Urology

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).