PIVOT Trial: No Overall Benefit to Radical Prostatectomy for Localized Prostate Cancer

WASHINGTON – Radical prostatectomy did not significantly reduce the overall rate of all-cause or disease-specific death compared with observation at 12 years in men with clinically localized prostate cancer who participated in the Prostate Cancer Intervention Versus Observation Trial (PIVOT), chief investigator Dr. Timothy J. Wilt has reported.

The surgery does, however, appear to have benefited men with higher prostate-specific antigen (PSA) scores and those with higher-risk disease, Dr. Wilt said.

The yet-to-be-published main results of the PIVOT trial offer a different take on the value of radical prostatectomy from the recently published results of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), a pre–PSA-era trial that showed a significant overall benefit to surgery, even in men with tumors deemed to be low-risk.

In the PIVOT trial, which enrolled men whose cancer was detected in the early-PSA era, those with lower PSA levels or tumors categorized as low risk clearly gained no benefit from surgery, said Dr. Wilt, professor of medicine at the University of Minnesota, Minneapolis, and core investigator of the Department of Veterans Affairs’ Center for Chronic Disease Outcomes Research.

"Surgery did not reduce mortality [overall and disease specific] more than observation in men with low-PSA or low-risk prostate cancer, but our results do suggest a benefit for surgery in higher-PSA or higher-risk groups," Dr. Wilt reported at the annual meeting of the American Urological Association.

Initiated in 1994, the PIVOT trial randomized 731 men at medical centers across the United States to receive radical prostatectomy (281) or watchful waiting, with palliative care for symptoms. To be eligible, patients had to be 75 years or younger, with clinically localized prostate cancer and a PSA value less than 50 ng/mL.

Their mean age was 67 years, and nearly one-third were African American. Approximately 85% described themselves as fully active. Their mean and median PSA scores were 10.2 ng/mL and 7.8 ng/mL, respectively. Using tumor risk categorizations that incorporated PSA values, Gleason scores, and tumor stage, approximately 43% had low-risk tumors, 36% had intermediate-risk tumors, and 21% had high-risk tumors.

Investigators completed enrollment in 2002 and followed patients through 2010 (with a median follow-up of 10 years), determining cumulative rates of death at specific time points through intention-to-treat analysis. The new findings come from the final, 12-year analysis.

At the 12-year mark, 354 of the 731 men (48.4%) had died, with absolute reductions in all-cause and disease-specific mortality of approximately 3% in the radical prostatectomy group compared with observation. Specifically, the absolute reduction in all-cause mortality was 2.9% (a hazard ratio of 0.88), and the absolute reduction in prostate cancer mortality was 2.7% (HR, 0.63), values that are not statistically significant, Dr. Wilt said.

The effect of surgery on all-cause and disease-specific mortality did not vary by age, race, self-perceived health status, or the presence of comorbidities. There was also no significant effect of surgery on death rates when men were categorized solely by their Gleason scores (6 or less vs. 7-10).

Prostate cancer mortality did, however, "vary substantially by tumor risk category, ranging from 3% in the low-risk category to 13% in high risk," Dr. Wilt said.

In men with low-risk disease, there was an absolute difference in prostate cancer mortality between the treatment groups of 1.4% in favor of observation. But in men with high-risk disease, the absolute difference was 8.4%, in favor of surgery, a difference that is significant but appears to be of "borderline" statistical significance, Dr. Wilt said after the meeting.

"That’s why we say that our results suggest that there might be a benefit in men with high-risk disease," he said.

One factor challenging the PIVOT trial analyses is variation in some of the pathology readings. While the impact of surgery on prostate cancer mortality for the high-risk group was "consistent whether local or central pathology readings were used [in the sub-analysis]," the benefit of surgery on prostate cancer mortality and all-cause mortality for the intermediate-risk group varied depending on whether local or central pathology readings were employed in the risk categorization and subanalysis, he said.

The impact of surgery was seen most clearly in the PSA-level subgroup. "We consistently found that surgery did not reduce [either all-cause or disease-specific] mortality for men with PSA levels less than or equal to 10, and we consistently found that radical prostatectomy reduced both overall and disease-specific mortality in men with PSAs above 10," he said in the interview.

"Overall, we’re most confident in our findings regarding men with low PSA, low-stage, or low-risk disease," he emphasized.

In men with PSA levels of 10 ng/mL or less, the difference in absolute risk for all-cause mortality was 2.7%, in favor of observation.

Among men whose PSA levels were greater than 10 ng/mL, those randomized to receive radical prostatectomy had a statistically significant 13.2% absolute reduction in all-cause mortality compared with the watchful waiting group, which means that "about 8 men would have to be treated to prevent 1 death in about 12 years," he said after the meeting.

The men enrolled in the PIVOT trial are different from those in the SPCG-4 for various reasons, Dr. Wilt noted. For one, the majority of patients in the Scandinavian trial were diagnosed through palpable tumors or significant urinary obstruction symptoms. "So they had more advanced disease, even though it was still considered clinically localized," he said.

While the PIVOT enrollees are more representative of men being diagnosed and treated in the United States, there still are differences between the early era of PSA testing – the mid-late 1990s, when many of the PIVOT participants were enrolled – and current times, when "nearly all men, for better or for worse, are getting multiple PSA tests and having smaller tumors found earlier," he said.

"The risk of overdiagnosis in the PIVOT study is high, and it’s much higher today," Dr. Wilt said after the meeting. "As we move further and further to finding smaller and smaller tumors that have a very good long-term prognosis even with no treatment ... the risk of overdiagnosis becomes even greater than what we [see in PIVOT.]"

This study was supported by the Department of Veteran Affairs, the Agency for Healthcare Research and Quality, and the National Cancer Institute. Dr. Wilt reported that he had nothing to disclose.

WASHINGTON – Radical prostatectomy did not significantly reduce the overall rate of all-cause or disease-specific death compared with observation at 12 years in men with clinically localized prostate cancer who participated in the Prostate Cancer Intervention Versus Observation Trial (PIVOT), chief investigator Dr. Timothy J. Wilt has reported.

The surgery does, however, appear to have benefited men with higher prostate-specific antigen (PSA) scores and those with higher-risk disease, Dr. Wilt said.

The yet-to-be-published main results of the PIVOT trial offer a different take on the value of radical prostatectomy from the recently published results of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), a pre–PSA-era trial that showed a significant overall benefit to surgery, even in men with tumors deemed to be low-risk.

In the PIVOT trial, which enrolled men whose cancer was detected in the early-PSA era, those with lower PSA levels or tumors categorized as low risk clearly gained no benefit from surgery, said Dr. Wilt, professor of medicine at the University of Minnesota, Minneapolis, and core investigator of the Department of Veterans Affairs’ Center for Chronic Disease Outcomes Research.

"Surgery did not reduce mortality [overall and disease specific] more than observation in men with low-PSA or low-risk prostate cancer, but our results do suggest a benefit for surgery in higher-PSA or higher-risk groups," Dr. Wilt reported at the annual meeting of the American Urological Association.

Initiated in 1994, the PIVOT trial randomized 731 men at medical centers across the United States to receive radical prostatectomy (281) or watchful waiting, with palliative care for symptoms. To be eligible, patients had to be 75 years or younger, with clinically localized prostate cancer and a PSA value less than 50 ng/mL.

Their mean age was 67 years, and nearly one-third were African American. Approximately 85% described themselves as fully active. Their mean and median PSA scores were 10.2 ng/mL and 7.8 ng/mL, respectively. Using tumor risk categorizations that incorporated PSA values, Gleason scores, and tumor stage, approximately 43% had low-risk tumors, 36% had intermediate-risk tumors, and 21% had high-risk tumors.

Investigators completed enrollment in 2002 and followed patients through 2010 (with a median follow-up of 10 years), determining cumulative rates of death at specific time points through intention-to-treat analysis. The new findings come from the final, 12-year analysis.

At the 12-year mark, 354 of the 731 men (48.4%) had died, with absolute reductions in all-cause and disease-specific mortality of approximately 3% in the radical prostatectomy group compared with observation. Specifically, the absolute reduction in all-cause mortality was 2.9% (a hazard ratio of 0.88), and the absolute reduction in prostate cancer mortality was 2.7% (HR, 0.63), values that are not statistically significant, Dr. Wilt said.

The effect of surgery on all-cause and disease-specific mortality did not vary by age, race, self-perceived health status, or the presence of comorbidities. There was also no significant effect of surgery on death rates when men were categorized solely by their Gleason scores (6 or less vs. 7-10).

Prostate cancer mortality did, however, "vary substantially by tumor risk category, ranging from 3% in the low-risk category to 13% in high risk," Dr. Wilt said.

In men with low-risk disease, there was an absolute difference in prostate cancer mortality between the treatment groups of 1.4% in favor of observation. But in men with high-risk disease, the absolute difference was 8.4%, in favor of surgery, a difference that is significant but appears to be of "borderline" statistical significance, Dr. Wilt said after the meeting.

"That’s why we say that our results suggest that there might be a benefit in men with high-risk disease," he said.

One factor challenging the PIVOT trial analyses is variation in some of the pathology readings. While the impact of surgery on prostate cancer mortality for the high-risk group was "consistent whether local or central pathology readings were used [in the sub-analysis]," the benefit of surgery on prostate cancer mortality and all-cause mortality for the intermediate-risk group varied depending on whether local or central pathology readings were employed in the risk categorization and subanalysis, he said.

The impact of surgery was seen most clearly in the PSA-level subgroup. "We consistently found that surgery did not reduce [either all-cause or disease-specific] mortality for men with PSA levels less than or equal to 10, and we consistently found that radical prostatectomy reduced both overall and disease-specific mortality in men with PSAs above 10," he said in the interview.

"Overall, we’re most confident in our findings regarding men with low PSA, low-stage, or low-risk disease," he emphasized.

In men with PSA levels of 10 ng/mL or less, the difference in absolute risk for all-cause mortality was 2.7%, in favor of observation.

Among men whose PSA levels were greater than 10 ng/mL, those randomized to receive radical prostatectomy had a statistically significant 13.2% absolute reduction in all-cause mortality compared with the watchful waiting group, which means that "about 8 men would have to be treated to prevent 1 death in about 12 years," he said after the meeting.

The men enrolled in the PIVOT trial are different from those in the SPCG-4 for various reasons, Dr. Wilt noted. For one, the majority of patients in the Scandinavian trial were diagnosed through palpable tumors or significant urinary obstruction symptoms. "So they had more advanced disease, even though it was still considered clinically localized," he said.

While the PIVOT enrollees are more representative of men being diagnosed and treated in the United States, there still are differences between the early era of PSA testing – the mid-late 1990s, when many of the PIVOT participants were enrolled – and current times, when "nearly all men, for better or for worse, are getting multiple PSA tests and having smaller tumors found earlier," he said.

"The risk of overdiagnosis in the PIVOT study is high, and it’s much higher today," Dr. Wilt said after the meeting. "As we move further and further to finding smaller and smaller tumors that have a very good long-term prognosis even with no treatment ... the risk of overdiagnosis becomes even greater than what we [see in PIVOT.]"

This study was supported by the Department of Veteran Affairs, the Agency for Healthcare Research and Quality, and the National Cancer Institute. Dr. Wilt reported that he had nothing to disclose.

WASHINGTON – Radical prostatectomy did not significantly reduce the overall rate of all-cause or disease-specific death compared with observation at 12 years in men with clinically localized prostate cancer who participated in the Prostate Cancer Intervention Versus Observation Trial (PIVOT), chief investigator Dr. Timothy J. Wilt has reported.

The surgery does, however, appear to have benefited men with higher prostate-specific antigen (PSA) scores and those with higher-risk disease, Dr. Wilt said.

The yet-to-be-published main results of the PIVOT trial offer a different take on the value of radical prostatectomy from the recently published results of the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), a pre–PSA-era trial that showed a significant overall benefit to surgery, even in men with tumors deemed to be low-risk.

In the PIVOT trial, which enrolled men whose cancer was detected in the early-PSA era, those with lower PSA levels or tumors categorized as low risk clearly gained no benefit from surgery, said Dr. Wilt, professor of medicine at the University of Minnesota, Minneapolis, and core investigator of the Department of Veterans Affairs’ Center for Chronic Disease Outcomes Research.

"Surgery did not reduce mortality [overall and disease specific] more than observation in men with low-PSA or low-risk prostate cancer, but our results do suggest a benefit for surgery in higher-PSA or higher-risk groups," Dr. Wilt reported at the annual meeting of the American Urological Association.

Initiated in 1994, the PIVOT trial randomized 731 men at medical centers across the United States to receive radical prostatectomy (281) or watchful waiting, with palliative care for symptoms. To be eligible, patients had to be 75 years or younger, with clinically localized prostate cancer and a PSA value less than 50 ng/mL.

Their mean age was 67 years, and nearly one-third were African American. Approximately 85% described themselves as fully active. Their mean and median PSA scores were 10.2 ng/mL and 7.8 ng/mL, respectively. Using tumor risk categorizations that incorporated PSA values, Gleason scores, and tumor stage, approximately 43% had low-risk tumors, 36% had intermediate-risk tumors, and 21% had high-risk tumors.

Investigators completed enrollment in 2002 and followed patients through 2010 (with a median follow-up of 10 years), determining cumulative rates of death at specific time points through intention-to-treat analysis. The new findings come from the final, 12-year analysis.

At the 12-year mark, 354 of the 731 men (48.4%) had died, with absolute reductions in all-cause and disease-specific mortality of approximately 3% in the radical prostatectomy group compared with observation. Specifically, the absolute reduction in all-cause mortality was 2.9% (a hazard ratio of 0.88), and the absolute reduction in prostate cancer mortality was 2.7% (HR, 0.63), values that are not statistically significant, Dr. Wilt said.

The effect of surgery on all-cause and disease-specific mortality did not vary by age, race, self-perceived health status, or the presence of comorbidities. There was also no significant effect of surgery on death rates when men were categorized solely by their Gleason scores (6 or less vs. 7-10).

Prostate cancer mortality did, however, "vary substantially by tumor risk category, ranging from 3% in the low-risk category to 13% in high risk," Dr. Wilt said.

In men with low-risk disease, there was an absolute difference in prostate cancer mortality between the treatment groups of 1.4% in favor of observation. But in men with high-risk disease, the absolute difference was 8.4%, in favor of surgery, a difference that is significant but appears to be of "borderline" statistical significance, Dr. Wilt said after the meeting.

"That’s why we say that our results suggest that there might be a benefit in men with high-risk disease," he said.

One factor challenging the PIVOT trial analyses is variation in some of the pathology readings. While the impact of surgery on prostate cancer mortality for the high-risk group was "consistent whether local or central pathology readings were used [in the sub-analysis]," the benefit of surgery on prostate cancer mortality and all-cause mortality for the intermediate-risk group varied depending on whether local or central pathology readings were employed in the risk categorization and subanalysis, he said.

The impact of surgery was seen most clearly in the PSA-level subgroup. "We consistently found that surgery did not reduce [either all-cause or disease-specific] mortality for men with PSA levels less than or equal to 10, and we consistently found that radical prostatectomy reduced both overall and disease-specific mortality in men with PSAs above 10," he said in the interview.

"Overall, we’re most confident in our findings regarding men with low PSA, low-stage, or low-risk disease," he emphasized.

In men with PSA levels of 10 ng/mL or less, the difference in absolute risk for all-cause mortality was 2.7%, in favor of observation.

Among men whose PSA levels were greater than 10 ng/mL, those randomized to receive radical prostatectomy had a statistically significant 13.2% absolute reduction in all-cause mortality compared with the watchful waiting group, which means that "about 8 men would have to be treated to prevent 1 death in about 12 years," he said after the meeting.

The men enrolled in the PIVOT trial are different from those in the SPCG-4 for various reasons, Dr. Wilt noted. For one, the majority of patients in the Scandinavian trial were diagnosed through palpable tumors or significant urinary obstruction symptoms. "So they had more advanced disease, even though it was still considered clinically localized," he said.

While the PIVOT enrollees are more representative of men being diagnosed and treated in the United States, there still are differences between the early era of PSA testing – the mid-late 1990s, when many of the PIVOT participants were enrolled – and current times, when "nearly all men, for better or for worse, are getting multiple PSA tests and having smaller tumors found earlier," he said.

"The risk of overdiagnosis in the PIVOT study is high, and it’s much higher today," Dr. Wilt said after the meeting. "As we move further and further to finding smaller and smaller tumors that have a very good long-term prognosis even with no treatment ... the risk of overdiagnosis becomes even greater than what we [see in PIVOT.]"

This study was supported by the Department of Veteran Affairs, the Agency for Healthcare Research and Quality, and the National Cancer Institute. Dr. Wilt reported that he had nothing to disclose.