Nephrology

Enzalutamide – formerly known as MDV3100 – prolonged overall survival by a median of 4.8 months and reduced the risk of death by 37%, according to newly published data from the phase III, placebo-controlled AFFIRM study of men with metastatic, castration-resistant prostate cancer.

An experimental oral agent inhibiting signaling by the androgen receptor, enzalutamide is under priority review by the Food and Drug Administration with an action date of Nov. 22, 2012, trial sponsors Medivation and Astellas Pharma have announced.

The randomized, double-blind AFFIRM trial underpins their New Drug Application in men with castration-resistant prostate cancer previously treated with docetaxel (Taxotere)-based chemotherapy. Based on the findings, an independent data and safety monitoring committee halted the trial, and those receiving placebo were offered treatment with enzalutamide.

At the time of a planned interim analysis, median overall survival was 18.4 months among 800 men randomized to receive a daily 160-mg oral dose of enzalutamide. It was 13.6 months in 399 men who received a placebo, Dr. Howard I. Scher of Memorial Sloan-Kettering Cancer Center, New York, and his colleagues reported "online first" Aug. 15 in the New England Journal of Medicine.

The drug was also superior to placebo with respect to all secondary end points, including prostate-specific antigen (PSA) response rate (54% vs. 2%), soft-tissue response rate (29% vs. 4%), FACT-P quality of life response (43% vs. 18%), time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25), radiographic progression-free survival (8.3 vs. 2.9 months; HR, 0.40), and time to first skeletal-related event (16.7 vs. 13.3 months; HR, 0.69). The results were consistent across all subgroups, and were maintained after adjustment for stratification factors and baseline prognostic factors.

They confirm that the androgen receptor and androgen-receptor signaling have a central role in the progression of prostate cancer "throughout the spectrum of disease," the investigators said (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).

Participants in AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) were men with progressive prostate cancer that had been treated with one or two chemotherapy regimens, at least one of which included docetaxel. The subjects, who were enrolled at 156 sites in 15 countries between September 2009 and November 2010, had a histologically or cytologically confirmed diagnosis of prostate cancer and testosterone levels of less than 50 ng/dL.

Despite longer observation with enzalutamide, adverse event rates were generally similar between the treatment and control groups; of note, those in the enzalutamide group experienced a lower incidence of adverse events of grade 3 or above (45.3% vs. 53.1%).

"The median time to any initial adverse event of grade 3 or higher was 8.4 months longer in the enzalutamide group than in the placebo groups (12.6 vs. 4.2 months) owing to improved long-term control of disease-related symptoms without an increase in drug reactions of grade 3 or higher," the investigators said.

More patients in the treatment group, however, experienced fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache. In addition, seizures occurred in five (0.6%) patients in the treatment group, whereas no seizures were reported in those receiving placebo. Predisposing factors were present in several patients experiencing seizures, including brain metastases in two patients, inadvertent IV administration of lidocaine in one patient, and brain atrophy in one patient.

The findings of this study substantiate preclinical work showing that androgen-receptor signaling contributes to disease progression despite castrate levels of testosterone and despite prior treatment with conventional antiandrogen therapy, the investigators said. This – coupled with other recent findings – establishes that these tumors are not refractory to hormones as previously thought, even after chemotherapy has been administered, they added.

"This novel agent is anticipated to join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with castration-resistant prostate cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy," they concluded, noting that clinical trials of the drug in earlier-stage prostate cancer are ongoing.

Earlier studies of enzalutamide have been announced in patients with metastatic chemotherapy-naive prostate cancer.

This study was supported by Medivation, the maker of enzalutamide, and Astellas Pharma Global Development. Dr. Scher reported relationships with Aragon Pharmaceuticals, Centocor Ortho Biotech, and other companies. He holds stock or stock options in Johnson & Johnson. Other study authors also made disclosures; details are available with the full text of the article at NEJM.org.

Dr. Scher presented results from the AFFIRM trial at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium in February 2012.

Click here to see a 2009 video of Dr. Scher discussing the rationale behind MDV3100 efficacy in advanced prostate cancer.

Enzalutamide – formerly known as MDV3100 – prolonged overall survival by a median of 4.8 months and reduced the risk of death by 37%, according to newly published data from the phase III, placebo-controlled AFFIRM study of men with metastatic, castration-resistant prostate cancer.

An experimental oral agent inhibiting signaling by the androgen receptor, enzalutamide is under priority review by the Food and Drug Administration with an action date of Nov. 22, 2012, trial sponsors Medivation and Astellas Pharma have announced.

The randomized, double-blind AFFIRM trial underpins their New Drug Application in men with castration-resistant prostate cancer previously treated with docetaxel (Taxotere)-based chemotherapy. Based on the findings, an independent data and safety monitoring committee halted the trial, and those receiving placebo were offered treatment with enzalutamide.

At the time of a planned interim analysis, median overall survival was 18.4 months among 800 men randomized to receive a daily 160-mg oral dose of enzalutamide. It was 13.6 months in 399 men who received a placebo, Dr. Howard I. Scher of Memorial Sloan-Kettering Cancer Center, New York, and his colleagues reported "online first" Aug. 15 in the New England Journal of Medicine.

The drug was also superior to placebo with respect to all secondary end points, including prostate-specific antigen (PSA) response rate (54% vs. 2%), soft-tissue response rate (29% vs. 4%), FACT-P quality of life response (43% vs. 18%), time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25), radiographic progression-free survival (8.3 vs. 2.9 months; HR, 0.40), and time to first skeletal-related event (16.7 vs. 13.3 months; HR, 0.69). The results were consistent across all subgroups, and were maintained after adjustment for stratification factors and baseline prognostic factors.

They confirm that the androgen receptor and androgen-receptor signaling have a central role in the progression of prostate cancer "throughout the spectrum of disease," the investigators said (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).

Participants in AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) were men with progressive prostate cancer that had been treated with one or two chemotherapy regimens, at least one of which included docetaxel. The subjects, who were enrolled at 156 sites in 15 countries between September 2009 and November 2010, had a histologically or cytologically confirmed diagnosis of prostate cancer and testosterone levels of less than 50 ng/dL.

Despite longer observation with enzalutamide, adverse event rates were generally similar between the treatment and control groups; of note, those in the enzalutamide group experienced a lower incidence of adverse events of grade 3 or above (45.3% vs. 53.1%).

"The median time to any initial adverse event of grade 3 or higher was 8.4 months longer in the enzalutamide group than in the placebo groups (12.6 vs. 4.2 months) owing to improved long-term control of disease-related symptoms without an increase in drug reactions of grade 3 or higher," the investigators said.

More patients in the treatment group, however, experienced fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache. In addition, seizures occurred in five (0.6%) patients in the treatment group, whereas no seizures were reported in those receiving placebo. Predisposing factors were present in several patients experiencing seizures, including brain metastases in two patients, inadvertent IV administration of lidocaine in one patient, and brain atrophy in one patient.

The findings of this study substantiate preclinical work showing that androgen-receptor signaling contributes to disease progression despite castrate levels of testosterone and despite prior treatment with conventional antiandrogen therapy, the investigators said. This – coupled with other recent findings – establishes that these tumors are not refractory to hormones as previously thought, even after chemotherapy has been administered, they added.

"This novel agent is anticipated to join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with castration-resistant prostate cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy," they concluded, noting that clinical trials of the drug in earlier-stage prostate cancer are ongoing.

Earlier studies of enzalutamide have been announced in patients with metastatic chemotherapy-naive prostate cancer.

This study was supported by Medivation, the maker of enzalutamide, and Astellas Pharma Global Development. Dr. Scher reported relationships with Aragon Pharmaceuticals, Centocor Ortho Biotech, and other companies. He holds stock or stock options in Johnson & Johnson. Other study authors also made disclosures; details are available with the full text of the article at NEJM.org.

Dr. Scher presented results from the AFFIRM trial at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium in February 2012.

Click here to see a 2009 video of Dr. Scher discussing the rationale behind MDV3100 efficacy in advanced prostate cancer.

Enzalutamide – formerly known as MDV3100 – prolonged overall survival by a median of 4.8 months and reduced the risk of death by 37%, according to newly published data from the phase III, placebo-controlled AFFIRM study of men with metastatic, castration-resistant prostate cancer.

An experimental oral agent inhibiting signaling by the androgen receptor, enzalutamide is under priority review by the Food and Drug Administration with an action date of Nov. 22, 2012, trial sponsors Medivation and Astellas Pharma have announced.

The randomized, double-blind AFFIRM trial underpins their New Drug Application in men with castration-resistant prostate cancer previously treated with docetaxel (Taxotere)-based chemotherapy. Based on the findings, an independent data and safety monitoring committee halted the trial, and those receiving placebo were offered treatment with enzalutamide.

At the time of a planned interim analysis, median overall survival was 18.4 months among 800 men randomized to receive a daily 160-mg oral dose of enzalutamide. It was 13.6 months in 399 men who received a placebo, Dr. Howard I. Scher of Memorial Sloan-Kettering Cancer Center, New York, and his colleagues reported "online first" Aug. 15 in the New England Journal of Medicine.

The drug was also superior to placebo with respect to all secondary end points, including prostate-specific antigen (PSA) response rate (54% vs. 2%), soft-tissue response rate (29% vs. 4%), FACT-P quality of life response (43% vs. 18%), time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25), radiographic progression-free survival (8.3 vs. 2.9 months; HR, 0.40), and time to first skeletal-related event (16.7 vs. 13.3 months; HR, 0.69). The results were consistent across all subgroups, and were maintained after adjustment for stratification factors and baseline prognostic factors.

They confirm that the androgen receptor and androgen-receptor signaling have a central role in the progression of prostate cancer "throughout the spectrum of disease," the investigators said (N. Engl. J. Med. 2012 [doi: 10.1056/NEJMoa1207506]).

Participants in AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) were men with progressive prostate cancer that had been treated with one or two chemotherapy regimens, at least one of which included docetaxel. The subjects, who were enrolled at 156 sites in 15 countries between September 2009 and November 2010, had a histologically or cytologically confirmed diagnosis of prostate cancer and testosterone levels of less than 50 ng/dL.

Despite longer observation with enzalutamide, adverse event rates were generally similar between the treatment and control groups; of note, those in the enzalutamide group experienced a lower incidence of adverse events of grade 3 or above (45.3% vs. 53.1%).

"The median time to any initial adverse event of grade 3 or higher was 8.4 months longer in the enzalutamide group than in the placebo groups (12.6 vs. 4.2 months) owing to improved long-term control of disease-related symptoms without an increase in drug reactions of grade 3 or higher," the investigators said.

More patients in the treatment group, however, experienced fatigue, diarrhea, hot flashes, musculoskeletal pain, and headache. In addition, seizures occurred in five (0.6%) patients in the treatment group, whereas no seizures were reported in those receiving placebo. Predisposing factors were present in several patients experiencing seizures, including brain metastases in two patients, inadvertent IV administration of lidocaine in one patient, and brain atrophy in one patient.

The findings of this study substantiate preclinical work showing that androgen-receptor signaling contributes to disease progression despite castrate levels of testosterone and despite prior treatment with conventional antiandrogen therapy, the investigators said. This – coupled with other recent findings – establishes that these tumors are not refractory to hormones as previously thought, even after chemotherapy has been administered, they added.

"This novel agent is anticipated to join the therapeutic armamentarium of anticancer drugs with diverse mechanisms of action that confer a survival benefit in men with castration-resistant prostate cancer. These results validate androgen-receptor signaling as a key therapeutic target throughout the clinical spectrum of prostate cancer, including in men who have received previous chemotherapy," they concluded, noting that clinical trials of the drug in earlier-stage prostate cancer are ongoing.

Earlier studies of enzalutamide have been announced in patients with metastatic chemotherapy-naive prostate cancer.

This study was supported by Medivation, the maker of enzalutamide, and Astellas Pharma Global Development. Dr. Scher reported relationships with Aragon Pharmaceuticals, Centocor Ortho Biotech, and other companies. He holds stock or stock options in Johnson & Johnson. Other study authors also made disclosures; details are available with the full text of the article at NEJM.org.

Dr. Scher presented results from the AFFIRM trial at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium in February 2012.

Click here to see a 2009 video of Dr. Scher discussing the rationale behind MDV3100 efficacy in advanced prostate cancer.

Amidst growing controversy over prostate-specific antigen screening, a new analysis raises the possibility that more men would be diagnosed with advanced prostate cancer without early testing.

The incidence of men presenting with prostate cancer that has already metastasized is three times lower than would be expected, if incidence figures from the pre-PSA era were extrapolated to today’s U.S. population, according to the report published online July 30 in Cancer.

Based on data for diagnoses made from 1983 to 1985, clinicians today could expect to see approximately 25,000 cases of prostate cancer that has already metastasized at presentation. But the actual number of such cases is three times lower, at approximately 8,000, said Emil N. Scosyrev, Ph.D., of the department of urology, University of Rochester (N.Y.) Medical Center, and his associates.

It would be erroneous to assume a causal relationship from these observational data, however, or to conclude that PSA testing alone contributed to this reduction. Temporal changes in other factors that influence prostate cancer almost certainly have contributed to the decrease, the investigators noted.

"Our current findings must be viewed primarily as a description of observed time trends rather than as definitive tests of causal hypotheses about screening," they said.

Dr. Scosyrev and his colleagues assessed age- and race-specific annual rates of presenting with metastatic prostate cancer from 1983 to 2008, using data from Surveillance, Epidemiology, and End Results (SEER) Program registries in San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta. The Food and Drug Administration approved PSA testing for clinical use in 1986, so the researchers compared prostate cancer data in the pre-PSA era (1983-1985) to that in the PSA era (1986-2008).

When men of all ages and races were considered together, 2,277 men in the SEER registries would be expected to present with metastatic prostate cancer in 2008, the most recent year for which data are available. However, the actual number who presented with metastatic prostate cancer that year was only 739 in the SEER registries.

These registries are thought to capture approximately 25% of all cases of prostate cancer in the U.S. each year. When the study figures are extrapolated to the entire U.S. population in 2008, only about 8,000 cases actually occurred when about 25,000 would have been expected to occur. This suggests that 17,000 cases of metastatic prostate cancer at presentation were prevented in 2008, the investigators said (Cancer 2012 July 30 [doi:1002/cncr.27503]).

It is important to note that other factors besides PSA testing also changed during this time period, which could not be accounted for in this observational study, the authors noted.

For example, obesity may be associated with an increased risk of prostate cancer, and the prevalence of obesity has certainly increased since 1983. "Hence, if obesity had a major influence on the incidence of presenting with [metastatic prostate cancer] during the study period, then the true benefit of screening may be underestimated in our study," Dr. Scosyrev and his associates said.

Medical imaging techniques also have improved over time, however, enabling earlier diagnosis of prostate cancer in more recent years.

"In particular, in the pre-PSA era, CT and bone scans were not as widespread (or of the same quality) as they are today, MRI and PET-CT were not available, and metastatic prostate cancer often was diagnosed because of symptomatic progression of metastatic lesions. In contrast, in the modern PSA era, metastatic prostate cancer is often diagnosed on staging imaging for high-risk disease," the authors added.

Another issue that must be considered, they said, "is the potential lead-time effect resulting from screening." To that end they offered the hypothetical case of a man who develops organ-confined prostate cancer at 70 years of age, micrometastates at 75, and overt metastatic disease at 80, and then dies of prostate cancer when he is 82 years of age.

"If this man were screened between ages 70 and 75 years, then his prostate cancer potentially could be cured. Conversely, screening between ages 75 and 80 years would result in an earlier diagnosis, but not in a cure," they wrote, going on to note substantial stage shifts in newly diagnosed prostate cancer after mass screening programs were introduced.

Because metastatic prostate cancer is highly symptomatic and "rapidly fatal," the authors said they "believe that many men with this disease would likely benefit from earlier diagnosis, either in terms of improved survival or at least from the palliative perspective (e.g., prevention or delay of skeletal complications)."

It also is important to remember that PSA screening has led to overdiagnosis and overtreatment of nonaggressive prostate cancer, another issue that could not be addressed in this study, they added.

"In particular, we could not determine the number of men who would need to undergo a biopsy for an elevated PSA and [be] treated for screen-detected prostate cancer to prevent one case of presenting with metastatic disease. This must be recognized as a limitation of the current study," the researchers said. Likewise, they could not investigate the optimal age to start or to stop screening.

This study was supported by the Ashley Family Foundation. No financial disclosures were reported.

Amidst growing controversy over prostate-specific antigen screening, a new analysis raises the possibility that more men would be diagnosed with advanced prostate cancer without early testing.

The incidence of men presenting with prostate cancer that has already metastasized is three times lower than would be expected, if incidence figures from the pre-PSA era were extrapolated to today’s U.S. population, according to the report published online July 30 in Cancer.

Based on data for diagnoses made from 1983 to 1985, clinicians today could expect to see approximately 25,000 cases of prostate cancer that has already metastasized at presentation. But the actual number of such cases is three times lower, at approximately 8,000, said Emil N. Scosyrev, Ph.D., of the department of urology, University of Rochester (N.Y.) Medical Center, and his associates.

It would be erroneous to assume a causal relationship from these observational data, however, or to conclude that PSA testing alone contributed to this reduction. Temporal changes in other factors that influence prostate cancer almost certainly have contributed to the decrease, the investigators noted.

"Our current findings must be viewed primarily as a description of observed time trends rather than as definitive tests of causal hypotheses about screening," they said.

Dr. Scosyrev and his colleagues assessed age- and race-specific annual rates of presenting with metastatic prostate cancer from 1983 to 2008, using data from Surveillance, Epidemiology, and End Results (SEER) Program registries in San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta. The Food and Drug Administration approved PSA testing for clinical use in 1986, so the researchers compared prostate cancer data in the pre-PSA era (1983-1985) to that in the PSA era (1986-2008).

When men of all ages and races were considered together, 2,277 men in the SEER registries would be expected to present with metastatic prostate cancer in 2008, the most recent year for which data are available. However, the actual number who presented with metastatic prostate cancer that year was only 739 in the SEER registries.

These registries are thought to capture approximately 25% of all cases of prostate cancer in the U.S. each year. When the study figures are extrapolated to the entire U.S. population in 2008, only about 8,000 cases actually occurred when about 25,000 would have been expected to occur. This suggests that 17,000 cases of metastatic prostate cancer at presentation were prevented in 2008, the investigators said (Cancer 2012 July 30 [doi:1002/cncr.27503]).

It is important to note that other factors besides PSA testing also changed during this time period, which could not be accounted for in this observational study, the authors noted.

For example, obesity may be associated with an increased risk of prostate cancer, and the prevalence of obesity has certainly increased since 1983. "Hence, if obesity had a major influence on the incidence of presenting with [metastatic prostate cancer] during the study period, then the true benefit of screening may be underestimated in our study," Dr. Scosyrev and his associates said.

Medical imaging techniques also have improved over time, however, enabling earlier diagnosis of prostate cancer in more recent years.

"In particular, in the pre-PSA era, CT and bone scans were not as widespread (or of the same quality) as they are today, MRI and PET-CT were not available, and metastatic prostate cancer often was diagnosed because of symptomatic progression of metastatic lesions. In contrast, in the modern PSA era, metastatic prostate cancer is often diagnosed on staging imaging for high-risk disease," the authors added.

Another issue that must be considered, they said, "is the potential lead-time effect resulting from screening." To that end they offered the hypothetical case of a man who develops organ-confined prostate cancer at 70 years of age, micrometastates at 75, and overt metastatic disease at 80, and then dies of prostate cancer when he is 82 years of age.

"If this man were screened between ages 70 and 75 years, then his prostate cancer potentially could be cured. Conversely, screening between ages 75 and 80 years would result in an earlier diagnosis, but not in a cure," they wrote, going on to note substantial stage shifts in newly diagnosed prostate cancer after mass screening programs were introduced.

Because metastatic prostate cancer is highly symptomatic and "rapidly fatal," the authors said they "believe that many men with this disease would likely benefit from earlier diagnosis, either in terms of improved survival or at least from the palliative perspective (e.g., prevention or delay of skeletal complications)."

It also is important to remember that PSA screening has led to overdiagnosis and overtreatment of nonaggressive prostate cancer, another issue that could not be addressed in this study, they added.

"In particular, we could not determine the number of men who would need to undergo a biopsy for an elevated PSA and [be] treated for screen-detected prostate cancer to prevent one case of presenting with metastatic disease. This must be recognized as a limitation of the current study," the researchers said. Likewise, they could not investigate the optimal age to start or to stop screening.

This study was supported by the Ashley Family Foundation. No financial disclosures were reported.

Amidst growing controversy over prostate-specific antigen screening, a new analysis raises the possibility that more men would be diagnosed with advanced prostate cancer without early testing.

The incidence of men presenting with prostate cancer that has already metastasized is three times lower than would be expected, if incidence figures from the pre-PSA era were extrapolated to today’s U.S. population, according to the report published online July 30 in Cancer.

Based on data for diagnoses made from 1983 to 1985, clinicians today could expect to see approximately 25,000 cases of prostate cancer that has already metastasized at presentation. But the actual number of such cases is three times lower, at approximately 8,000, said Emil N. Scosyrev, Ph.D., of the department of urology, University of Rochester (N.Y.) Medical Center, and his associates.

It would be erroneous to assume a causal relationship from these observational data, however, or to conclude that PSA testing alone contributed to this reduction. Temporal changes in other factors that influence prostate cancer almost certainly have contributed to the decrease, the investigators noted.

"Our current findings must be viewed primarily as a description of observed time trends rather than as definitive tests of causal hypotheses about screening," they said.

Dr. Scosyrev and his colleagues assessed age- and race-specific annual rates of presenting with metastatic prostate cancer from 1983 to 2008, using data from Surveillance, Epidemiology, and End Results (SEER) Program registries in San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta. The Food and Drug Administration approved PSA testing for clinical use in 1986, so the researchers compared prostate cancer data in the pre-PSA era (1983-1985) to that in the PSA era (1986-2008).

When men of all ages and races were considered together, 2,277 men in the SEER registries would be expected to present with metastatic prostate cancer in 2008, the most recent year for which data are available. However, the actual number who presented with metastatic prostate cancer that year was only 739 in the SEER registries.

These registries are thought to capture approximately 25% of all cases of prostate cancer in the U.S. each year. When the study figures are extrapolated to the entire U.S. population in 2008, only about 8,000 cases actually occurred when about 25,000 would have been expected to occur. This suggests that 17,000 cases of metastatic prostate cancer at presentation were prevented in 2008, the investigators said (Cancer 2012 July 30 [doi:1002/cncr.27503]).

It is important to note that other factors besides PSA testing also changed during this time period, which could not be accounted for in this observational study, the authors noted.

For example, obesity may be associated with an increased risk of prostate cancer, and the prevalence of obesity has certainly increased since 1983. "Hence, if obesity had a major influence on the incidence of presenting with [metastatic prostate cancer] during the study period, then the true benefit of screening may be underestimated in our study," Dr. Scosyrev and his associates said.

Medical imaging techniques also have improved over time, however, enabling earlier diagnosis of prostate cancer in more recent years.

"In particular, in the pre-PSA era, CT and bone scans were not as widespread (or of the same quality) as they are today, MRI and PET-CT were not available, and metastatic prostate cancer often was diagnosed because of symptomatic progression of metastatic lesions. In contrast, in the modern PSA era, metastatic prostate cancer is often diagnosed on staging imaging for high-risk disease," the authors added.

Another issue that must be considered, they said, "is the potential lead-time effect resulting from screening." To that end they offered the hypothetical case of a man who develops organ-confined prostate cancer at 70 years of age, micrometastates at 75, and overt metastatic disease at 80, and then dies of prostate cancer when he is 82 years of age.

"If this man were screened between ages 70 and 75 years, then his prostate cancer potentially could be cured. Conversely, screening between ages 75 and 80 years would result in an earlier diagnosis, but not in a cure," they wrote, going on to note substantial stage shifts in newly diagnosed prostate cancer after mass screening programs were introduced.

Because metastatic prostate cancer is highly symptomatic and "rapidly fatal," the authors said they "believe that many men with this disease would likely benefit from earlier diagnosis, either in terms of improved survival or at least from the palliative perspective (e.g., prevention or delay of skeletal complications)."

It also is important to remember that PSA screening has led to overdiagnosis and overtreatment of nonaggressive prostate cancer, another issue that could not be addressed in this study, they added.

"In particular, we could not determine the number of men who would need to undergo a biopsy for an elevated PSA and [be] treated for screen-detected prostate cancer to prevent one case of presenting with metastatic disease. This must be recognized as a limitation of the current study," the researchers said. Likewise, they could not investigate the optimal age to start or to stop screening.

This study was supported by the Ashley Family Foundation. No financial disclosures were reported.

Anemia drugs sold under the brand names of Procrit, Aranesp, and Epogen come under new and scathing scrutiny in an exclusive report published July 20 in the Washington Post.

The investigative article by Peter Whoriskey alleges that pharmaceutical giants Amgen and Johnson & Johnson "wildly overstated" benefits while understating potentially lethal side effects of these erythropoiesis-stimulating agents (ESAs).

While safety trials required by the Food and Drug Administration lagged for more than a decade, the companies successfully lobbied for a payment system that rewarded physicians for giving large doses of their high-priced drugs, according to the report.

Use of the drugs declined in recent years after studies showed higher mortality rates in patients given ESAs. Epoetin-alfa (Procrit and Epogen) and darbepoetin alfa (Aranesp) are used to treat anemia in patients undergoing cancer chemotherapy or dialysis for chronic kidney disease.

Anemia drugs sold under the brand names of Procrit, Aranesp, and Epogen come under new and scathing scrutiny in an exclusive report published July 20 in the Washington Post.

The investigative article by Peter Whoriskey alleges that pharmaceutical giants Amgen and Johnson & Johnson "wildly overstated" benefits while understating potentially lethal side effects of these erythropoiesis-stimulating agents (ESAs).

While safety trials required by the Food and Drug Administration lagged for more than a decade, the companies successfully lobbied for a payment system that rewarded physicians for giving large doses of their high-priced drugs, according to the report.

Use of the drugs declined in recent years after studies showed higher mortality rates in patients given ESAs. Epoetin-alfa (Procrit and Epogen) and darbepoetin alfa (Aranesp) are used to treat anemia in patients undergoing cancer chemotherapy or dialysis for chronic kidney disease.

Anemia drugs sold under the brand names of Procrit, Aranesp, and Epogen come under new and scathing scrutiny in an exclusive report published July 20 in the Washington Post.

The investigative article by Peter Whoriskey alleges that pharmaceutical giants Amgen and Johnson & Johnson "wildly overstated" benefits while understating potentially lethal side effects of these erythropoiesis-stimulating agents (ESAs).

While safety trials required by the Food and Drug Administration lagged for more than a decade, the companies successfully lobbied for a payment system that rewarded physicians for giving large doses of their high-priced drugs, according to the report.

Use of the drugs declined in recent years after studies showed higher mortality rates in patients given ESAs. Epoetin-alfa (Procrit and Epogen) and darbepoetin alfa (Aranesp) are used to treat anemia in patients undergoing cancer chemotherapy or dialysis for chronic kidney disease.

Compared with observation, radical prostatectomy failed to reduce either disease-specific or all-cause mortality significantly among men with clinically localized prostate cancer that was diagnosed early in the era of PSA testing, according to a report published online July 18 in the New England Journal of Medicine.

The lack of benefit from prostatectomy was "particularly robust" among men with a PSA value of 10 ng/mL or less, and in those with low-risk tumors. "Our findings support observation for men with localized prostate cancer, especially those who have a low PSA value and those who have low-risk disease," said Dr. Timothy J. Wilt and his associates in the PIVOT (Prostate Cancer Intervention Versus Observation) study.

PIVOT was a randomized trial designed specifically to compare outcomes after radical prostatectomy with those after observation. It involved 731 patients who were diagnosed as having clinically localized prostate cancer in 1994-2002, early in the PSA-testing era.

The participants were treated at 44 Veterans Affairs centers and eight National Cancer Institute sites across the country. Investigators had planned to randomize 2,000 men, but scaled down the trial because of "recruitment difficulties." In all, 364 men were randomly assigned to radical prostatectomy using a technique chosen at the surgeon’s discretion, and 367 were assigned to observation.

Of these, 281 in the surgery group and 36 in the observation group underwent radical prostatectomy, whereas 53 and 292, respectively, underwent observation. Other interventions included external-beam radiotherapy and brachytherapy. Any additional interventions were decided upon by the patient and his physician.

Investigators followed participants every 6 months for 8-15 years. Patients (mean age, 67 years) underwent bone scans every 5 years. Approximately one-third of the patients were black, and 85% were fully independent in performing the activities of daily living.

Some 40% of the men were found to have low-risk tumors, 34% had intermediate-risk, 21% had high-risk, and 5% had unknown risk because of missing data. Findings were reported on an intention-to-treat basis.

During a median follow-up of 10 years, 47.0% of the surgical group and 49.9% of the observation group died from any cause, a difference that was not significant. Median survival was 13.0 years with radical prostatectomy and 12.4 years with observation, also an insignificant difference.

"The absolute reduction in mortality with radical prostatectomy was not significant at any interval and declined over time, from 4.6 percentage points at 4 years to 2.9 percentage points at 12 years," the investigators said (New Engl. J. Med. 2012 July 19 [doi:10.1056/NEJMoa1113162]).

This trend suggests that longer follow-up would not alter the results, added Dr. Wilt of the Center for Chronic Disease Outcomes Research of the Minneapolis VA Health Care System and his coauthors.

The results were similar with prostate cancer–specific mortality.

Death that was definitely attributable to prostate cancer or its treatment occurred in 4.4% of the men in the surgical group and 4.9% of those in the observation group, a nonsignificant difference. Disease-specific mortality was identical between the two groups at 4 years and was not significantly different at 12 years.

Subgroup analyses showed that radical prostatectomy did not improve all-cause mortality according to patient age, race, performance status, or comorbidities, nor did it vary by tumor score on the Gleason histologic scale. However, the surgery was associated with a slight (13.2%) decline in all-cause mortality in the subgroup of men who had PSA values greater than 10 ng/mL.

The finding of no mortality benefit was particularly strong among men with low-risk cancers (defined as those with PSA values of 10 ng/mL or lower, a score of 6 or less on the Gleason scale, and a stage T1a-c or T2a tumor). In this subgroup, prostatectomy was actually associated with a nonsignificant 15% increase in mortality, Dr. Wilt and his associates said.

Perioperative complications, including one death, developed in 21.4% of men in the radical prostatectomy group. Wound infection was the most common complication, occurring in 4.3% of the men. Other problems included urinary tract infection, bleeding requiring transfusion, and the need for urinary catheterization for more than 30 days.

At 2 years, urinary incontinence and erectile dysfunction were more common among patients in the surgical group than in those in the observation group.

This study was supported by the Department of Veterans Affairs, the National Cancer Institute, and the Agency for Healthcare Quality and Research. Dr. Wilt reported no financial conflicts of interest, and his associates reported ties to numerous industry sources.

Compared with observation, radical prostatectomy failed to reduce either disease-specific or all-cause mortality significantly among men with clinically localized prostate cancer that was diagnosed early in the era of PSA testing, according to a report published online July 18 in the New England Journal of Medicine.

The lack of benefit from prostatectomy was "particularly robust" among men with a PSA value of 10 ng/mL or less, and in those with low-risk tumors. "Our findings support observation for men with localized prostate cancer, especially those who have a low PSA value and those who have low-risk disease," said Dr. Timothy J. Wilt and his associates in the PIVOT (Prostate Cancer Intervention Versus Observation) study.

PIVOT was a randomized trial designed specifically to compare outcomes after radical prostatectomy with those after observation. It involved 731 patients who were diagnosed as having clinically localized prostate cancer in 1994-2002, early in the PSA-testing era.

The participants were treated at 44 Veterans Affairs centers and eight National Cancer Institute sites across the country. Investigators had planned to randomize 2,000 men, but scaled down the trial because of "recruitment difficulties." In all, 364 men were randomly assigned to radical prostatectomy using a technique chosen at the surgeon’s discretion, and 367 were assigned to observation.

Of these, 281 in the surgery group and 36 in the observation group underwent radical prostatectomy, whereas 53 and 292, respectively, underwent observation. Other interventions included external-beam radiotherapy and brachytherapy. Any additional interventions were decided upon by the patient and his physician.

Investigators followed participants every 6 months for 8-15 years. Patients (mean age, 67 years) underwent bone scans every 5 years. Approximately one-third of the patients were black, and 85% were fully independent in performing the activities of daily living.

Some 40% of the men were found to have low-risk tumors, 34% had intermediate-risk, 21% had high-risk, and 5% had unknown risk because of missing data. Findings were reported on an intention-to-treat basis.

During a median follow-up of 10 years, 47.0% of the surgical group and 49.9% of the observation group died from any cause, a difference that was not significant. Median survival was 13.0 years with radical prostatectomy and 12.4 years with observation, also an insignificant difference.

"The absolute reduction in mortality with radical prostatectomy was not significant at any interval and declined over time, from 4.6 percentage points at 4 years to 2.9 percentage points at 12 years," the investigators said (New Engl. J. Med. 2012 July 19 [doi:10.1056/NEJMoa1113162]).

This trend suggests that longer follow-up would not alter the results, added Dr. Wilt of the Center for Chronic Disease Outcomes Research of the Minneapolis VA Health Care System and his coauthors.

The results were similar with prostate cancer–specific mortality.

Death that was definitely attributable to prostate cancer or its treatment occurred in 4.4% of the men in the surgical group and 4.9% of those in the observation group, a nonsignificant difference. Disease-specific mortality was identical between the two groups at 4 years and was not significantly different at 12 years.

Subgroup analyses showed that radical prostatectomy did not improve all-cause mortality according to patient age, race, performance status, or comorbidities, nor did it vary by tumor score on the Gleason histologic scale. However, the surgery was associated with a slight (13.2%) decline in all-cause mortality in the subgroup of men who had PSA values greater than 10 ng/mL.

The finding of no mortality benefit was particularly strong among men with low-risk cancers (defined as those with PSA values of 10 ng/mL or lower, a score of 6 or less on the Gleason scale, and a stage T1a-c or T2a tumor). In this subgroup, prostatectomy was actually associated with a nonsignificant 15% increase in mortality, Dr. Wilt and his associates said.

Perioperative complications, including one death, developed in 21.4% of men in the radical prostatectomy group. Wound infection was the most common complication, occurring in 4.3% of the men. Other problems included urinary tract infection, bleeding requiring transfusion, and the need for urinary catheterization for more than 30 days.

At 2 years, urinary incontinence and erectile dysfunction were more common among patients in the surgical group than in those in the observation group.

This study was supported by the Department of Veterans Affairs, the National Cancer Institute, and the Agency for Healthcare Quality and Research. Dr. Wilt reported no financial conflicts of interest, and his associates reported ties to numerous industry sources.

Compared with observation, radical prostatectomy failed to reduce either disease-specific or all-cause mortality significantly among men with clinically localized prostate cancer that was diagnosed early in the era of PSA testing, according to a report published online July 18 in the New England Journal of Medicine.

The lack of benefit from prostatectomy was "particularly robust" among men with a PSA value of 10 ng/mL or less, and in those with low-risk tumors. "Our findings support observation for men with localized prostate cancer, especially those who have a low PSA value and those who have low-risk disease," said Dr. Timothy J. Wilt and his associates in the PIVOT (Prostate Cancer Intervention Versus Observation) study.

PIVOT was a randomized trial designed specifically to compare outcomes after radical prostatectomy with those after observation. It involved 731 patients who were diagnosed as having clinically localized prostate cancer in 1994-2002, early in the PSA-testing era.

The participants were treated at 44 Veterans Affairs centers and eight National Cancer Institute sites across the country. Investigators had planned to randomize 2,000 men, but scaled down the trial because of "recruitment difficulties." In all, 364 men were randomly assigned to radical prostatectomy using a technique chosen at the surgeon’s discretion, and 367 were assigned to observation.

Of these, 281 in the surgery group and 36 in the observation group underwent radical prostatectomy, whereas 53 and 292, respectively, underwent observation. Other interventions included external-beam radiotherapy and brachytherapy. Any additional interventions were decided upon by the patient and his physician.

Investigators followed participants every 6 months for 8-15 years. Patients (mean age, 67 years) underwent bone scans every 5 years. Approximately one-third of the patients were black, and 85% were fully independent in performing the activities of daily living.

Some 40% of the men were found to have low-risk tumors, 34% had intermediate-risk, 21% had high-risk, and 5% had unknown risk because of missing data. Findings were reported on an intention-to-treat basis.

During a median follow-up of 10 years, 47.0% of the surgical group and 49.9% of the observation group died from any cause, a difference that was not significant. Median survival was 13.0 years with radical prostatectomy and 12.4 years with observation, also an insignificant difference.

"The absolute reduction in mortality with radical prostatectomy was not significant at any interval and declined over time, from 4.6 percentage points at 4 years to 2.9 percentage points at 12 years," the investigators said (New Engl. J. Med. 2012 July 19 [doi:10.1056/NEJMoa1113162]).

This trend suggests that longer follow-up would not alter the results, added Dr. Wilt of the Center for Chronic Disease Outcomes Research of the Minneapolis VA Health Care System and his coauthors.

The results were similar with prostate cancer–specific mortality.

Death that was definitely attributable to prostate cancer or its treatment occurred in 4.4% of the men in the surgical group and 4.9% of those in the observation group, a nonsignificant difference. Disease-specific mortality was identical between the two groups at 4 years and was not significantly different at 12 years.

Subgroup analyses showed that radical prostatectomy did not improve all-cause mortality according to patient age, race, performance status, or comorbidities, nor did it vary by tumor score on the Gleason histologic scale. However, the surgery was associated with a slight (13.2%) decline in all-cause mortality in the subgroup of men who had PSA values greater than 10 ng/mL.

The finding of no mortality benefit was particularly strong among men with low-risk cancers (defined as those with PSA values of 10 ng/mL or lower, a score of 6 or less on the Gleason scale, and a stage T1a-c or T2a tumor). In this subgroup, prostatectomy was actually associated with a nonsignificant 15% increase in mortality, Dr. Wilt and his associates said.

Perioperative complications, including one death, developed in 21.4% of men in the radical prostatectomy group. Wound infection was the most common complication, occurring in 4.3% of the men. Other problems included urinary tract infection, bleeding requiring transfusion, and the need for urinary catheterization for more than 30 days.

At 2 years, urinary incontinence and erectile dysfunction were more common among patients in the surgical group than in those in the observation group.

This study was supported by the Department of Veterans Affairs, the National Cancer Institute, and the Agency for Healthcare Quality and Research. Dr. Wilt reported no financial conflicts of interest, and his associates reported ties to numerous industry sources.

NATIONAL HARBOR, MD – The prognosis for older adult kidney transplant recipients has improved dramatically in recent years, and these individuals deserve to be referred for transplantation more often than they currently are, according to transplant surgeon, Dr. Dorry Segev.

Dr. Segev pointed to data from his own and other studies, showing that not only have survival rates among older adult kidney recipients improved, but the use of donor kidneys from older adults can in some cases be considered acceptable for younger recipients.

"What we knew about transplantation 20 years ago is completely different now. Immunosuppression agents are better, clinical protocols are better. ...Those aged 65 and older can have pretty good outcomes with transplantation," said Dr. Segev of the department of surgery at Johns Hopkins University, Baltimore.

Today, 2-year survival following kidney transplantation among those aged 65 and older is approximately 90%, based on data from 7,823 patients who were transplanted in 2009-2011, in contrast to about 80% among 1,153 who were transplanted in 1991-1993. And, older adults who do receive kidney transplants have almost double the survival benefit, compared with those who remain on the waiting list. "We’re transplanting more older adults, and they’re doing better," Dr. Segev said

Nevertheless, about 300,000 adults aged 65 years and older are currently on the waiting list for donor kidneys, and there is evidence that these individuals are referred for transplantation less often than younger individuals with chronic kidney disease. In another study from Dr. Segev’s group, national registry data on 6,988 Medicare recipients (aged 65 and older) of a first kidney transplant in 1999-2006 were compared with those of 128,850 older adults with end-stage renal disease in those same years who did not have absolute or relative contraindications to transplantation (J. Am. Geriatr. Soc. 2012;60:1-7).

Of the 11,756 who would be considered "excellent" candidates for transplantation (defined as greater than 87% predicted 3-year posttransplantation survival, corresponding to the top 20% of transplanted older adults), just 24% had access to transplantation and 13% actually received a kidney transplant. It was estimated that 11% of these candidates would have identified a suitable live donor had they been referred for kidney transplantation. "Those who should be transplanted are getting referred at an extremely low rate," Dr. Segev commented.

One way to counter the belief that donor kidneys are "wasted" on adults with lower remaining life expectancy is to consider kidney options that may not be appropriate for younger recipients, including "expanded criteria" donor kidneys, older living donors, and a special category designated by the Centers for Disease Control and Prevention as "infectious disease risk" donors.

"Expanded criteria" donors (ECDs) include those who are aged 60 years and older, or age 50-59 with two of the following three criteria: hypertension, stroke as the cause of death, or terminal creatinine greater than 1.5 mg/dL. There is a separate recipient waiting list for ECDs, of which "many are great kidneys," Dr. Segev said.

In a review of 142,907 first-time deceased-donor kidney registrants who were reported to UNOS (United Network for Organ Sharing) between 2003 and 2008, Dr. Segev and his associates found that just 67% of adults older than 65 years who were predicted to benefit from ECDs were listed for them, with huge variation (0% to 100%) by center (Am. J. Transplant. 2010;10:802-9).

Older living donors are another potential – but underutilized – source of donor kidneys for their peers. Among 219 healthy adults aged 70 and older who have donated kidneys at 80 U.S. transplantation centers, graft loss in the recipients was significantly higher than were matched 50- to 59-year-old, live-donor allografts, but were similar to matched, nonextended-criteria, 50- to 59-year-old, deceased-donor allografts. Mortality among the older living kidney donors was no higher than that among healthy matched controls, and in fact they lived longer (Clin. J. Am. Soc. Nephrol. 2011;6:2887-93).

"The study showed that donors do well and recipients do well, particularly older recipients. ... Many older adults have a social network of other older adults who would be willing to donate if they knew it was possible," Dr. Segev said.

Another source of alternative donor organs that might be appropriate for selected elderly patients are those from the Centers for Disease Control and Prevention’s "Infectious Risk Donors." These include men who have sex with men (MSM), injection drug users, hemophiliacs, prostitutes, those exposed to HIV, those who have had sex with anyone in the previous categories, and incarcerated individuals. Such donors account for nearly 10% of the donor pool, and their organs are discarded more often than other donor organs.

"It seems wasteful to discard these. There should be someone on the list who would benefit from them, even with higher infectious risk. The real diseases we worry about – HIV and HCV [hepatitis C virus] – take years for sequelae to develop," Dr. Segev said.

In two separate studies, the risk of infection from such an organ per 10,000 donors during the "window period" prior to positive test results for injection drug users was 4.9 for HIV and 32.4 for HCV. For MSM, those risks were 4.2 and 3.5, respectively, and for commercial sex workers, 2.7 and 12.3, respectively. The others incurred lower risks (Am. J. Transplant. 2011;1176-87; 11:1188-200).

New data from Dr. Segev’s group suggest that the risk of a poor outcome (defined as 33% or more of the year after the kidney transplantation that was spent hospitalized or dying) among older transplant recipients increases by an adjusted odds ratio of 1.42 per 10 years. Years on pretransplantation dialysis also was a significant predictor (1.11), whereas the receipt of a live donor organ was protective (0.59).

In all, the risks of kidney transplantation for older adults include the upfront risks of surgery, particularly among those with comorbidities; the risk of immunosuppression; and the ongoing need for medical follow-up. But the benefits can include longer survival and improved quality of life, Dr. Segev said.

Dr. Segev disclosed that he is a consultant, scientific advisor, and speaker for Sanofi.

NATIONAL HARBOR, MD – The prognosis for older adult kidney transplant recipients has improved dramatically in recent years, and these individuals deserve to be referred for transplantation more often than they currently are, according to transplant surgeon, Dr. Dorry Segev.

Dr. Segev pointed to data from his own and other studies, showing that not only have survival rates among older adult kidney recipients improved, but the use of donor kidneys from older adults can in some cases be considered acceptable for younger recipients.

"What we knew about transplantation 20 years ago is completely different now. Immunosuppression agents are better, clinical protocols are better. ...Those aged 65 and older can have pretty good outcomes with transplantation," said Dr. Segev of the department of surgery at Johns Hopkins University, Baltimore.

Today, 2-year survival following kidney transplantation among those aged 65 and older is approximately 90%, based on data from 7,823 patients who were transplanted in 2009-2011, in contrast to about 80% among 1,153 who were transplanted in 1991-1993. And, older adults who do receive kidney transplants have almost double the survival benefit, compared with those who remain on the waiting list. "We’re transplanting more older adults, and they’re doing better," Dr. Segev said

Nevertheless, about 300,000 adults aged 65 years and older are currently on the waiting list for donor kidneys, and there is evidence that these individuals are referred for transplantation less often than younger individuals with chronic kidney disease. In another study from Dr. Segev’s group, national registry data on 6,988 Medicare recipients (aged 65 and older) of a first kidney transplant in 1999-2006 were compared with those of 128,850 older adults with end-stage renal disease in those same years who did not have absolute or relative contraindications to transplantation (J. Am. Geriatr. Soc. 2012;60:1-7).

Of the 11,756 who would be considered "excellent" candidates for transplantation (defined as greater than 87% predicted 3-year posttransplantation survival, corresponding to the top 20% of transplanted older adults), just 24% had access to transplantation and 13% actually received a kidney transplant. It was estimated that 11% of these candidates would have identified a suitable live donor had they been referred for kidney transplantation. "Those who should be transplanted are getting referred at an extremely low rate," Dr. Segev commented.

One way to counter the belief that donor kidneys are "wasted" on adults with lower remaining life expectancy is to consider kidney options that may not be appropriate for younger recipients, including "expanded criteria" donor kidneys, older living donors, and a special category designated by the Centers for Disease Control and Prevention as "infectious disease risk" donors.

"Expanded criteria" donors (ECDs) include those who are aged 60 years and older, or age 50-59 with two of the following three criteria: hypertension, stroke as the cause of death, or terminal creatinine greater than 1.5 mg/dL. There is a separate recipient waiting list for ECDs, of which "many are great kidneys," Dr. Segev said.

In a review of 142,907 first-time deceased-donor kidney registrants who were reported to UNOS (United Network for Organ Sharing) between 2003 and 2008, Dr. Segev and his associates found that just 67% of adults older than 65 years who were predicted to benefit from ECDs were listed for them, with huge variation (0% to 100%) by center (Am. J. Transplant. 2010;10:802-9).

Older living donors are another potential – but underutilized – source of donor kidneys for their peers. Among 219 healthy adults aged 70 and older who have donated kidneys at 80 U.S. transplantation centers, graft loss in the recipients was significantly higher than were matched 50- to 59-year-old, live-donor allografts, but were similar to matched, nonextended-criteria, 50- to 59-year-old, deceased-donor allografts. Mortality among the older living kidney donors was no higher than that among healthy matched controls, and in fact they lived longer (Clin. J. Am. Soc. Nephrol. 2011;6:2887-93).

"The study showed that donors do well and recipients do well, particularly older recipients. ... Many older adults have a social network of other older adults who would be willing to donate if they knew it was possible," Dr. Segev said.

Another source of alternative donor organs that might be appropriate for selected elderly patients are those from the Centers for Disease Control and Prevention’s "Infectious Risk Donors." These include men who have sex with men (MSM), injection drug users, hemophiliacs, prostitutes, those exposed to HIV, those who have had sex with anyone in the previous categories, and incarcerated individuals. Such donors account for nearly 10% of the donor pool, and their organs are discarded more often than other donor organs.

"It seems wasteful to discard these. There should be someone on the list who would benefit from them, even with higher infectious risk. The real diseases we worry about – HIV and HCV [hepatitis C virus] – take years for sequelae to develop," Dr. Segev said.

In two separate studies, the risk of infection from such an organ per 10,000 donors during the "window period" prior to positive test results for injection drug users was 4.9 for HIV and 32.4 for HCV. For MSM, those risks were 4.2 and 3.5, respectively, and for commercial sex workers, 2.7 and 12.3, respectively. The others incurred lower risks (Am. J. Transplant. 2011;1176-87; 11:1188-200).

New data from Dr. Segev’s group suggest that the risk of a poor outcome (defined as 33% or more of the year after the kidney transplantation that was spent hospitalized or dying) among older transplant recipients increases by an adjusted odds ratio of 1.42 per 10 years. Years on pretransplantation dialysis also was a significant predictor (1.11), whereas the receipt of a live donor organ was protective (0.59).

In all, the risks of kidney transplantation for older adults include the upfront risks of surgery, particularly among those with comorbidities; the risk of immunosuppression; and the ongoing need for medical follow-up. But the benefits can include longer survival and improved quality of life, Dr. Segev said.

Dr. Segev disclosed that he is a consultant, scientific advisor, and speaker for Sanofi.

NATIONAL HARBOR, MD – The prognosis for older adult kidney transplant recipients has improved dramatically in recent years, and these individuals deserve to be referred for transplantation more often than they currently are, according to transplant surgeon, Dr. Dorry Segev.

Dr. Segev pointed to data from his own and other studies, showing that not only have survival rates among older adult kidney recipients improved, but the use of donor kidneys from older adults can in some cases be considered acceptable for younger recipients.

"What we knew about transplantation 20 years ago is completely different now. Immunosuppression agents are better, clinical protocols are better. ...Those aged 65 and older can have pretty good outcomes with transplantation," said Dr. Segev of the department of surgery at Johns Hopkins University, Baltimore.

Today, 2-year survival following kidney transplantation among those aged 65 and older is approximately 90%, based on data from 7,823 patients who were transplanted in 2009-2011, in contrast to about 80% among 1,153 who were transplanted in 1991-1993. And, older adults who do receive kidney transplants have almost double the survival benefit, compared with those who remain on the waiting list. "We’re transplanting more older adults, and they’re doing better," Dr. Segev said

Nevertheless, about 300,000 adults aged 65 years and older are currently on the waiting list for donor kidneys, and there is evidence that these individuals are referred for transplantation less often than younger individuals with chronic kidney disease. In another study from Dr. Segev’s group, national registry data on 6,988 Medicare recipients (aged 65 and older) of a first kidney transplant in 1999-2006 were compared with those of 128,850 older adults with end-stage renal disease in those same years who did not have absolute or relative contraindications to transplantation (J. Am. Geriatr. Soc. 2012;60:1-7).

Of the 11,756 who would be considered "excellent" candidates for transplantation (defined as greater than 87% predicted 3-year posttransplantation survival, corresponding to the top 20% of transplanted older adults), just 24% had access to transplantation and 13% actually received a kidney transplant. It was estimated that 11% of these candidates would have identified a suitable live donor had they been referred for kidney transplantation. "Those who should be transplanted are getting referred at an extremely low rate," Dr. Segev commented.

One way to counter the belief that donor kidneys are "wasted" on adults with lower remaining life expectancy is to consider kidney options that may not be appropriate for younger recipients, including "expanded criteria" donor kidneys, older living donors, and a special category designated by the Centers for Disease Control and Prevention as "infectious disease risk" donors.

"Expanded criteria" donors (ECDs) include those who are aged 60 years and older, or age 50-59 with two of the following three criteria: hypertension, stroke as the cause of death, or terminal creatinine greater than 1.5 mg/dL. There is a separate recipient waiting list for ECDs, of which "many are great kidneys," Dr. Segev said.

In a review of 142,907 first-time deceased-donor kidney registrants who were reported to UNOS (United Network for Organ Sharing) between 2003 and 2008, Dr. Segev and his associates found that just 67% of adults older than 65 years who were predicted to benefit from ECDs were listed for them, with huge variation (0% to 100%) by center (Am. J. Transplant. 2010;10:802-9).

Older living donors are another potential – but underutilized – source of donor kidneys for their peers. Among 219 healthy adults aged 70 and older who have donated kidneys at 80 U.S. transplantation centers, graft loss in the recipients was significantly higher than were matched 50- to 59-year-old, live-donor allografts, but were similar to matched, nonextended-criteria, 50- to 59-year-old, deceased-donor allografts. Mortality among the older living kidney donors was no higher than that among healthy matched controls, and in fact they lived longer (Clin. J. Am. Soc. Nephrol. 2011;6:2887-93).

"The study showed that donors do well and recipients do well, particularly older recipients. ... Many older adults have a social network of other older adults who would be willing to donate if they knew it was possible," Dr. Segev said.

Another source of alternative donor organs that might be appropriate for selected elderly patients are those from the Centers for Disease Control and Prevention’s "Infectious Risk Donors." These include men who have sex with men (MSM), injection drug users, hemophiliacs, prostitutes, those exposed to HIV, those who have had sex with anyone in the previous categories, and incarcerated individuals. Such donors account for nearly 10% of the donor pool, and their organs are discarded more often than other donor organs.

"It seems wasteful to discard these. There should be someone on the list who would benefit from them, even with higher infectious risk. The real diseases we worry about – HIV and HCV [hepatitis C virus] – take years for sequelae to develop," Dr. Segev said.

In two separate studies, the risk of infection from such an organ per 10,000 donors during the "window period" prior to positive test results for injection drug users was 4.9 for HIV and 32.4 for HCV. For MSM, those risks were 4.2 and 3.5, respectively, and for commercial sex workers, 2.7 and 12.3, respectively. The others incurred lower risks (Am. J. Transplant. 2011;1176-87; 11:1188-200).

New data from Dr. Segev’s group suggest that the risk of a poor outcome (defined as 33% or more of the year after the kidney transplantation that was spent hospitalized or dying) among older transplant recipients increases by an adjusted odds ratio of 1.42 per 10 years. Years on pretransplantation dialysis also was a significant predictor (1.11), whereas the receipt of a live donor organ was protective (0.59).

In all, the risks of kidney transplantation for older adults include the upfront risks of surgery, particularly among those with comorbidities; the risk of immunosuppression; and the ongoing need for medical follow-up. But the benefits can include longer survival and improved quality of life, Dr. Segev said.

Dr. Segev disclosed that he is a consultant, scientific advisor, and speaker for Sanofi.

A man’s life expectancy should serve as the basis for determining, on a case-by-case basis, whether prostate-specific antigen screening is appropriate, according to a new provisional clinical opinion issued by the American Society of Clinical Oncology.

Specifically, for men who are not expected to live longer than 10 years, ASCO agrees with the May 2012 guideline from the U.S. Preventive Services Task Force (USPSTF) that the risks brought on by PSA screening outweigh the benefits (Ann. Intern Med. 2012 May 22 [epub ahead of print]).

For men with a longer life expectancy, however, "it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives but is associated with harms, including complications from unnecessary biopsy, surgery, or radiation treatment," ASCO panel cochair Dr. Ethan Basch and his associates wrote (J. Clin. Oncol. 2012 July 16 [doi:10.1200/JCO.2012.43.3441]).

The ASCO panel also recommended that information written in lay language be available to clinicians and their patients to facilitate the discussion of the benefits and harms associated with PSA testing before the routine ordering of a PSA test. A "decision aid," based on the ASCO provisional clinical opinion (PCO), was to be made available at www.asco.org/pco/psa.

Calculation of life expectancy is based on multiple individual factors and circumstances. The PCO mentions one available life expectancy calculator as an example, but the ASCO panel does not endorse any one calculator over another.

ASCO Differs on PSAs for Younger Men

In an interview, Dr. Basch said that the ASCO panel evaluated essentially the same data as did the USPSTF. This included screening studies and treatment studies in which men who screened positive for cancer based on PSA testing were randomly assigned to either prostate surgery or watchful waiting. The multidisciplinary ASCO panel, which includes individuals with clinical expertise in medical oncology, urology, radiation oncology, and statistics, paid particular attention to subgroup analyses and statistical issues, however.

"For older men or those with shorter life expectancy, our current recommendations are the same as [those of] the USPSTF. For younger men there is a divergence, in an area where research results are complex and the balance between risks and benefits is close.

"Ultimately, it was the judgment of the ASCO panel that the balance between risks and harms for younger men depends on individual values and preferences, and therefore must be evaluated on a case-by-case basis by a patient and his physician, and must be well informed by scientifically accurate decision tools," said Dr. Basch, a medical oncologist specializing in prostate cancer at Memorial Sloan-Kettering Cancer Center, New York.

USPSTF Official Sees Similarities

Although urologists denounced the USPSTF recommendations at the annual meeting of the American Urological Association, and delegates to the American Medical Association did likewise at their meeting, ASCO agrees more than it disagrees with the controversial guideline, according to Dr. Michael L. LeFevre, co–vice chair of the task force.

"I’m struck by the similarities between the recommendations more than the differences," he said in an interview.

"ASCO concluded that the benefits don’t outweigh the harms, and even with [fewer than] 10 years’ life expectancy, the benefits might not outweigh the harms. ... We certainly also say that that assessment doesn’t mean that an individual clinician cannot offer screening, nor that an individual man can’t request screening,"

"The similarity between the two guidelines is that anybody doing PSA screening should be doing it as an informed choice," added Dr. LeFevre, the Future of Family Medicine professor and vice chair of the department of family and community medicine at the University of Missouri, Columbia.

The USPSTF tries to update its recommendations every 5 years, but may update earlier if important studies are published, as happened in this case. Two major studies are not yet published, Dr. Lefevre noted: PIVOT (Prostate Cancer Intervention Vs. Observation Trial) probably won’t prompt an update, but the PROTECT study "is large enough that I’m really hoping it will inform some of the unanswered questions that we have today."

Two Trials Key to ASCO Opinion

A "provisional clinical opinion" (PCO) is ASCO’s evidence-based approach to offering rapid responses to emerging data in clinical oncology. It is intended "to offer timely clinical direction to ASCO members after publication or presentation of potentially practice-changing data from major studies." In this case, the authors used the Agency for Health Research and Quality’s (AHRQ’s) review, which was also the basis for the USPSTF’s review.

Of the five randomized controlled trials identified, the ASCO panel deemed only two to be of sufficient quality. The PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer) screening trial, involving 76,685 men aged 55-74 years, showed no statistically significant differences in overall or prostate cancer–specific mortality at 7 years between men who were offered annual PSA screens and those who received usual care. However, half of the "usual care" group also received PSA screenings (J. Natl. Cancer Inst. 2012;104:125-32).

In contrast, in the multicenter ERSPC (European Randomized Study of Screening for Prostate Cancer) trial, which involved 182,160 men aged 50-74 years, those aged 55-69 who received PSA testing once every 4 years had a 20% reduction in prostate cancer–specific mortality (but not overall mortality) at 9 years, with the result maintained at 11 years (N. Engl. J. Med. 2009;360:1320-8).

In a subanalysis of the Swedish ERSPC center involving 20,000 men after 14 years of follow-up, statistically significant differences in prostate cancer–specific mortality of up to 56% were detected in favor of the PSA-screened (Lancet Oncol. 2010;11:725-32).

The AHRQ systematic review reported that the false-positive rates associated with PSA screening were 12.9% in the PLCO trial after four rounds of screening, and 12.5% in one center of the ERSPC after three rounds of screening. In PLCO, harms associated with diagnostic evaluations, including biopsy, were reported to be infection, bleeding, and urinary difficulty (68 events per 10,000 evaluations). In one center of the ERSPC trial, among 5,802 biopsies performed, reported harms were fever (3.5%), urinary retention (0.4%), hospitalization for signs of prostatitis or urosepsis (0.5%), and hematuria (22.6%) and hematospermia (50.4%) more than 3 days after biopsy.

"It is important to recognize that risk-benefit ratios can be substantially affected in studies and in practice by altering screening strategies, by changing treatment strategies, by changing measurement approaches, and by considering different lengths of follow-up.

"The ASCO guideline suggests that we can improve outcomes by becoming wiser about how we screen, wiser about who we treat, wiser about avoiding and managing harms of treatment, and wiser about how we communicate with patients," Dr. Basch said in the interview.

He added that physicians should not offer or order PSA screening unless they are "prepared to engage in shared decision making that enables an informed choice by patients." The current decision aid, designed to assist in that conversation, is a first version. "It is ASCO’s hope that it will be tested and refined in the future to become as efficient and useful as possible. It is also a hope that provision of accurate information to clarify decision making will make the PSA discussion more efficient and meaningful."

Hopefully, this process will be made easier in the future with new screening tests and new ways of using the PSA test that are currently under evaluation. Also, Dr. Basch said, "more mature results of ongoing screening studies, final results of treatment studies, and investigations of active surveillance approaches are all likely to improve our understanding of how screening and treatment can be optimized."

Dr. Basch reported no relevant disclosures, but one other ASCO panel member, Dr. Andrew Vickers, disclosed financial ties to GlaxoSmithKline and Genomic Health. USPHTF members such as Dr. LeFevre are vetted for disclosure.

A man’s life expectancy should serve as the basis for determining, on a case-by-case basis, whether prostate-specific antigen screening is appropriate, according to a new provisional clinical opinion issued by the American Society of Clinical Oncology.

Specifically, for men who are not expected to live longer than 10 years, ASCO agrees with the May 2012 guideline from the U.S. Preventive Services Task Force (USPSTF) that the risks brought on by PSA screening outweigh the benefits (Ann. Intern Med. 2012 May 22 [epub ahead of print]).

For men with a longer life expectancy, however, "it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives but is associated with harms, including complications from unnecessary biopsy, surgery, or radiation treatment," ASCO panel cochair Dr. Ethan Basch and his associates wrote (J. Clin. Oncol. 2012 July 16 [doi:10.1200/JCO.2012.43.3441]).

The ASCO panel also recommended that information written in lay language be available to clinicians and their patients to facilitate the discussion of the benefits and harms associated with PSA testing before the routine ordering of a PSA test. A "decision aid," based on the ASCO provisional clinical opinion (PCO), was to be made available at www.asco.org/pco/psa.

Calculation of life expectancy is based on multiple individual factors and circumstances. The PCO mentions one available life expectancy calculator as an example, but the ASCO panel does not endorse any one calculator over another.

ASCO Differs on PSAs for Younger Men

In an interview, Dr. Basch said that the ASCO panel evaluated essentially the same data as did the USPSTF. This included screening studies and treatment studies in which men who screened positive for cancer based on PSA testing were randomly assigned to either prostate surgery or watchful waiting. The multidisciplinary ASCO panel, which includes individuals with clinical expertise in medical oncology, urology, radiation oncology, and statistics, paid particular attention to subgroup analyses and statistical issues, however.

"For older men or those with shorter life expectancy, our current recommendations are the same as [those of] the USPSTF. For younger men there is a divergence, in an area where research results are complex and the balance between risks and benefits is close.

"Ultimately, it was the judgment of the ASCO panel that the balance between risks and harms for younger men depends on individual values and preferences, and therefore must be evaluated on a case-by-case basis by a patient and his physician, and must be well informed by scientifically accurate decision tools," said Dr. Basch, a medical oncologist specializing in prostate cancer at Memorial Sloan-Kettering Cancer Center, New York.

USPSTF Official Sees Similarities

Although urologists denounced the USPSTF recommendations at the annual meeting of the American Urological Association, and delegates to the American Medical Association did likewise at their meeting, ASCO agrees more than it disagrees with the controversial guideline, according to Dr. Michael L. LeFevre, co–vice chair of the task force.

"I’m struck by the similarities between the recommendations more than the differences," he said in an interview.

"ASCO concluded that the benefits don’t outweigh the harms, and even with [fewer than] 10 years’ life expectancy, the benefits might not outweigh the harms. ... We certainly also say that that assessment doesn’t mean that an individual clinician cannot offer screening, nor that an individual man can’t request screening,"

"The similarity between the two guidelines is that anybody doing PSA screening should be doing it as an informed choice," added Dr. LeFevre, the Future of Family Medicine professor and vice chair of the department of family and community medicine at the University of Missouri, Columbia.

The USPSTF tries to update its recommendations every 5 years, but may update earlier if important studies are published, as happened in this case. Two major studies are not yet published, Dr. Lefevre noted: PIVOT (Prostate Cancer Intervention Vs. Observation Trial) probably won’t prompt an update, but the PROTECT study "is large enough that I’m really hoping it will inform some of the unanswered questions that we have today."

Two Trials Key to ASCO Opinion

A "provisional clinical opinion" (PCO) is ASCO’s evidence-based approach to offering rapid responses to emerging data in clinical oncology. It is intended "to offer timely clinical direction to ASCO members after publication or presentation of potentially practice-changing data from major studies." In this case, the authors used the Agency for Health Research and Quality’s (AHRQ’s) review, which was also the basis for the USPSTF’s review.

Of the five randomized controlled trials identified, the ASCO panel deemed only two to be of sufficient quality. The PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer) screening trial, involving 76,685 men aged 55-74 years, showed no statistically significant differences in overall or prostate cancer–specific mortality at 7 years between men who were offered annual PSA screens and those who received usual care. However, half of the "usual care" group also received PSA screenings (J. Natl. Cancer Inst. 2012;104:125-32).

In contrast, in the multicenter ERSPC (European Randomized Study of Screening for Prostate Cancer) trial, which involved 182,160 men aged 50-74 years, those aged 55-69 who received PSA testing once every 4 years had a 20% reduction in prostate cancer–specific mortality (but not overall mortality) at 9 years, with the result maintained at 11 years (N. Engl. J. Med. 2009;360:1320-8).

In a subanalysis of the Swedish ERSPC center involving 20,000 men after 14 years of follow-up, statistically significant differences in prostate cancer–specific mortality of up to 56% were detected in favor of the PSA-screened (Lancet Oncol. 2010;11:725-32).

The AHRQ systematic review reported that the false-positive rates associated with PSA screening were 12.9% in the PLCO trial after four rounds of screening, and 12.5% in one center of the ERSPC after three rounds of screening. In PLCO, harms associated with diagnostic evaluations, including biopsy, were reported to be infection, bleeding, and urinary difficulty (68 events per 10,000 evaluations). In one center of the ERSPC trial, among 5,802 biopsies performed, reported harms were fever (3.5%), urinary retention (0.4%), hospitalization for signs of prostatitis or urosepsis (0.5%), and hematuria (22.6%) and hematospermia (50.4%) more than 3 days after biopsy.

"It is important to recognize that risk-benefit ratios can be substantially affected in studies and in practice by altering screening strategies, by changing treatment strategies, by changing measurement approaches, and by considering different lengths of follow-up.

"The ASCO guideline suggests that we can improve outcomes by becoming wiser about how we screen, wiser about who we treat, wiser about avoiding and managing harms of treatment, and wiser about how we communicate with patients," Dr. Basch said in the interview.

He added that physicians should not offer or order PSA screening unless they are "prepared to engage in shared decision making that enables an informed choice by patients." The current decision aid, designed to assist in that conversation, is a first version. "It is ASCO’s hope that it will be tested and refined in the future to become as efficient and useful as possible. It is also a hope that provision of accurate information to clarify decision making will make the PSA discussion more efficient and meaningful."

Hopefully, this process will be made easier in the future with new screening tests and new ways of using the PSA test that are currently under evaluation. Also, Dr. Basch said, "more mature results of ongoing screening studies, final results of treatment studies, and investigations of active surveillance approaches are all likely to improve our understanding of how screening and treatment can be optimized."

Dr. Basch reported no relevant disclosures, but one other ASCO panel member, Dr. Andrew Vickers, disclosed financial ties to GlaxoSmithKline and Genomic Health. USPHTF members such as Dr. LeFevre are vetted for disclosure.

A man’s life expectancy should serve as the basis for determining, on a case-by-case basis, whether prostate-specific antigen screening is appropriate, according to a new provisional clinical opinion issued by the American Society of Clinical Oncology.

Specifically, for men who are not expected to live longer than 10 years, ASCO agrees with the May 2012 guideline from the U.S. Preventive Services Task Force (USPSTF) that the risks brought on by PSA screening outweigh the benefits (Ann. Intern Med. 2012 May 22 [epub ahead of print]).

For men with a longer life expectancy, however, "it is recommended that physicians discuss with their patients whether PSA testing for prostate cancer screening is appropriate for them. PSA testing may save lives but is associated with harms, including complications from unnecessary biopsy, surgery, or radiation treatment," ASCO panel cochair Dr. Ethan Basch and his associates wrote (J. Clin. Oncol. 2012 July 16 [doi:10.1200/JCO.2012.43.3441]).

The ASCO panel also recommended that information written in lay language be available to clinicians and their patients to facilitate the discussion of the benefits and harms associated with PSA testing before the routine ordering of a PSA test. A "decision aid," based on the ASCO provisional clinical opinion (PCO), was to be made available at www.asco.org/pco/psa.

Calculation of life expectancy is based on multiple individual factors and circumstances. The PCO mentions one available life expectancy calculator as an example, but the ASCO panel does not endorse any one calculator over another.

ASCO Differs on PSAs for Younger Men

In an interview, Dr. Basch said that the ASCO panel evaluated essentially the same data as did the USPSTF. This included screening studies and treatment studies in which men who screened positive for cancer based on PSA testing were randomly assigned to either prostate surgery or watchful waiting. The multidisciplinary ASCO panel, which includes individuals with clinical expertise in medical oncology, urology, radiation oncology, and statistics, paid particular attention to subgroup analyses and statistical issues, however.

"For older men or those with shorter life expectancy, our current recommendations are the same as [those of] the USPSTF. For younger men there is a divergence, in an area where research results are complex and the balance between risks and benefits is close.

"Ultimately, it was the judgment of the ASCO panel that the balance between risks and harms for younger men depends on individual values and preferences, and therefore must be evaluated on a case-by-case basis by a patient and his physician, and must be well informed by scientifically accurate decision tools," said Dr. Basch, a medical oncologist specializing in prostate cancer at Memorial Sloan-Kettering Cancer Center, New York.

USPSTF Official Sees Similarities

Although urologists denounced the USPSTF recommendations at the annual meeting of the American Urological Association, and delegates to the American Medical Association did likewise at their meeting, ASCO agrees more than it disagrees with the controversial guideline, according to Dr. Michael L. LeFevre, co–vice chair of the task force.

"I’m struck by the similarities between the recommendations more than the differences," he said in an interview.

"ASCO concluded that the benefits don’t outweigh the harms, and even with [fewer than] 10 years’ life expectancy, the benefits might not outweigh the harms. ... We certainly also say that that assessment doesn’t mean that an individual clinician cannot offer screening, nor that an individual man can’t request screening,"

"The similarity between the two guidelines is that anybody doing PSA screening should be doing it as an informed choice," added Dr. LeFevre, the Future of Family Medicine professor and vice chair of the department of family and community medicine at the University of Missouri, Columbia.

The USPSTF tries to update its recommendations every 5 years, but may update earlier if important studies are published, as happened in this case. Two major studies are not yet published, Dr. Lefevre noted: PIVOT (Prostate Cancer Intervention Vs. Observation Trial) probably won’t prompt an update, but the PROTECT study "is large enough that I’m really hoping it will inform some of the unanswered questions that we have today."

Two Trials Key to ASCO Opinion

A "provisional clinical opinion" (PCO) is ASCO’s evidence-based approach to offering rapid responses to emerging data in clinical oncology. It is intended "to offer timely clinical direction to ASCO members after publication or presentation of potentially practice-changing data from major studies." In this case, the authors used the Agency for Health Research and Quality’s (AHRQ’s) review, which was also the basis for the USPSTF’s review.

Of the five randomized controlled trials identified, the ASCO panel deemed only two to be of sufficient quality. The PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer) screening trial, involving 76,685 men aged 55-74 years, showed no statistically significant differences in overall or prostate cancer–specific mortality at 7 years between men who were offered annual PSA screens and those who received usual care. However, half of the "usual care" group also received PSA screenings (J. Natl. Cancer Inst. 2012;104:125-32).

In contrast, in the multicenter ERSPC (European Randomized Study of Screening for Prostate Cancer) trial, which involved 182,160 men aged 50-74 years, those aged 55-69 who received PSA testing once every 4 years had a 20% reduction in prostate cancer–specific mortality (but not overall mortality) at 9 years, with the result maintained at 11 years (N. Engl. J. Med. 2009;360:1320-8).

In a subanalysis of the Swedish ERSPC center involving 20,000 men after 14 years of follow-up, statistically significant differences in prostate cancer–specific mortality of up to 56% were detected in favor of the PSA-screened (Lancet Oncol. 2010;11:725-32).

The AHRQ systematic review reported that the false-positive rates associated with PSA screening were 12.9% in the PLCO trial after four rounds of screening, and 12.5% in one center of the ERSPC after three rounds of screening. In PLCO, harms associated with diagnostic evaluations, including biopsy, were reported to be infection, bleeding, and urinary difficulty (68 events per 10,000 evaluations). In one center of the ERSPC trial, among 5,802 biopsies performed, reported harms were fever (3.5%), urinary retention (0.4%), hospitalization for signs of prostatitis or urosepsis (0.5%), and hematuria (22.6%) and hematospermia (50.4%) more than 3 days after biopsy.

"It is important to recognize that risk-benefit ratios can be substantially affected in studies and in practice by altering screening strategies, by changing treatment strategies, by changing measurement approaches, and by considering different lengths of follow-up.

"The ASCO guideline suggests that we can improve outcomes by becoming wiser about how we screen, wiser about who we treat, wiser about avoiding and managing harms of treatment, and wiser about how we communicate with patients," Dr. Basch said in the interview.

He added that physicians should not offer or order PSA screening unless they are "prepared to engage in shared decision making that enables an informed choice by patients." The current decision aid, designed to assist in that conversation, is a first version. "It is ASCO’s hope that it will be tested and refined in the future to become as efficient and useful as possible. It is also a hope that provision of accurate information to clarify decision making will make the PSA discussion more efficient and meaningful."

Hopefully, this process will be made easier in the future with new screening tests and new ways of using the PSA test that are currently under evaluation. Also, Dr. Basch said, "more mature results of ongoing screening studies, final results of treatment studies, and investigations of active surveillance approaches are all likely to improve our understanding of how screening and treatment can be optimized."

Dr. Basch reported no relevant disclosures, but one other ASCO panel member, Dr. Andrew Vickers, disclosed financial ties to GlaxoSmithKline and Genomic Health. USPHTF members such as Dr. LeFevre are vetted for disclosure.

NATIONAL HARBOR, MD. – Facebook is being used to directly solicit living kidney donors, and some aspects of that use raise privacy and ethical issues, according to Dr. Alex Chang.

The social networking site has been widely praised since its May 1 launch of a program allowing users to add organ donor status to their timelines and facilitating users’ linking to their state or national organ donor registries. However, its use for directly soliciting living donors raises issues of concern that organ transplant programs need to recognize and respond to, said Dr. Chang, a nephrology fellow at Loyola University Medical Center, Maywood, Ill.

"What I like about what Facebook has done is that it increases organ donation awareness and makes it personal. ... Facebook, I think, will dramatically increase organ registries if this is implemented well. However, careful consideration of the risks and benefits should be taken prior to being a living kidney donor," Dr. Chang said in an interview at a meeting sponsored by the National Kidney Foundation.

In their poster presentation at the meeting, Dr. Chang and his colleagues analyzed 144 English-language pages on Facebook devoted to soliciting a living kidney donor for a specific person in need. Potential organ recipients ranged in age from 2 to 69 years, and included all racial and ethnic groups and blood types. Of the pages for which the relationships between the page creator and the patient could be determined, 37% were created by the patients themselves, 31% by their children, and 32% by other family or friends.

People posted a range of information from one-sentence requests to explicit medical histories, as well as photographs of family and of the patient receiving hemodialysis.

"Much more careful consideration of the ethical implications of using social media is needed. The privacy issue is huge. ... Many people do not realize the vast amount of information that can be garnered from their Facebook pages, and when you add medical information to that, the risk is increased more," he said.

Although the contribution of Facebook in soliciting donors couldn’t be determined, 30% of the pages reported that donors had been tested, and 12% that a kidney transplant had been received. Individuals for whom donors were tested were significantly more likely to be white and to have more than 50 posts by others on their sites.

The risks of kidney donation were mentioned by 5% of the pages; only 11% mentioned associated costs. "I thought that was pretty astonishing since you are asking a very serious favor of your friends and family and/or strangers, and there is little mention of the actual risks and costs. Oftentimes, donors are caught unaware of certain financial costs such as missing 2 weeks of work and [the fact that] the long-term consequences of living kidney donation are still not totally certain. I believe this deserves fair mention if this method of media is being used for this purpose," Dr. Chang said.

Also of concern: Offers to sell kidneys were posted on 3% of pages.

"In my view I think it is premature to promote using Facebook to solicit living kidney donors. However it is happening and will continue to happen. I think that transplant programs have to recognize this and come up with plans on how to deal with social media–mediated living kidney transplant."

Dr. Chang said he had no relevant financial disclosures.

NATIONAL HARBOR, MD. – Facebook is being used to directly solicit living kidney donors, and some aspects of that use raise privacy and ethical issues, according to Dr. Alex Chang.

The social networking site has been widely praised since its May 1 launch of a program allowing users to add organ donor status to their timelines and facilitating users’ linking to their state or national organ donor registries. However, its use for directly soliciting living donors raises issues of concern that organ transplant programs need to recognize and respond to, said Dr. Chang, a nephrology fellow at Loyola University Medical Center, Maywood, Ill.

"What I like about what Facebook has done is that it increases organ donation awareness and makes it personal. ... Facebook, I think, will dramatically increase organ registries if this is implemented well. However, careful consideration of the risks and benefits should be taken prior to being a living kidney donor," Dr. Chang said in an interview at a meeting sponsored by the National Kidney Foundation.

In their poster presentation at the meeting, Dr. Chang and his colleagues analyzed 144 English-language pages on Facebook devoted to soliciting a living kidney donor for a specific person in need. Potential organ recipients ranged in age from 2 to 69 years, and included all racial and ethnic groups and blood types. Of the pages for which the relationships between the page creator and the patient could be determined, 37% were created by the patients themselves, 31% by their children, and 32% by other family or friends.

People posted a range of information from one-sentence requests to explicit medical histories, as well as photographs of family and of the patient receiving hemodialysis.

"Much more careful consideration of the ethical implications of using social media is needed. The privacy issue is huge. ... Many people do not realize the vast amount of information that can be garnered from their Facebook pages, and when you add medical information to that, the risk is increased more," he said.

Although the contribution of Facebook in soliciting donors couldn’t be determined, 30% of the pages reported that donors had been tested, and 12% that a kidney transplant had been received. Individuals for whom donors were tested were significantly more likely to be white and to have more than 50 posts by others on their sites.

The risks of kidney donation were mentioned by 5% of the pages; only 11% mentioned associated costs. "I thought that was pretty astonishing since you are asking a very serious favor of your friends and family and/or strangers, and there is little mention of the actual risks and costs. Oftentimes, donors are caught unaware of certain financial costs such as missing 2 weeks of work and [the fact that] the long-term consequences of living kidney donation are still not totally certain. I believe this deserves fair mention if this method of media is being used for this purpose," Dr. Chang said.

Also of concern: Offers to sell kidneys were posted on 3% of pages.

"In my view I think it is premature to promote using Facebook to solicit living kidney donors. However it is happening and will continue to happen. I think that transplant programs have to recognize this and come up with plans on how to deal with social media–mediated living kidney transplant."

Dr. Chang said he had no relevant financial disclosures.

NATIONAL HARBOR, MD. – Facebook is being used to directly solicit living kidney donors, and some aspects of that use raise privacy and ethical issues, according to Dr. Alex Chang.

The social networking site has been widely praised since its May 1 launch of a program allowing users to add organ donor status to their timelines and facilitating users’ linking to their state or national organ donor registries. However, its use for directly soliciting living donors raises issues of concern that organ transplant programs need to recognize and respond to, said Dr. Chang, a nephrology fellow at Loyola University Medical Center, Maywood, Ill.

"What I like about what Facebook has done is that it increases organ donation awareness and makes it personal. ... Facebook, I think, will dramatically increase organ registries if this is implemented well. However, careful consideration of the risks and benefits should be taken prior to being a living kidney donor," Dr. Chang said in an interview at a meeting sponsored by the National Kidney Foundation.

In their poster presentation at the meeting, Dr. Chang and his colleagues analyzed 144 English-language pages on Facebook devoted to soliciting a living kidney donor for a specific person in need. Potential organ recipients ranged in age from 2 to 69 years, and included all racial and ethnic groups and blood types. Of the pages for which the relationships between the page creator and the patient could be determined, 37% were created by the patients themselves, 31% by their children, and 32% by other family or friends.

People posted a range of information from one-sentence requests to explicit medical histories, as well as photographs of family and of the patient receiving hemodialysis.

"Much more careful consideration of the ethical implications of using social media is needed. The privacy issue is huge. ... Many people do not realize the vast amount of information that can be garnered from their Facebook pages, and when you add medical information to that, the risk is increased more," he said.

Although the contribution of Facebook in soliciting donors couldn’t be determined, 30% of the pages reported that donors had been tested, and 12% that a kidney transplant had been received. Individuals for whom donors were tested were significantly more likely to be white and to have more than 50 posts by others on their sites.

The risks of kidney donation were mentioned by 5% of the pages; only 11% mentioned associated costs. "I thought that was pretty astonishing since you are asking a very serious favor of your friends and family and/or strangers, and there is little mention of the actual risks and costs. Oftentimes, donors are caught unaware of certain financial costs such as missing 2 weeks of work and [the fact that] the long-term consequences of living kidney donation are still not totally certain. I believe this deserves fair mention if this method of media is being used for this purpose," Dr. Chang said.

Also of concern: Offers to sell kidneys were posted on 3% of pages.

"In my view I think it is premature to promote using Facebook to solicit living kidney donors. However it is happening and will continue to happen. I think that transplant programs have to recognize this and come up with plans on how to deal with social media–mediated living kidney transplant."

Dr. Chang said he had no relevant financial disclosures.

ATLANTA – At 15 years after treatment, disease-related quality of life measures appear similar in men with prostate cancer, regardless of whether they had radical prostatectomy or external radiation beam therapy.

The significant differences in sexual, urinary, and bowel function that were apparent in the first 5 years, largely disappeared as time advanced, Dr. Matthew Resnick reported, based on a new subanalysis of men in the Prostate Cancer Outcomes Study.

The convergence of outcomes may not have so much to do with treatment type as it does advancing age, he said at the annual meeting of the American Urologic Association. This is especially apparent in erectile dysfunction, according to Dr. Resnick, a urologic surgeon at Vanderbilt University Medical Center, Nashville, Tenn.

"Age really is the most significant determinant of decline in erectile function over time," he said. "About 50% of men older than 70 have erectile dysfunction."

The Prostate Cancer Outcomes Study (PCOS) enrolled patients from six Surveillance, Epidemiology, and End Results (SEER) tumor registries to examine long-term functional outcomes in men who were diagnosed with prostate cancer between 1994 and 1995.

This subanalysis included 1,655 men aged 55-74 years, who underwent either external beam radiation or radical prostatectomy during that period. They filled out quality of life surveys at baseline, and at 6 months and 1, 2, 5, and 15 years after their diagnosis. Since younger, healthier men may be more likely to have surgery, the authors used a propensity score analysis in an attempt to control for age. Most of the group (70%) underwent radical prostatectomy; 30% had radiation therapy.

Overall, men who had surgery were significantly more likely to experience urinary and sexual dysfunction, while the radiation group was significantly more likely to experience bowel dysfunction.

The differences were most obvious early in the follow-up period. At 2 and 5 years after treatment, men in the surgery group were significantly more likely to report erectile dysfunction than those were those treated with radiation. (odds ratio, 3.46 and 1.96 respectively). By 15 years, this difference had disappeared, however.

Men who had surgery were also significantly more likely to report having no sexual activity at 2 years (OR, 1.83), but at 5 and 15 years, there were no significant differences between the groups.

The surgical group was more likely to report urinary dysfunction compared with the radiation-treated cohort. Having no urinary control was significantly more likely at 2 and 5 years (OR, 6.2 and 5.1 respectively), but not at 15 years. Urine leakage was also significantly more likely in the surgery group at 2 and 5 years (OR, 13.0 and 5.5, respectively), but not at 15 years.

The need for pads to stay dry was significantly more likely at both 2 and 5 years for the surgery group (OR, 26 and 12, respectively). The surgery group was still significantly more likely to need pads at 15 years, although the difference was somewhat attenuated (OR, 4.5).

Not surprisingly, Dr. Resnick said, men in the surgery group were also significantly more likely to report being bothered by their urinary problems at 2 and 5 years, (OR, 6 and 7, respectively), but not at 15 years.

Finally, patients who underwent radiation therapy were more likely to be bothered by bowel dysfunction throughout the follow-up period; by 15 years after treatment, bowel issues were 3.4 times more common among this group.

While more studies on long-term functional outcomes are needed, Dr. Resnick said this information can be helpful in pretreatment decision-making – a time when patients need to weigh the risks of impaired function associated with each treatment paradigm.

"In terms of evaluating the patient up-front, we can use this information to elicit their preferences [for treatment]. That is an important piece of the plan."

The study was funded by the National Cancer Institute. Dr. Resnick had no financial disclosures.

*Headline was revised 07/12/12.

ATLANTA – At 15 years after treatment, disease-related quality of life measures appear similar in men with prostate cancer, regardless of whether they had radical prostatectomy or external radiation beam therapy.

The significant differences in sexual, urinary, and bowel function that were apparent in the first 5 years, largely disappeared as time advanced, Dr. Matthew Resnick reported, based on a new subanalysis of men in the Prostate Cancer Outcomes Study.

The convergence of outcomes may not have so much to do with treatment type as it does advancing age, he said at the annual meeting of the American Urologic Association. This is especially apparent in erectile dysfunction, according to Dr. Resnick, a urologic surgeon at Vanderbilt University Medical Center, Nashville, Tenn.

"Age really is the most significant determinant of decline in erectile function over time," he said. "About 50% of men older than 70 have erectile dysfunction."

The Prostate Cancer Outcomes Study (PCOS) enrolled patients from six Surveillance, Epidemiology, and End Results (SEER) tumor registries to examine long-term functional outcomes in men who were diagnosed with prostate cancer between 1994 and 1995.

This subanalysis included 1,655 men aged 55-74 years, who underwent either external beam radiation or radical prostatectomy during that period. They filled out quality of life surveys at baseline, and at 6 months and 1, 2, 5, and 15 years after their diagnosis. Since younger, healthier men may be more likely to have surgery, the authors used a propensity score analysis in an attempt to control for age. Most of the group (70%) underwent radical prostatectomy; 30% had radiation therapy.

Overall, men who had surgery were significantly more likely to experience urinary and sexual dysfunction, while the radiation group was significantly more likely to experience bowel dysfunction.

The differences were most obvious early in the follow-up period. At 2 and 5 years after treatment, men in the surgery group were significantly more likely to report erectile dysfunction than those were those treated with radiation. (odds ratio, 3.46 and 1.96 respectively). By 15 years, this difference had disappeared, however.

Men who had surgery were also significantly more likely to report having no sexual activity at 2 years (OR, 1.83), but at 5 and 15 years, there were no significant differences between the groups.

The surgical group was more likely to report urinary dysfunction compared with the radiation-treated cohort. Having no urinary control was significantly more likely at 2 and 5 years (OR, 6.2 and 5.1 respectively), but not at 15 years. Urine leakage was also significantly more likely in the surgery group at 2 and 5 years (OR, 13.0 and 5.5, respectively), but not at 15 years.

The need for pads to stay dry was significantly more likely at both 2 and 5 years for the surgery group (OR, 26 and 12, respectively). The surgery group was still significantly more likely to need pads at 15 years, although the difference was somewhat attenuated (OR, 4.5).

Not surprisingly, Dr. Resnick said, men in the surgery group were also significantly more likely to report being bothered by their urinary problems at 2 and 5 years, (OR, 6 and 7, respectively), but not at 15 years.

Finally, patients who underwent radiation therapy were more likely to be bothered by bowel dysfunction throughout the follow-up period; by 15 years after treatment, bowel issues were 3.4 times more common among this group.

While more studies on long-term functional outcomes are needed, Dr. Resnick said this information can be helpful in pretreatment decision-making – a time when patients need to weigh the risks of impaired function associated with each treatment paradigm.

"In terms of evaluating the patient up-front, we can use this information to elicit their preferences [for treatment]. That is an important piece of the plan."

The study was funded by the National Cancer Institute. Dr. Resnick had no financial disclosures.

*Headline was revised 07/12/12.

ATLANTA – At 15 years after treatment, disease-related quality of life measures appear similar in men with prostate cancer, regardless of whether they had radical prostatectomy or external radiation beam therapy.

The significant differences in sexual, urinary, and bowel function that were apparent in the first 5 years, largely disappeared as time advanced, Dr. Matthew Resnick reported, based on a new subanalysis of men in the Prostate Cancer Outcomes Study.

The convergence of outcomes may not have so much to do with treatment type as it does advancing age, he said at the annual meeting of the American Urologic Association. This is especially apparent in erectile dysfunction, according to Dr. Resnick, a urologic surgeon at Vanderbilt University Medical Center, Nashville, Tenn.

"Age really is the most significant determinant of decline in erectile function over time," he said. "About 50% of men older than 70 have erectile dysfunction."

The Prostate Cancer Outcomes Study (PCOS) enrolled patients from six Surveillance, Epidemiology, and End Results (SEER) tumor registries to examine long-term functional outcomes in men who were diagnosed with prostate cancer between 1994 and 1995.

This subanalysis included 1,655 men aged 55-74 years, who underwent either external beam radiation or radical prostatectomy during that period. They filled out quality of life surveys at baseline, and at 6 months and 1, 2, 5, and 15 years after their diagnosis. Since younger, healthier men may be more likely to have surgery, the authors used a propensity score analysis in an attempt to control for age. Most of the group (70%) underwent radical prostatectomy; 30% had radiation therapy.

Overall, men who had surgery were significantly more likely to experience urinary and sexual dysfunction, while the radiation group was significantly more likely to experience bowel dysfunction.

The differences were most obvious early in the follow-up period. At 2 and 5 years after treatment, men in the surgery group were significantly more likely to report erectile dysfunction than those were those treated with radiation. (odds ratio, 3.46 and 1.96 respectively). By 15 years, this difference had disappeared, however.

Men who had surgery were also significantly more likely to report having no sexual activity at 2 years (OR, 1.83), but at 5 and 15 years, there were no significant differences between the groups.

The surgical group was more likely to report urinary dysfunction compared with the radiation-treated cohort. Having no urinary control was significantly more likely at 2 and 5 years (OR, 6.2 and 5.1 respectively), but not at 15 years. Urine leakage was also significantly more likely in the surgery group at 2 and 5 years (OR, 13.0 and 5.5, respectively), but not at 15 years.

The need for pads to stay dry was significantly more likely at both 2 and 5 years for the surgery group (OR, 26 and 12, respectively). The surgery group was still significantly more likely to need pads at 15 years, although the difference was somewhat attenuated (OR, 4.5).

Not surprisingly, Dr. Resnick said, men in the surgery group were also significantly more likely to report being bothered by their urinary problems at 2 and 5 years, (OR, 6 and 7, respectively), but not at 15 years.

Finally, patients who underwent radiation therapy were more likely to be bothered by bowel dysfunction throughout the follow-up period; by 15 years after treatment, bowel issues were 3.4 times more common among this group.

While more studies on long-term functional outcomes are needed, Dr. Resnick said this information can be helpful in pretreatment decision-making – a time when patients need to weigh the risks of impaired function associated with each treatment paradigm.

"In terms of evaluating the patient up-front, we can use this information to elicit their preferences [for treatment]. That is an important piece of the plan."

The study was funded by the National Cancer Institute. Dr. Resnick had no financial disclosures.

*Headline was revised 07/12/12.

CHICAGO – Take your pick: The tyrosine kinase inhibitors sunitinib and sorafenib do/do not appear to have significant cardiac toxicity when used in adjuvant therapy for renal cell carcinoma.

Conflicting studies presented at the annual meeting of the American Society of Clinical Oncology suggest that – for now at least – it’s a toss-up.

A cardiac substudy of the phase III ECOG (Eastern Cooperative Oncology Group) E2805 ASSURE (Adjuvant Sunitinib or Sorafenib for Unfavorable Renal Carcinoma) trial, comparing either sunitinib (Sutent) or sorafenib (Nexavar) with placebo in patients with resected renal cell carcinoma (RCC), showed that neither TKI was associated with significant declines in left ventricular ejection fraction (LVEF) or other cardiac adverse events when compared with placebo, said Dr. Naomi B. Haas of the University of Pennsylvania, Philadelphia.

Left ventricular dysfunction that did occur with the TKIs was reversible, and ischemic events were uncommon and not clearly linked to therapy, she added.

"The implications for patients: Further prospective study on the effects of these agents is needed in patients who have preexisting cardiac dysfunction. This was a well population we were looking at," said Dr. Haas.

However, a retrospective study by Dr. Phillip S. Hall and colleagues at Stanford (Calif.) University found evidence of significant cardiac toxicity in patients with metastatic renal cell carcinoma that was treated with both agents and with other targeted therapies at their institution.

"Cardiovascular toxicity is an important adverse event related to targeted-therapy administration. Close monitoring for the development of CV toxicity with the use of these agents should become standard of care, as early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality," they wrote in a poster presentation.

TKIs on Trial

Previous studies, most of them retrospective, have reported cardiac dysfunction with TKI use ranging from 1% to 28%. The proposed mechanism of action is through the metabolic dysfunction of cardiac myocytes, Dr. Haas said.

She and her coinvestigators in the ECOG E2805 ASSURE trial looked at data from a cardiac substudy, and asked whether either sorafenib or sunitinib was associated with a decline in LVEF, clinically significant heart failure (HF) or other effects, using multigated acquisition scans (MUGA) at baseline and at 3, 6, and 12 months (study end) or at the end of treatment.

There were nine cases of the primary end point (a decline in LVEF of 16% or greater from baseline) among 397 patients on sunitinib, seven among 394 patients on sorafenib, and five among 502 patients on placebo. The respective event rates were 2.3%, 1.8%, and 1.0%; these differences were not clinically significant.

The numbers for other cardiac events – including LVEF decline of 16% or more below the institutional level of normal occurring after 6 months, or a grade 2 or 3 left ventricular systolic or diastolic dysfunction – were also similar among the groups, occurring in 12, 11, and 11 patients, respectively.

"Looking at the data as they stand, it on the face of it is very reassuring, with the primary end point being met in a very small proportion of patients," commented the invited discussant Dr. Tim Eisen, professor of oncology at the University of Cambridge (England).

He pointed out, however, that new cardiac events were seen in the study past 6 months of therapy, which indicated that investigators should continue to monitor patients for cardiotoxicities throughout the course of therapy and in follow-up.

TKIs in Practice

The Stanford investigators looked at the incidence of hypertension, left ventricular dysfunction, changes in serum markers of cardiovascular toxicity, and heart failure in 159 patients with metastatic RCC who were treated from 2004 through 2011. They found that 116 of 159 patients (73%) developed cardiovascular toxicities.

"Sunitinib was the most frequently used and most common offending agent, with 66 of 101 sunitinib-treated patients (65%) developing a form of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was notable that CV toxicity was observed in 68%, 66%, and 51% of patients treated with bevacizumab, sorafenib, and pazopanib as well," the investigators wrote.

They noted that there were fewer toxicities with mTOR (mammalian target of rapamycin) inhibitors than with TKIs, but the sample sizes were small.

The ECOG E2805 trial was supported by the National Cancer Institute. The Stanford study was internally funded. Dr. Haas reported having a consulting or advisory role to Boehringer Ingelheim, Dendreon, Novartis, and Pfizer, and receiving research funding from GlaxoSmithKline. Dr. Hall reported having no relevant disclosures. Dr. Eisen has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.

CHICAGO – Take your pick: The tyrosine kinase inhibitors sunitinib and sorafenib do/do not appear to have significant cardiac toxicity when used in adjuvant therapy for renal cell carcinoma.

Conflicting studies presented at the annual meeting of the American Society of Clinical Oncology suggest that – for now at least – it’s a toss-up.

A cardiac substudy of the phase III ECOG (Eastern Cooperative Oncology Group) E2805 ASSURE (Adjuvant Sunitinib or Sorafenib for Unfavorable Renal Carcinoma) trial, comparing either sunitinib (Sutent) or sorafenib (Nexavar) with placebo in patients with resected renal cell carcinoma (RCC), showed that neither TKI was associated with significant declines in left ventricular ejection fraction (LVEF) or other cardiac adverse events when compared with placebo, said Dr. Naomi B. Haas of the University of Pennsylvania, Philadelphia.

Left ventricular dysfunction that did occur with the TKIs was reversible, and ischemic events were uncommon and not clearly linked to therapy, she added.

"The implications for patients: Further prospective study on the effects of these agents is needed in patients who have preexisting cardiac dysfunction. This was a well population we were looking at," said Dr. Haas.

However, a retrospective study by Dr. Phillip S. Hall and colleagues at Stanford (Calif.) University found evidence of significant cardiac toxicity in patients with metastatic renal cell carcinoma that was treated with both agents and with other targeted therapies at their institution.

"Cardiovascular toxicity is an important adverse event related to targeted-therapy administration. Close monitoring for the development of CV toxicity with the use of these agents should become standard of care, as early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality," they wrote in a poster presentation.

TKIs on Trial

Previous studies, most of them retrospective, have reported cardiac dysfunction with TKI use ranging from 1% to 28%. The proposed mechanism of action is through the metabolic dysfunction of cardiac myocytes, Dr. Haas said.

She and her coinvestigators in the ECOG E2805 ASSURE trial looked at data from a cardiac substudy, and asked whether either sorafenib or sunitinib was associated with a decline in LVEF, clinically significant heart failure (HF) or other effects, using multigated acquisition scans (MUGA) at baseline and at 3, 6, and 12 months (study end) or at the end of treatment.

There were nine cases of the primary end point (a decline in LVEF of 16% or greater from baseline) among 397 patients on sunitinib, seven among 394 patients on sorafenib, and five among 502 patients on placebo. The respective event rates were 2.3%, 1.8%, and 1.0%; these differences were not clinically significant.

The numbers for other cardiac events – including LVEF decline of 16% or more below the institutional level of normal occurring after 6 months, or a grade 2 or 3 left ventricular systolic or diastolic dysfunction – were also similar among the groups, occurring in 12, 11, and 11 patients, respectively.

"Looking at the data as they stand, it on the face of it is very reassuring, with the primary end point being met in a very small proportion of patients," commented the invited discussant Dr. Tim Eisen, professor of oncology at the University of Cambridge (England).

He pointed out, however, that new cardiac events were seen in the study past 6 months of therapy, which indicated that investigators should continue to monitor patients for cardiotoxicities throughout the course of therapy and in follow-up.

TKIs in Practice

The Stanford investigators looked at the incidence of hypertension, left ventricular dysfunction, changes in serum markers of cardiovascular toxicity, and heart failure in 159 patients with metastatic RCC who were treated from 2004 through 2011. They found that 116 of 159 patients (73%) developed cardiovascular toxicities.

"Sunitinib was the most frequently used and most common offending agent, with 66 of 101 sunitinib-treated patients (65%) developing a form of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was notable that CV toxicity was observed in 68%, 66%, and 51% of patients treated with bevacizumab, sorafenib, and pazopanib as well," the investigators wrote.

They noted that there were fewer toxicities with mTOR (mammalian target of rapamycin) inhibitors than with TKIs, but the sample sizes were small.

The ECOG E2805 trial was supported by the National Cancer Institute. The Stanford study was internally funded. Dr. Haas reported having a consulting or advisory role to Boehringer Ingelheim, Dendreon, Novartis, and Pfizer, and receiving research funding from GlaxoSmithKline. Dr. Hall reported having no relevant disclosures. Dr. Eisen has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.

CHICAGO – Take your pick: The tyrosine kinase inhibitors sunitinib and sorafenib do/do not appear to have significant cardiac toxicity when used in adjuvant therapy for renal cell carcinoma.

Conflicting studies presented at the annual meeting of the American Society of Clinical Oncology suggest that – for now at least – it’s a toss-up.

A cardiac substudy of the phase III ECOG (Eastern Cooperative Oncology Group) E2805 ASSURE (Adjuvant Sunitinib or Sorafenib for Unfavorable Renal Carcinoma) trial, comparing either sunitinib (Sutent) or sorafenib (Nexavar) with placebo in patients with resected renal cell carcinoma (RCC), showed that neither TKI was associated with significant declines in left ventricular ejection fraction (LVEF) or other cardiac adverse events when compared with placebo, said Dr. Naomi B. Haas of the University of Pennsylvania, Philadelphia.

Left ventricular dysfunction that did occur with the TKIs was reversible, and ischemic events were uncommon and not clearly linked to therapy, she added.

"The implications for patients: Further prospective study on the effects of these agents is needed in patients who have preexisting cardiac dysfunction. This was a well population we were looking at," said Dr. Haas.

However, a retrospective study by Dr. Phillip S. Hall and colleagues at Stanford (Calif.) University found evidence of significant cardiac toxicity in patients with metastatic renal cell carcinoma that was treated with both agents and with other targeted therapies at their institution.

"Cardiovascular toxicity is an important adverse event related to targeted-therapy administration. Close monitoring for the development of CV toxicity with the use of these agents should become standard of care, as early detection of asymptomatic patients could preempt symptomatic toxicity and reduce treatment-related morbidity and mortality," they wrote in a poster presentation.

TKIs on Trial

Previous studies, most of them retrospective, have reported cardiac dysfunction with TKI use ranging from 1% to 28%. The proposed mechanism of action is through the metabolic dysfunction of cardiac myocytes, Dr. Haas said.

She and her coinvestigators in the ECOG E2805 ASSURE trial looked at data from a cardiac substudy, and asked whether either sorafenib or sunitinib was associated with a decline in LVEF, clinically significant heart failure (HF) or other effects, using multigated acquisition scans (MUGA) at baseline and at 3, 6, and 12 months (study end) or at the end of treatment.

There were nine cases of the primary end point (a decline in LVEF of 16% or greater from baseline) among 397 patients on sunitinib, seven among 394 patients on sorafenib, and five among 502 patients on placebo. The respective event rates were 2.3%, 1.8%, and 1.0%; these differences were not clinically significant.

The numbers for other cardiac events – including LVEF decline of 16% or more below the institutional level of normal occurring after 6 months, or a grade 2 or 3 left ventricular systolic or diastolic dysfunction – were also similar among the groups, occurring in 12, 11, and 11 patients, respectively.

"Looking at the data as they stand, it on the face of it is very reassuring, with the primary end point being met in a very small proportion of patients," commented the invited discussant Dr. Tim Eisen, professor of oncology at the University of Cambridge (England).

He pointed out, however, that new cardiac events were seen in the study past 6 months of therapy, which indicated that investigators should continue to monitor patients for cardiotoxicities throughout the course of therapy and in follow-up.

TKIs in Practice

The Stanford investigators looked at the incidence of hypertension, left ventricular dysfunction, changes in serum markers of cardiovascular toxicity, and heart failure in 159 patients with metastatic RCC who were treated from 2004 through 2011. They found that 116 of 159 patients (73%) developed cardiovascular toxicities.

"Sunitinib was the most frequently used and most common offending agent, with 66 of 101 sunitinib-treated patients (65%) developing a form of CV toxicity, or 32 of 101 (32%) excluding hypertension. However, it was notable that CV toxicity was observed in 68%, 66%, and 51% of patients treated with bevacizumab, sorafenib, and pazopanib as well," the investigators wrote.

They noted that there were fewer toxicities with mTOR (mammalian target of rapamycin) inhibitors than with TKIs, but the sample sizes were small.

The ECOG E2805 trial was supported by the National Cancer Institute. The Stanford study was internally funded. Dr. Haas reported having a consulting or advisory role to Boehringer Ingelheim, Dendreon, Novartis, and Pfizer, and receiving research funding from GlaxoSmithKline. Dr. Hall reported having no relevant disclosures. Dr. Eisen has received honoraria and serves in a consulting or advisory role to Astellas and AVEO.