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said 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.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said 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.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

After 13 years of follow-up, men who underwent annual screening for prostate cancer were no less likely to die of prostate cancer than were men who received usual care and opportunistic screening.

Cumulative mortality rates from prostate cancer differed by a statistically insignificant rate of 0.3 deaths per 10,000 person years in the intervention and usual-care arms of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial, published online Jan. 6 in the Journal of the National Cancer Institute. Further, age, comorbidity status, and pretrial prostate-specific antigen (PSA) testing did not influence the results, wrote Dr. Gerald L. Andriole of Washington University, St. Louis, and his colleagues.

The PLCO trial randomly assigned 76,693 men, aged 55-74 years, to either 6 years of annual PSA screening in combination with 4 years of annual digital rectal examination (38,343) or to usual care (38,350), which included screening tests as recommended by physicians.

The goal was to evaluate the effect of adding annual screening and compare outcomes to the opportunistic screening already in place, the researchers said. It was expected that the impacts of earlier diagnosis and a persistent excess of cases because of annual screening in the intervention arm would exceed the impacts of opportunistic screening.

Prior to the study, 44% of all participants had undergone PSA screening. During the trial, 52% of the usual-care group, compared with the entire intervention group, underwent PSA testing.

The researchers had previously reported 7- and 10-year follow-up results. At 7 years of follow-up, yearly screening was associated with an increased incidence of prostate cancer diagnosis as compared with usual care. The rates of prostate cancer mortality and of all-cause mortality, however, were the same for both groups. Similarly, after 10 years of follow-up, no mortality benefit was observed for the intervention, the investigators reported previously (N. Engl. J. Med. 2009;360:1320-1328).

For the current study, Dr. Andriole and his associates ascertained all incident prostate cancer diagnoses and deaths through 13 years of follow-up or through December 31, 2009, and estimated relative risks as the ratio of observed rates of diagnoses and deaths in the intervention and control arms. They examined the interactions between prostate cancer mortality by trial arm and age, comorbidities, and pretrial PSA testing using Poisson regression modeling (J. Natl. Cancer Inst. 6 Jan. 2012 [doi: 10.1093/jnci/djr500]).

At 13 years, 4,250 of the 38,340 participants in the intervention arm had been diagnosed with prostate cancer, compared with 3,815 of the 38,345 control participants. "The cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10,000 person-years, respectively, resulting in a statistically significant 12% relative increase in the intervention arm," the authors wrote. Of the prostate cancer diagnoses, 401 in the intervention arm and 454 in the usual care arm were high-grade prostate cancers with Gleason scores of 8-10.

At 13 years of follow-up, there were 158 deaths in the intervention arm and 145 deaths in the usual-care arm. "The cumulative mortality rates from prostate cancer were 3.7 and 3.4 deaths per 10,000 person-years, respectively, resulting in a non-statistically significant difference between the two arms," according to the authors. The examination of mortality rates per 10,000 person-years and relative risks of prostate cancer mortality by age, comorbidity, and pretrial PSA testing produced no statistically significant interactions.

Deaths from all causes other than prostate, lung, and colorectal cancers differed by a factor of "borderline" statistical significance, with 5,783 deaths in the intervention arm and 5,982 in the usual-care arm, Dr. Andriole and his associates wrote. "Intervention and control arms showed 23% and 22% deaths, respectively, from non-PLCO cancers, and 21% and 19% deaths, respectively, from ischemic heart disease."

The authors acknowledged limitations of the study, including the possibility that a reduction in prostate cancer mortality in the analysis has somehow been masked by "the sticking diagnosis effect." In other words, more deaths were attributed to prostate cancer in the intervention arm. This possibility is supported by the statistically significant lower all-cause mortality in the intervention group as compared with the usual-care group. The percentage of deaths from other causes was higher in the intervention arm, so an error in cause of death attribution likely does not account for the excess prostate cancer deaths in the intervention group, they concluded.

The investigators plan to update the mortality findings through 15 years of follow-up, when those data become available.

Some of the study authors report relationships with Amgen, Augmenix, Bayer, Cambridge Endo, Caris, Envisioneering Medical, France Foundation, GenProbe, GlaxoSmithKline, Human Genome Sciences, Myriad Genetics, Steba Biotech, Ortho Clinical Diagnostics, and Viking Medical.

After 13 years of follow-up, men who underwent annual screening for prostate cancer were no less likely to die of prostate cancer than were men who received usual care and opportunistic screening.

Cumulative mortality rates from prostate cancer differed by a statistically insignificant rate of 0.3 deaths per 10,000 person years in the intervention and usual-care arms of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial, published online Jan. 6 in the Journal of the National Cancer Institute. Further, age, comorbidity status, and pretrial prostate-specific antigen (PSA) testing did not influence the results, wrote Dr. Gerald L. Andriole of Washington University, St. Louis, and his colleagues.

The PLCO trial randomly assigned 76,693 men, aged 55-74 years, to either 6 years of annual PSA screening in combination with 4 years of annual digital rectal examination (38,343) or to usual care (38,350), which included screening tests as recommended by physicians.

The goal was to evaluate the effect of adding annual screening and compare outcomes to the opportunistic screening already in place, the researchers said. It was expected that the impacts of earlier diagnosis and a persistent excess of cases because of annual screening in the intervention arm would exceed the impacts of opportunistic screening.

Prior to the study, 44% of all participants had undergone PSA screening. During the trial, 52% of the usual-care group, compared with the entire intervention group, underwent PSA testing.

The researchers had previously reported 7- and 10-year follow-up results. At 7 years of follow-up, yearly screening was associated with an increased incidence of prostate cancer diagnosis as compared with usual care. The rates of prostate cancer mortality and of all-cause mortality, however, were the same for both groups. Similarly, after 10 years of follow-up, no mortality benefit was observed for the intervention, the investigators reported previously (N. Engl. J. Med. 2009;360:1320-1328).

For the current study, Dr. Andriole and his associates ascertained all incident prostate cancer diagnoses and deaths through 13 years of follow-up or through December 31, 2009, and estimated relative risks as the ratio of observed rates of diagnoses and deaths in the intervention and control arms. They examined the interactions between prostate cancer mortality by trial arm and age, comorbidities, and pretrial PSA testing using Poisson regression modeling (J. Natl. Cancer Inst. 6 Jan. 2012 [doi: 10.1093/jnci/djr500]).

At 13 years, 4,250 of the 38,340 participants in the intervention arm had been diagnosed with prostate cancer, compared with 3,815 of the 38,345 control participants. "The cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10,000 person-years, respectively, resulting in a statistically significant 12% relative increase in the intervention arm," the authors wrote. Of the prostate cancer diagnoses, 401 in the intervention arm and 454 in the usual care arm were high-grade prostate cancers with Gleason scores of 8-10.

At 13 years of follow-up, there were 158 deaths in the intervention arm and 145 deaths in the usual-care arm. "The cumulative mortality rates from prostate cancer were 3.7 and 3.4 deaths per 10,000 person-years, respectively, resulting in a non-statistically significant difference between the two arms," according to the authors. The examination of mortality rates per 10,000 person-years and relative risks of prostate cancer mortality by age, comorbidity, and pretrial PSA testing produced no statistically significant interactions.

Deaths from all causes other than prostate, lung, and colorectal cancers differed by a factor of "borderline" statistical significance, with 5,783 deaths in the intervention arm and 5,982 in the usual-care arm, Dr. Andriole and his associates wrote. "Intervention and control arms showed 23% and 22% deaths, respectively, from non-PLCO cancers, and 21% and 19% deaths, respectively, from ischemic heart disease."

The authors acknowledged limitations of the study, including the possibility that a reduction in prostate cancer mortality in the analysis has somehow been masked by "the sticking diagnosis effect." In other words, more deaths were attributed to prostate cancer in the intervention arm. This possibility is supported by the statistically significant lower all-cause mortality in the intervention group as compared with the usual-care group. The percentage of deaths from other causes was higher in the intervention arm, so an error in cause of death attribution likely does not account for the excess prostate cancer deaths in the intervention group, they concluded.

The investigators plan to update the mortality findings through 15 years of follow-up, when those data become available.

Some of the study authors report relationships with Amgen, Augmenix, Bayer, Cambridge Endo, Caris, Envisioneering Medical, France Foundation, GenProbe, GlaxoSmithKline, Human Genome Sciences, Myriad Genetics, Steba Biotech, Ortho Clinical Diagnostics, and Viking Medical.

After 13 years of follow-up, men who underwent annual screening for prostate cancer were no less likely to die of prostate cancer than were men who received usual care and opportunistic screening.

Cumulative mortality rates from prostate cancer differed by a statistically insignificant rate of 0.3 deaths per 10,000 person years in the intervention and usual-care arms of the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial, published online Jan. 6 in the Journal of the National Cancer Institute. Further, age, comorbidity status, and pretrial prostate-specific antigen (PSA) testing did not influence the results, wrote Dr. Gerald L. Andriole of Washington University, St. Louis, and his colleagues.

The PLCO trial randomly assigned 76,693 men, aged 55-74 years, to either 6 years of annual PSA screening in combination with 4 years of annual digital rectal examination (38,343) or to usual care (38,350), which included screening tests as recommended by physicians.

The goal was to evaluate the effect of adding annual screening and compare outcomes to the opportunistic screening already in place, the researchers said. It was expected that the impacts of earlier diagnosis and a persistent excess of cases because of annual screening in the intervention arm would exceed the impacts of opportunistic screening.

Prior to the study, 44% of all participants had undergone PSA screening. During the trial, 52% of the usual-care group, compared with the entire intervention group, underwent PSA testing.

The researchers had previously reported 7- and 10-year follow-up results. At 7 years of follow-up, yearly screening was associated with an increased incidence of prostate cancer diagnosis as compared with usual care. The rates of prostate cancer mortality and of all-cause mortality, however, were the same for both groups. Similarly, after 10 years of follow-up, no mortality benefit was observed for the intervention, the investigators reported previously (N. Engl. J. Med. 2009;360:1320-1328).

For the current study, Dr. Andriole and his associates ascertained all incident prostate cancer diagnoses and deaths through 13 years of follow-up or through December 31, 2009, and estimated relative risks as the ratio of observed rates of diagnoses and deaths in the intervention and control arms. They examined the interactions between prostate cancer mortality by trial arm and age, comorbidities, and pretrial PSA testing using Poisson regression modeling (J. Natl. Cancer Inst. 6 Jan. 2012 [doi: 10.1093/jnci/djr500]).

At 13 years, 4,250 of the 38,340 participants in the intervention arm had been diagnosed with prostate cancer, compared with 3,815 of the 38,345 control participants. "The cumulative incidence rates for prostate cancer in the intervention and control arms were 108.4 and 97.1 per 10,000 person-years, respectively, resulting in a statistically significant 12% relative increase in the intervention arm," the authors wrote. Of the prostate cancer diagnoses, 401 in the intervention arm and 454 in the usual care arm were high-grade prostate cancers with Gleason scores of 8-10.

At 13 years of follow-up, there were 158 deaths in the intervention arm and 145 deaths in the usual-care arm. "The cumulative mortality rates from prostate cancer were 3.7 and 3.4 deaths per 10,000 person-years, respectively, resulting in a non-statistically significant difference between the two arms," according to the authors. The examination of mortality rates per 10,000 person-years and relative risks of prostate cancer mortality by age, comorbidity, and pretrial PSA testing produced no statistically significant interactions.

Deaths from all causes other than prostate, lung, and colorectal cancers differed by a factor of "borderline" statistical significance, with 5,783 deaths in the intervention arm and 5,982 in the usual-care arm, Dr. Andriole and his associates wrote. "Intervention and control arms showed 23% and 22% deaths, respectively, from non-PLCO cancers, and 21% and 19% deaths, respectively, from ischemic heart disease."

The authors acknowledged limitations of the study, including the possibility that a reduction in prostate cancer mortality in the analysis has somehow been masked by "the sticking diagnosis effect." In other words, more deaths were attributed to prostate cancer in the intervention arm. This possibility is supported by the statistically significant lower all-cause mortality in the intervention group as compared with the usual-care group. The percentage of deaths from other causes was higher in the intervention arm, so an error in cause of death attribution likely does not account for the excess prostate cancer deaths in the intervention group, they concluded.

The investigators plan to update the mortality findings through 15 years of follow-up, when those data become available.

Some of the study authors report relationships with Amgen, Augmenix, Bayer, Cambridge Endo, Caris, Envisioneering Medical, France Foundation, GenProbe, GlaxoSmithKline, Human Genome Sciences, Myriad Genetics, Steba Biotech, Ortho Clinical Diagnostics, and Viking Medical.

Evidence does not conclusively support widespread prostate cancer screening of healthy men for reduction of deaths in the long term, according to a systematic review of the literature.

In a move that could spark as much or more controversy as its recommendation against routine mammography for women in their 40s, the U.S. Preventive Services Task Force is taking this evidence and recommending against routine prostate-specific antigen (PSA) testing for healthy men in draft guidelines to be opened to public comment on Oct. 11.

Dr. Roger Chou and his colleagues conducted the review for the task force. They identified randomized trials of PSA-based screening, randomized trials, and cohort studies that compared prostatectomy or radiation therapy with watchful waiting, and large observational studies of perioperative adverse effects associated with surgical treatment.

"Screening based on PSA identifies additional prostate cancers, but most trials found no statistically significant effect on prostate cancer–specific mortality," the authors wrote. "Recent meta-analyses of randomized trials included in this review found no pooled effects of screening on prostate cancer–specific mortality."

In its 2008 recommendations, the task force previously had determined there was insufficient evidence for improved health outcomes (including reduced prostate cancer–specific and all-cause mortality) associated with prostate cancer screening for men younger than 75 years (Ann. Intern. Med. 2008;149:185-91). At the same time, they recommended against screening men 75 years or older, citing enough conclusive evidence to suggest the harms of screening and treatment would outweigh the potential benefits.

The current task force recommendations say no to PSA screening for all healthy men, regardless of age.

Dr. Chou and his colleagues noted the two largest, highest-quality studies in their review yielded conflicting results. The ERSPC (European Randomized Study of Screening for Prostate Cancer) randomly assessed 182,000 men aged 50-74 years to PSA testing or usual care (N. Engl. J. Med. 2009;360:1320-8). After a median 9 years, they found no statistically significant difference between groups in prostate cancer–specific mortality (relative risk, 0.85). A prespecified subgroup analysis did, however, show a 20% reduction in relative risk (0.80).

Investigators for the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial found no significant difference after 10 years in a study of 76,693 men ages 55 to 74 years randomized to PSA screening and digital rectal examinations vs. usual care (relative risk 1.1) (N. Engl. J. Med. 2009;360:1310-9).

"There is a substantial, cultural belief that prostate cancer screening saves lives. That does not reflect what the evidence shows."

"We think the task force reached a reasonable conclusion based on the evidence that they reviewed," said Dr. Len Lichtenfeld, deputy chief medical officer at the American Cancer Society, when asked to comment.

"What I think has to start happening is that doctors and their patients have to have a lot more honest conversations ... that this is not a test that has been shown unequivocally to have value when applied to large numbers of men, as it is being done today," Dr. Lichtenfeld said.

This call for more open and honest communication with patients about the relative risks and benefits of PSA testing is an essential feature of the society’s own 2010 recommendations on prostate cancer screening.

"At that time, we had looked at these same studies and we said we were unable to demonstrate conclusively that prostate cancer screening saves lives," Dr. Lichtenfeld said. "We weren’t advocating for or against [PSA test screening] but thought men needed to know that the evidence that this saves lives was limited and that the potential harms of diagnosis and treatment were real."

Public and physician perceptions, as well as the relative ease of ordering the PSA blood test, are real challenges to overcome, Dr. Lichtenfeld said. "There is a substantial, cultural belief – not only in the community but among health professionals – that prostate cancer screening saves lives. That does not reflect what the evidence shows."

"This is an easy test – it’s a blood test – go ahead and just do it. Why not?" he added. "Well, the ‘why nots’ are the men who are incontinent, the men who are impotent, the men who have radiation cystitis 15 years later [from resultant treatment] and are in so much pain that they can’t function."

The potential harms associated with false-positive tests and subsequent interventions are addressed in the systematic review. For example, about 1 in 200 men who undergo a prostate biopsy as a result of screening experiences a serious infection or urinary retention. The authors also noted that screening is likely to lead to overdiagnosis because the PSA enzyme test can pick up low-risk cancers that, left undetected and untreated, would not have caused death during a man’s lifetime.

Treatment of approximately three men with prostatectomy or seven men with radiation therapy instead of watchful waiting would each result in one additional case of erectile dysfunction, the review revealed. Similarly, treatment of five men with prostatectomy instead of watchful waiting would result in one additional case of urinary incontinence.

"Everybody wants to believe that PSA screening saved their lives. Well, it may work for some men, but the problem is we cannot tell which men it works for," Dr. Lichtenfeld said. "And it clearly does not work well enough for enough men that it justifies a uniform recommendation that requires men to be screened."

"I don’t believe PSA screening is going to go away," he said. "But I do believe doctors and patients are going to have more appropriate discussions about the potential value." For more of Dr. Lichtenfeld’s perspective, see his blog post.

Dr. Lichtenfeld had no relevant financial disclosures. Dr. Chou received a research grant and travel support from the Agency for Healthcare Research and Quality, which funded the systematic review study.

Evidence does not conclusively support widespread prostate cancer screening of healthy men for reduction of deaths in the long term, according to a systematic review of the literature.

In a move that could spark as much or more controversy as its recommendation against routine mammography for women in their 40s, the U.S. Preventive Services Task Force is taking this evidence and recommending against routine prostate-specific antigen (PSA) testing for healthy men in draft guidelines to be opened to public comment on Oct. 11.

Dr. Roger Chou and his colleagues conducted the review for the task force. They identified randomized trials of PSA-based screening, randomized trials, and cohort studies that compared prostatectomy or radiation therapy with watchful waiting, and large observational studies of perioperative adverse effects associated with surgical treatment.

"Screening based on PSA identifies additional prostate cancers, but most trials found no statistically significant effect on prostate cancer–specific mortality," the authors wrote. "Recent meta-analyses of randomized trials included in this review found no pooled effects of screening on prostate cancer–specific mortality."

In its 2008 recommendations, the task force previously had determined there was insufficient evidence for improved health outcomes (including reduced prostate cancer–specific and all-cause mortality) associated with prostate cancer screening for men younger than 75 years (Ann. Intern. Med. 2008;149:185-91). At the same time, they recommended against screening men 75 years or older, citing enough conclusive evidence to suggest the harms of screening and treatment would outweigh the potential benefits.

The current task force recommendations say no to PSA screening for all healthy men, regardless of age.

Dr. Chou and his colleagues noted the two largest, highest-quality studies in their review yielded conflicting results. The ERSPC (European Randomized Study of Screening for Prostate Cancer) randomly assessed 182,000 men aged 50-74 years to PSA testing or usual care (N. Engl. J. Med. 2009;360:1320-8). After a median 9 years, they found no statistically significant difference between groups in prostate cancer–specific mortality (relative risk, 0.85). A prespecified subgroup analysis did, however, show a 20% reduction in relative risk (0.80).

Investigators for the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial found no significant difference after 10 years in a study of 76,693 men ages 55 to 74 years randomized to PSA screening and digital rectal examinations vs. usual care (relative risk 1.1) (N. Engl. J. Med. 2009;360:1310-9).

"There is a substantial, cultural belief that prostate cancer screening saves lives. That does not reflect what the evidence shows."

"We think the task force reached a reasonable conclusion based on the evidence that they reviewed," said Dr. Len Lichtenfeld, deputy chief medical officer at the American Cancer Society, when asked to comment.

"What I think has to start happening is that doctors and their patients have to have a lot more honest conversations ... that this is not a test that has been shown unequivocally to have value when applied to large numbers of men, as it is being done today," Dr. Lichtenfeld said.

This call for more open and honest communication with patients about the relative risks and benefits of PSA testing is an essential feature of the society’s own 2010 recommendations on prostate cancer screening.

"At that time, we had looked at these same studies and we said we were unable to demonstrate conclusively that prostate cancer screening saves lives," Dr. Lichtenfeld said. "We weren’t advocating for or against [PSA test screening] but thought men needed to know that the evidence that this saves lives was limited and that the potential harms of diagnosis and treatment were real."

Public and physician perceptions, as well as the relative ease of ordering the PSA blood test, are real challenges to overcome, Dr. Lichtenfeld said. "There is a substantial, cultural belief – not only in the community but among health professionals – that prostate cancer screening saves lives. That does not reflect what the evidence shows."

"This is an easy test – it’s a blood test – go ahead and just do it. Why not?" he added. "Well, the ‘why nots’ are the men who are incontinent, the men who are impotent, the men who have radiation cystitis 15 years later [from resultant treatment] and are in so much pain that they can’t function."

The potential harms associated with false-positive tests and subsequent interventions are addressed in the systematic review. For example, about 1 in 200 men who undergo a prostate biopsy as a result of screening experiences a serious infection or urinary retention. The authors also noted that screening is likely to lead to overdiagnosis because the PSA enzyme test can pick up low-risk cancers that, left undetected and untreated, would not have caused death during a man’s lifetime.

Treatment of approximately three men with prostatectomy or seven men with radiation therapy instead of watchful waiting would each result in one additional case of erectile dysfunction, the review revealed. Similarly, treatment of five men with prostatectomy instead of watchful waiting would result in one additional case of urinary incontinence.

"Everybody wants to believe that PSA screening saved their lives. Well, it may work for some men, but the problem is we cannot tell which men it works for," Dr. Lichtenfeld said. "And it clearly does not work well enough for enough men that it justifies a uniform recommendation that requires men to be screened."

"I don’t believe PSA screening is going to go away," he said. "But I do believe doctors and patients are going to have more appropriate discussions about the potential value." For more of Dr. Lichtenfeld’s perspective, see his blog post.

Dr. Lichtenfeld had no relevant financial disclosures. Dr. Chou received a research grant and travel support from the Agency for Healthcare Research and Quality, which funded the systematic review study.

Evidence does not conclusively support widespread prostate cancer screening of healthy men for reduction of deaths in the long term, according to a systematic review of the literature.

In a move that could spark as much or more controversy as its recommendation against routine mammography for women in their 40s, the U.S. Preventive Services Task Force is taking this evidence and recommending against routine prostate-specific antigen (PSA) testing for healthy men in draft guidelines to be opened to public comment on Oct. 11.

Dr. Roger Chou and his colleagues conducted the review for the task force. They identified randomized trials of PSA-based screening, randomized trials, and cohort studies that compared prostatectomy or radiation therapy with watchful waiting, and large observational studies of perioperative adverse effects associated with surgical treatment.

"Screening based on PSA identifies additional prostate cancers, but most trials found no statistically significant effect on prostate cancer–specific mortality," the authors wrote. "Recent meta-analyses of randomized trials included in this review found no pooled effects of screening on prostate cancer–specific mortality."

In its 2008 recommendations, the task force previously had determined there was insufficient evidence for improved health outcomes (including reduced prostate cancer–specific and all-cause mortality) associated with prostate cancer screening for men younger than 75 years (Ann. Intern. Med. 2008;149:185-91). At the same time, they recommended against screening men 75 years or older, citing enough conclusive evidence to suggest the harms of screening and treatment would outweigh the potential benefits.

The current task force recommendations say no to PSA screening for all healthy men, regardless of age.

Dr. Chou and his colleagues noted the two largest, highest-quality studies in their review yielded conflicting results. The ERSPC (European Randomized Study of Screening for Prostate Cancer) randomly assessed 182,000 men aged 50-74 years to PSA testing or usual care (N. Engl. J. Med. 2009;360:1320-8). After a median 9 years, they found no statistically significant difference between groups in prostate cancer–specific mortality (relative risk, 0.85). A prespecified subgroup analysis did, however, show a 20% reduction in relative risk (0.80).

Investigators for the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial found no significant difference after 10 years in a study of 76,693 men ages 55 to 74 years randomized to PSA screening and digital rectal examinations vs. usual care (relative risk 1.1) (N. Engl. J. Med. 2009;360:1310-9).

"There is a substantial, cultural belief that prostate cancer screening saves lives. That does not reflect what the evidence shows."

"We think the task force reached a reasonable conclusion based on the evidence that they reviewed," said Dr. Len Lichtenfeld, deputy chief medical officer at the American Cancer Society, when asked to comment.

"What I think has to start happening is that doctors and their patients have to have a lot more honest conversations ... that this is not a test that has been shown unequivocally to have value when applied to large numbers of men, as it is being done today," Dr. Lichtenfeld said.

This call for more open and honest communication with patients about the relative risks and benefits of PSA testing is an essential feature of the society’s own 2010 recommendations on prostate cancer screening.

"At that time, we had looked at these same studies and we said we were unable to demonstrate conclusively that prostate cancer screening saves lives," Dr. Lichtenfeld said. "We weren’t advocating for or against [PSA test screening] but thought men needed to know that the evidence that this saves lives was limited and that the potential harms of diagnosis and treatment were real."

Public and physician perceptions, as well as the relative ease of ordering the PSA blood test, are real challenges to overcome, Dr. Lichtenfeld said. "There is a substantial, cultural belief – not only in the community but among health professionals – that prostate cancer screening saves lives. That does not reflect what the evidence shows."

"This is an easy test – it’s a blood test – go ahead and just do it. Why not?" he added. "Well, the ‘why nots’ are the men who are incontinent, the men who are impotent, the men who have radiation cystitis 15 years later [from resultant treatment] and are in so much pain that they can’t function."

The potential harms associated with false-positive tests and subsequent interventions are addressed in the systematic review. For example, about 1 in 200 men who undergo a prostate biopsy as a result of screening experiences a serious infection or urinary retention. The authors also noted that screening is likely to lead to overdiagnosis because the PSA enzyme test can pick up low-risk cancers that, left undetected and untreated, would not have caused death during a man’s lifetime.

Treatment of approximately three men with prostatectomy or seven men with radiation therapy instead of watchful waiting would each result in one additional case of erectile dysfunction, the review revealed. Similarly, treatment of five men with prostatectomy instead of watchful waiting would result in one additional case of urinary incontinence.

"Everybody wants to believe that PSA screening saved their lives. Well, it may work for some men, but the problem is we cannot tell which men it works for," Dr. Lichtenfeld said. "And it clearly does not work well enough for enough men that it justifies a uniform recommendation that requires men to be screened."

"I don’t believe PSA screening is going to go away," he said. "But I do believe doctors and patients are going to have more appropriate discussions about the potential value." For more of Dr. Lichtenfeld’s perspective, see his blog post.

Dr. Lichtenfeld had no relevant financial disclosures. Dr. Chou received a research grant and travel support from the Agency for Healthcare Research and Quality, which funded the systematic review study.

The erectile dysfunction drug tadalafil has been approved for treatment of the signs and symptoms of benign prostatic hyperplasia, the Food and Drug Administration announced on Oct. 6.

Tadalafil, the phosphodiesterase-5 (PDE5) inhibitor marketed as Cialis by Eli Lilly, was also approved for treating BPH and erectile dysfunction (ED), when they occur simultaneously, according to the FDA statement. The agency first approved tadalafil for treating erectile dysfunction in 2003.

Men with BPH have an enlarged prostate, which can cause symptoms ranging from difficulty urinating and a weak urine stream to a sudden urge to urinate and more frequent urination.

In two studies of men with BPH, those treated with 5 mg/day of tadalafil experienced statistically significant improvements in symptoms, as indicated by reductions in the total International Prostate Symptom Score (IPSS), when compared with the score in men who received a placebo.

Similarly, in a placebo-controlled study of men with both ED and BPH, those treated with 5 mg/day of tadalafil had improvements in symptoms of both conditions, with the ED improvement measured by the erectile function domain score of the International Index of Erectile Function.

The FDA noted that tadalafil is contraindicated in patients taking nitrates, such as nitroglycerin, because it has been shown to potentiate the hypotensive effects of nitrates. In addition, combining tadalafil with alpha-blockers for treating BPH "is not recommended because the combination has not been adequately studied for the treatment of BPH, and there is a risk of lowering blood pressure," the statement said.

Tadalafil is the first PDE5 inhibitor to be approved for BPH. The eight drugs previously approved for treating BPH symptoms are the 5-alpha reductase inhibitors finasteride (Proscar) and dutasteride (Avodart); alpha-blockers terazosin (Hytrin), doxazosin (Cardura), tamsulosin (Flomax), alfuzosin (Uroxatral), and silodosin (Rapaflo); and the combination of dutasteride plus tamsulosin (Jalyn).

The erectile dysfunction drug tadalafil has been approved for treatment of the signs and symptoms of benign prostatic hyperplasia, the Food and Drug Administration announced on Oct. 6.

Tadalafil, the phosphodiesterase-5 (PDE5) inhibitor marketed as Cialis by Eli Lilly, was also approved for treating BPH and erectile dysfunction (ED), when they occur simultaneously, according to the FDA statement. The agency first approved tadalafil for treating erectile dysfunction in 2003.

Men with BPH have an enlarged prostate, which can cause symptoms ranging from difficulty urinating and a weak urine stream to a sudden urge to urinate and more frequent urination.

In two studies of men with BPH, those treated with 5 mg/day of tadalafil experienced statistically significant improvements in symptoms, as indicated by reductions in the total International Prostate Symptom Score (IPSS), when compared with the score in men who received a placebo.

Similarly, in a placebo-controlled study of men with both ED and BPH, those treated with 5 mg/day of tadalafil had improvements in symptoms of both conditions, with the ED improvement measured by the erectile function domain score of the International Index of Erectile Function.

The FDA noted that tadalafil is contraindicated in patients taking nitrates, such as nitroglycerin, because it has been shown to potentiate the hypotensive effects of nitrates. In addition, combining tadalafil with alpha-blockers for treating BPH "is not recommended because the combination has not been adequately studied for the treatment of BPH, and there is a risk of lowering blood pressure," the statement said.

Tadalafil is the first PDE5 inhibitor to be approved for BPH. The eight drugs previously approved for treating BPH symptoms are the 5-alpha reductase inhibitors finasteride (Proscar) and dutasteride (Avodart); alpha-blockers terazosin (Hytrin), doxazosin (Cardura), tamsulosin (Flomax), alfuzosin (Uroxatral), and silodosin (Rapaflo); and the combination of dutasteride plus tamsulosin (Jalyn).

The erectile dysfunction drug tadalafil has been approved for treatment of the signs and symptoms of benign prostatic hyperplasia, the Food and Drug Administration announced on Oct. 6.

Tadalafil, the phosphodiesterase-5 (PDE5) inhibitor marketed as Cialis by Eli Lilly, was also approved for treating BPH and erectile dysfunction (ED), when they occur simultaneously, according to the FDA statement. The agency first approved tadalafil for treating erectile dysfunction in 2003.

Men with BPH have an enlarged prostate, which can cause symptoms ranging from difficulty urinating and a weak urine stream to a sudden urge to urinate and more frequent urination.

In two studies of men with BPH, those treated with 5 mg/day of tadalafil experienced statistically significant improvements in symptoms, as indicated by reductions in the total International Prostate Symptom Score (IPSS), when compared with the score in men who received a placebo.

Similarly, in a placebo-controlled study of men with both ED and BPH, those treated with 5 mg/day of tadalafil had improvements in symptoms of both conditions, with the ED improvement measured by the erectile function domain score of the International Index of Erectile Function.

The FDA noted that tadalafil is contraindicated in patients taking nitrates, such as nitroglycerin, because it has been shown to potentiate the hypotensive effects of nitrates. In addition, combining tadalafil with alpha-blockers for treating BPH "is not recommended because the combination has not been adequately studied for the treatment of BPH, and there is a risk of lowering blood pressure," the statement said.

Tadalafil is the first PDE5 inhibitor to be approved for BPH. The eight drugs previously approved for treating BPH symptoms are the 5-alpha reductase inhibitors finasteride (Proscar) and dutasteride (Avodart); alpha-blockers terazosin (Hytrin), doxazosin (Cardura), tamsulosin (Flomax), alfuzosin (Uroxatral), and silodosin (Rapaflo); and the combination of dutasteride plus tamsulosin (Jalyn).