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Re: Radical Prostatectomy Versus Observation for Localized Prostate Cancer
Urological Survey
Urological Oncology: Prostate Cancer Re: Radical Prostatectomy Versus Observation for Localized Prostate Cancer T. J. Wilt, M. K. Brawer, K. M. Jones, M. J. Barry, W. J. Aronson, S. Fox, J. R. Gingrich, J. T. Wei, P. Gilhooly, B. M. Grob, I. Nsouli, P. Iyer, R. Cartagena, G. Snider, C. Roehrborn, R. Sharifi, W. Blank, P. Pandya, G. L. Andriole, D. Culkin and T. Wheeler; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Health Care System and Section of General Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota N Engl J Med 2012; 367: 203–213.
Background: The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. Methods: From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. Results: During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P⫽0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P⫽0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P⫽0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P⫽0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. Conclusions: Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostatecancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. Editorial Comment: This study began in the early PSA era and was originally designed to study 2,000 men who were randomly assigned to either radical prostatectomy or observation. The study itself was severely flawed. For one thing, it was statistically underpowered; the scientists recruited only 731 men, instead of the 2,000. (An editorial that accompanied this article stated that it would require 1,200 patients to fulfill the statistical goal that the study authors reported.1) Also, although “a life expectancy of at least 10 years” was an entry criterion, by 10 years almost half of the participants had died, leaving only 176 men in the surgery group and 187 observation men, and by 15 years only 30% were alive. This explains their strategy in randomization, which is a major violation of their investigational protocol. They did not recruit healthy men who would be candidates for surgery and randomize them to observation; rather, they recruited men with a limited life expectancy who were candidates for observation and randomized them to surgery. The study authors concluded that “among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce 0022-5347/12/1886-2225/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2012.09.067 Vol. 188, 2225-2232, December 2012 Printed in U.S.A.
www.jurology.com
2225
2226
PROSTATE CANCER
all-cause or prostate cancer mortality, as compared with observation.” This study is a straw man; its authors wanted to mislead readers by suggesting that their findings apply to all men with prostate cancer when, in fact, their results only apply to men who are older or in poor health, and this finding is far from newsworthy. For 3 decades we have said that men who have a life expectancy of 10 years or less should not undergo surgery. And yet, much of the news media took this story at face value. For example, The New York Times reported, “A new study shows that prostate cancer surgery, which often leaves men impotent or incontinent, does not appear to save the lives of men with early stage disease, who account for most of the cases, and many of these men would do just as well to choose no treatment at all.” This study, the newspaper added, was “game-changing.” Men who have already undergone surgery might well have wondered, “What have I done?” Unfortunately, many young men with aggressive, curable disease will only remember this sound bite. The study authors never conceded that their observations at 10 years of followup should not be applied to younger men. But an ever growing volume of evidence shows that in men with low volume cancer progression continues for many years. For example, in a study from Sweden of men with very small cancers who were treated with observation alone, death rates from prostate cancer remained very low (15 per 100,000 persons) for the first 15 years— but beyond that point they skyrocketed (to 44 per 100,000 persons), and nearly all of these men eventually died of prostate cancer.2 The PIVOT authors did not admit this likelihood in their study. Because only 30% of the cohort was alive at 15 years, this study will never have followup long enough to answer this question. With all of these shortcomings, it is surprising that they were able to demonstrate some significant benefits of surgery: there was an overall 60% decrease in the risk of metastases and a reduction in prostate cancer mortality in patients who had a PSA greater than 10 ng/ml or were in the high risk category. All that the PIVOT results tell us is that in a man who has a life expectancy of 10 years or less and who has low volume disease surgery is not an ideal option. This is old news, and is far from being a “game-changer.” The information in this article is simply not good enough to be of help to an otherwise healthy man in his forties, fifties or early sixties trying to figure out what he should do. Patrick C. Walsh, M.D. 1. Thompson IM Jr and Tangen CM: Prostate cancer— uncertainty and a way forward. N Engl J Med 2012; 367: 270. 2. Johansson JE, Andrén O, Andersson SO et al: Natural history of early, localized prostate cancer. JAMA 2004; 291: 2713.
Re: Projecting Prostate Cancer Mortality in the PCPT and REDUCE Chemoprevention Trials P. F. Pinsky, A. Black, R. Grubb, E. D. Crawford, G. Andriole, I. Thompson and H. Parnes Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland Cancer 2012; Epub ahead of print.
Background: Two recent chemoprevention trials demonstrated significant reductions in overall prostate cancer incidence. However, a possible increase in high-grade disease has raised concerns that the harms of the drugs, including mortality because of high-grade disease, may outweigh the benefits. The authors attempted to estimate the effect of these drugs on prostate cancer mortality to be able to better evaluate the cost-benefit tradeoff. Methods: The authors analyzed prostate cancer incidence in the Prostate Cancer Prevention Trial (PCPT) and Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which evaluated finasteride and the related compound dutasteride, respectively (both vs placebo). They used 13-year prostate cancer survival data from the Prostate, Lung, Colorectal and Ovarian (PLCO) trial to project prostate cancer mortality from incidence patterns; survival rates were applied to incident cancers according to prognostic strata, which were defined by Gleason score, prostate-specific antigen level, and clinical stage. For PCPT, the analysis was performed using both original trial results and previously published adjusted analyses that attempted to
Urological Oncology: Prostate Cancer Re: Radical Prostatectomy Versus Observation for Localized Prostate Cancer T. J. Wilt, M. K. Brawer, K. M. Jones, M. J. Barry, W. J. Aronson, S. Fox, J. R. Gingrich, J. T. Wei, P. Gilhooly, B. M. Grob, I. Nsouli, P. Iyer, R. Cartagena, G. Snider, C. Roehrborn, R. Sharifi, W. Blank, P. Pandya, G. L. Andriole, D. Culkin and T. Wheeler; Prostate Cancer Intervention versus Observation Trial (PIVOT) Study Group Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Health Care System and Section of General Medicine, University of Minnesota School of Medicine, Minneapolis, Minnesota N Engl J Med 2012; 367: 203–213.
Background: The effectiveness of surgery versus observation for men with localized prostate cancer detected by means of prostate-specific antigen (PSA) testing is not known. Methods: From November 1994 through January 2002, we randomly assigned 731 men with localized prostate cancer (mean age, 67 years; median PSA value, 7.8 ng per milliliter) to radical prostatectomy or observation and followed them through January 2010. The primary outcome was all-cause mortality; the secondary outcome was prostate-cancer mortality. Results: During the median follow-up of 10.0 years, 171 of 364 men (47.0%) assigned to radical prostatectomy died, as compared with 183 of 367 (49.9%) assigned to observation (hazard ratio, 0.88; 95% confidence interval [CI], 0.71 to 1.08; P⫽0.22; absolute risk reduction, 2.9 percentage points). Among men assigned to radical prostatectomy, 21 (5.8%) died from prostate cancer or treatment, as compared with 31 men (8.4%) assigned to observation (hazard ratio, 0.63; 95% CI, 0.36 to 1.09; P⫽0.09; absolute risk reduction, 2.6 percentage points). The effect of treatment on all-cause and prostate-cancer mortality did not differ according to age, race, coexisting conditions, self-reported performance status, or histologic features of the tumor. Radical prostatectomy was associated with reduced all-cause mortality among men with a PSA value greater than 10 ng per milliliter (P⫽0.04 for interaction) and possibly among those with intermediate-risk or high-risk tumors (P⫽0.07 for interaction). Adverse events within 30 days after surgery occurred in 21.4% of men, including one death. Conclusions: Among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce all-cause or prostatecancer mortality, as compared with observation, through at least 12 years of follow-up. Absolute differences were less than 3 percentage points. Editorial Comment: This study began in the early PSA era and was originally designed to study 2,000 men who were randomly assigned to either radical prostatectomy or observation. The study itself was severely flawed. For one thing, it was statistically underpowered; the scientists recruited only 731 men, instead of the 2,000. (An editorial that accompanied this article stated that it would require 1,200 patients to fulfill the statistical goal that the study authors reported.1) Also, although “a life expectancy of at least 10 years” was an entry criterion, by 10 years almost half of the participants had died, leaving only 176 men in the surgery group and 187 observation men, and by 15 years only 30% were alive. This explains their strategy in randomization, which is a major violation of their investigational protocol. They did not recruit healthy men who would be candidates for surgery and randomize them to observation; rather, they recruited men with a limited life expectancy who were candidates for observation and randomized them to surgery. The study authors concluded that “among men with localized prostate cancer detected during the early era of PSA testing, radical prostatectomy did not significantly reduce 0022-5347/12/1886-2225/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
http://dx.doi.org/10.1016/j.juro.2012.09.067 Vol. 188, 2225-2232, December 2012 Printed in U.S.A.
www.jurology.com
2225
2226
PROSTATE CANCER
all-cause or prostate cancer mortality, as compared with observation.” This study is a straw man; its authors wanted to mislead readers by suggesting that their findings apply to all men with prostate cancer when, in fact, their results only apply to men who are older or in poor health, and this finding is far from newsworthy. For 3 decades we have said that men who have a life expectancy of 10 years or less should not undergo surgery. And yet, much of the news media took this story at face value. For example, The New York Times reported, “A new study shows that prostate cancer surgery, which often leaves men impotent or incontinent, does not appear to save the lives of men with early stage disease, who account for most of the cases, and many of these men would do just as well to choose no treatment at all.” This study, the newspaper added, was “game-changing.” Men who have already undergone surgery might well have wondered, “What have I done?” Unfortunately, many young men with aggressive, curable disease will only remember this sound bite. The study authors never conceded that their observations at 10 years of followup should not be applied to younger men. But an ever growing volume of evidence shows that in men with low volume cancer progression continues for many years. For example, in a study from Sweden of men with very small cancers who were treated with observation alone, death rates from prostate cancer remained very low (15 per 100,000 persons) for the first 15 years— but beyond that point they skyrocketed (to 44 per 100,000 persons), and nearly all of these men eventually died of prostate cancer.2 The PIVOT authors did not admit this likelihood in their study. Because only 30% of the cohort was alive at 15 years, this study will never have followup long enough to answer this question. With all of these shortcomings, it is surprising that they were able to demonstrate some significant benefits of surgery: there was an overall 60% decrease in the risk of metastases and a reduction in prostate cancer mortality in patients who had a PSA greater than 10 ng/ml or were in the high risk category. All that the PIVOT results tell us is that in a man who has a life expectancy of 10 years or less and who has low volume disease surgery is not an ideal option. This is old news, and is far from being a “game-changer.” The information in this article is simply not good enough to be of help to an otherwise healthy man in his forties, fifties or early sixties trying to figure out what he should do. Patrick C. Walsh, M.D. 1. Thompson IM Jr and Tangen CM: Prostate cancer— uncertainty and a way forward. N Engl J Med 2012; 367: 270. 2. Johansson JE, Andrén O, Andersson SO et al: Natural history of early, localized prostate cancer. JAMA 2004; 291: 2713.
Re: Projecting Prostate Cancer Mortality in the PCPT and REDUCE Chemoprevention Trials P. F. Pinsky, A. Black, R. Grubb, E. D. Crawford, G. Andriole, I. Thompson and H. Parnes Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland Cancer 2012; Epub ahead of print.
Background: Two recent chemoprevention trials demonstrated significant reductions in overall prostate cancer incidence. However, a possible increase in high-grade disease has raised concerns that the harms of the drugs, including mortality because of high-grade disease, may outweigh the benefits. The authors attempted to estimate the effect of these drugs on prostate cancer mortality to be able to better evaluate the cost-benefit tradeoff. Methods: The authors analyzed prostate cancer incidence in the Prostate Cancer Prevention Trial (PCPT) and Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which evaluated finasteride and the related compound dutasteride, respectively (both vs placebo). They used 13-year prostate cancer survival data from the Prostate, Lung, Colorectal and Ovarian (PLCO) trial to project prostate cancer mortality from incidence patterns; survival rates were applied to incident cancers according to prognostic strata, which were defined by Gleason score, prostate-specific antigen level, and clinical stage. For PCPT, the analysis was performed using both original trial results and previously published adjusted analyses that attempted to