- Email: [email protected]
What Do We Really Know about Prostate Cancer?
european urology 52 (2007) 948–950
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Editorial –
referring to the article published on pp. 1028–1035 of this issue
What Do We Really Know about Prostate Cancer? Peter Albertsen * Division of Urology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030 USA
The appropriate management of localized prostate cancer remains an enigma. As urologists, we are all too familiar with the tragic course followed by men with advancing metastatic disease. From a urologist’s perspective, disease progression is inevitable and justifies aggressive screening for prostatespecific antigen (PSA) and treatment of localized disease with either surgery or radiation. Unfortunately, this may not be the appropriate strategy to care for many patients. In their manuscript in this issue of European Urology Adolfsson et al remind us that only 42 of 112 patients presenting with localized prostate cancer between 1978 and 1982 died of their disease [1]. The other 70 men died from a cause unrelated to prostate cancer. Even if we assume that all men with clinically localized disease can be cured with surgery or radiation, their study suggests that at most only 38% of men are likely to benefit from a program of screening and treatment. Public health officials and administrators who control health care budgets are becoming increasingly aware of these data. Therefore, as urologists, we need to develop more sophisticated algorithms for diagnosing and treating prostate cancer if we are to remain the experts who manage this disease. What do we know about prostate cancer? First, it is clear that prostate cancer is a chronic disease in the vast majority of patients. Adolfsson and several others have shown us that most men can live with prostate cancer for a very long time [1–3]. Many require no treatment. Second, these same studies have shown us that prostate cancer continues to
progress even as long as 20 yr following diagnosis. There is no time following diagnosis when we can reassure a man that his disease will never pose a clinical problem. Third, PSA testing results in a dramatic increase in the number of men diagnosed with this disease. What are we less certain about regarding prostate cancer? We do not fully understand who is destined to have progressive disease and who harbors indolent disease. Pathologists have taught us that men with poorly differentiated disease have a much worse prognosis than men with well or moderately differentiated disease. Several decades ago aspiration cytology was the standard method of detecting prostate cancer in Sweden. Pathologists there became adept at discerning men with bad cancers from those with less aggressive disease. In the United States, Gleason disseminated his system of identifying men with poorly differentiated disease from those with well-differentiated disease. Since then researchers have explored many other genetic probes including the analysis of cellular ploidy to separate bad cancers from good cancers [4]. Unfortunately, these studies have yet to yield significant, new information independent from that provided by basic histology. Also, unfortunately, even this standard is not absolute. Contemporary Gleason scoring has inflated values so that many tumors previously read as low grade are now reported as Gleason 6 disease [5]. We are also uncertain about the efficacy of our treatments. The Swedish randomized trial comparing outcomes following radical surgery versus
DOI of original article: 10.1016/j.eururo.2007.04.002 * Tel. +1 860 679 3676; Fax: +1 860 679 1318. E-mail address: [email protected]. 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2007.04.021
european urology 52 (2007) 948–950
watchful waiting has provided us with critical data [6]. Their most recent update shows a modest benefit to surgery after 10 yr of follow-up. Fourteen percent of men treated with watchful waiting have died from their disease as compared with only 7% of men who underwent radical prostatectomy. We know even less about outcomes following radiation therapy other than that the results are probably comparable with surgery for at least 10 yr and are improved in men with advanced, localized disease if radiation is supplemented with androgen ablation [7]. What do we know the least about prostate cancer? At this point we have no real understanding of the natural history of screen-detected prostate cancer. All of the natural history studies published to date, including the one by Adolfsson et al [1], include only men presenting with obstructive symptoms or with a palpable nodule on rectal examination. In contemporary practice in North America, these patients are rare. More commonly men with an elevated PSA value following 1, 2, or 3 yr and sometimes as many as 10 yr of PSA testing undergo a transrectal ultrasound and biopsy of their prostate. This, in turn, has produced a dramatic increase in the number of new cases of prostate cancer. What percentage of these men are destined to die from their disease in the absence of treatment? Several studies have shown us that the pool of men with subclinical disease is considerably greater than the pool of men who present with obstructive symptoms or prostate nodules [8]. As a consequence, repeated PSA testing is uncovering large numbers of patients who never would have presented with localized disease similar to the cohort assembled by Adolfsson et al. It may be true that some of the men identified by PSA testing are destined to develop metastatic disease if left untreated, but there is a much higher probability that a significant number of men identified by PSA testing are not destined to suffer effects of their disease at all. PSA testing also leads to the diagnosis of prostate cancer in men at much younger ages than was common during the era when the Adolfsson et al cohort was assembled. Do we actually alter the course of this disease by finding and treating it earlier or are we just witnessing the typical effects of lead time that have been estimated by Draisma et al [9] to be at least 10 yr among men diagnosed in their fifties and >5 yr among men diagnosed in their seventies? Randomized trials are currently underway that will help provide important insights into these uncertainties. The European Randomized Trial of
949
Screening for Prostate Cancer is soon expected to present results concerning the efficacy of population-based PSA testing. The Prostate, Lung, Colorectal, Ovary (PLCO) trial being conducted in the United States will provide some insights concerning the actual impact of PSA testing in a primary care setting. The Prostate Cancer Intervention versus Observation Trial (PIVOT) being conducted in the United States by the Veterans Affairs Administration should provide information concerning the efficacy of radical prostatectomy in a population of men whose cancers have been identified by PSA testing. Finally, the Prostate Testing for Cancer and Treatment (ProTeCT) trial being conducted in the United Kingdom should provide answers concerning the impact of both screening and treatment with either surgery or radiation. Unfortunately, many of these trials are still several years away from reporting results. How should we manage this disease in the interim? Although still controversial, a growing number of researchers have begun to advocate a policy of active surveillance for men with localized, lowgrade, small-volume disease [10]. Urologists practicing in countries where widespread PSA testing has occurred for many years have noticed an increasing number of men diagnosed with minute quantities of Gleason 6 disease. One or two cores of 10 or 12 obtained often have <20% involvement with disease. This is clearly not the disease described in the present paper by Adolfsson et al. Furthermore, these patients are likely to have a prognosis that is much better than those described in that paper. In fact, there is a high probability that this disease will progress very slowly over the next several decades. No protocol has been established to monitor men on an active surveillance program, but those proposed are similar to the one outlined by Adolfsson et al. Most researchers suggest periodic PSA testing, possibly every 4–6 mo. Most researchers also suggest a repeat biopsy, usually between 1 and 2 yr following the initial diagnosis. After that most protocols suggest periodic prostate biopsy every 1–3 yr. Active surveillance is continued provided a patient’s serum PSA remains stable and there is no evidence of disease progression either by volume or by increased grade. Early reports suggest that a number of men will progress during the first few years based on these strict criteria, but a significant number will not. Hopefully this approach will match aggressive treatments with those men who have aggressive disease and no treatment for those men who harbor indolent disease. Whitmore’s saying ‘‘Is treatment possible, when it is necessary and is it necessary when it is
950
european urology 52 (2007) 948–950
possible?’’ has become an axiom among urologists. By publishing their results, Adolfsson et al remind us that this challenge is still very real. All men diagnosed with prostate cancer following PSA testing are not destined to die from their disease just as all men in Sweden who presented with prostate symptoms or a nodule in 1978–1982 did not die of theirs. Data from these historical series should provide contemporary clinicians with the courage to recommend active surveillance for some of their patients. Advising all men with newly diagnosed, localized prostate cancer to undergo surgery or radiation would have been wrong in 1980 just as it is wrong today. Similarly, advising all men to undergo watchful waiting was wrong in 38% of cases in 1980 as it would be today. In contemporary practice we have only two tools, serum PSA and tissue histology. We should try to use them to their best advantage until research into genetic markers provides us with better alternatives.
References [1] Adolfsson J, Tribukait B, Levitt S. The 20-yr outcome in patients with well- or moderately differentiated clinically localized prostate cancer diagnosed in the pre-PSA era: the prognostic value of tumor ploidy and comorbidity. Eur Urol 2007;52:1028–35.
[2] Johansson JE, Andren O, Andersson SO, et al. Natural history of early localized prostate cancer. JAMA 2004; 291:2713–9. [3] Albertsen PC, Hanley JA, Fine J. 20 year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005;293:2095–101. [4] Tribukait B. Flow cytometry in assessing the clinical aggressiveness of genito-urinary neoplasms. World J Urol 1987;5:108–22. [5] Albertsen PC, Hanley JA, Barrows GH, et al. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005;97:1236–7. [6] Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Eng J Med 2005;352:1977–84. [7] Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer: a phase III randomized trial. Lancet 2002;360:103–6. [8] Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or = 4.0 ng per millilitre. N Eng J Med 2004;350: 2239–46. [9] Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostate specific antigen screening: estimates from the European randomized study of screening for prostate cancer. J Natl Cancer Inst 2003; 95:868–78. [10] Warlick C, Trock BJ, Landis P, et al. Delayed versus immediate surgical intervention and prostate cancer outcome. J Natl Cancer Inst 2006;98:355–7.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Editorial –
referring to the article published on pp. 1028–1035 of this issue
What Do We Really Know about Prostate Cancer? Peter Albertsen * Division of Urology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030 USA
The appropriate management of localized prostate cancer remains an enigma. As urologists, we are all too familiar with the tragic course followed by men with advancing metastatic disease. From a urologist’s perspective, disease progression is inevitable and justifies aggressive screening for prostatespecific antigen (PSA) and treatment of localized disease with either surgery or radiation. Unfortunately, this may not be the appropriate strategy to care for many patients. In their manuscript in this issue of European Urology Adolfsson et al remind us that only 42 of 112 patients presenting with localized prostate cancer between 1978 and 1982 died of their disease [1]. The other 70 men died from a cause unrelated to prostate cancer. Even if we assume that all men with clinically localized disease can be cured with surgery or radiation, their study suggests that at most only 38% of men are likely to benefit from a program of screening and treatment. Public health officials and administrators who control health care budgets are becoming increasingly aware of these data. Therefore, as urologists, we need to develop more sophisticated algorithms for diagnosing and treating prostate cancer if we are to remain the experts who manage this disease. What do we know about prostate cancer? First, it is clear that prostate cancer is a chronic disease in the vast majority of patients. Adolfsson and several others have shown us that most men can live with prostate cancer for a very long time [1–3]. Many require no treatment. Second, these same studies have shown us that prostate cancer continues to
progress even as long as 20 yr following diagnosis. There is no time following diagnosis when we can reassure a man that his disease will never pose a clinical problem. Third, PSA testing results in a dramatic increase in the number of men diagnosed with this disease. What are we less certain about regarding prostate cancer? We do not fully understand who is destined to have progressive disease and who harbors indolent disease. Pathologists have taught us that men with poorly differentiated disease have a much worse prognosis than men with well or moderately differentiated disease. Several decades ago aspiration cytology was the standard method of detecting prostate cancer in Sweden. Pathologists there became adept at discerning men with bad cancers from those with less aggressive disease. In the United States, Gleason disseminated his system of identifying men with poorly differentiated disease from those with well-differentiated disease. Since then researchers have explored many other genetic probes including the analysis of cellular ploidy to separate bad cancers from good cancers [4]. Unfortunately, these studies have yet to yield significant, new information independent from that provided by basic histology. Also, unfortunately, even this standard is not absolute. Contemporary Gleason scoring has inflated values so that many tumors previously read as low grade are now reported as Gleason 6 disease [5]. We are also uncertain about the efficacy of our treatments. The Swedish randomized trial comparing outcomes following radical surgery versus
DOI of original article: 10.1016/j.eururo.2007.04.002 * Tel. +1 860 679 3676; Fax: +1 860 679 1318. E-mail address: [email protected]. 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2007.04.021
european urology 52 (2007) 948–950
watchful waiting has provided us with critical data [6]. Their most recent update shows a modest benefit to surgery after 10 yr of follow-up. Fourteen percent of men treated with watchful waiting have died from their disease as compared with only 7% of men who underwent radical prostatectomy. We know even less about outcomes following radiation therapy other than that the results are probably comparable with surgery for at least 10 yr and are improved in men with advanced, localized disease if radiation is supplemented with androgen ablation [7]. What do we know the least about prostate cancer? At this point we have no real understanding of the natural history of screen-detected prostate cancer. All of the natural history studies published to date, including the one by Adolfsson et al [1], include only men presenting with obstructive symptoms or with a palpable nodule on rectal examination. In contemporary practice in North America, these patients are rare. More commonly men with an elevated PSA value following 1, 2, or 3 yr and sometimes as many as 10 yr of PSA testing undergo a transrectal ultrasound and biopsy of their prostate. This, in turn, has produced a dramatic increase in the number of new cases of prostate cancer. What percentage of these men are destined to die from their disease in the absence of treatment? Several studies have shown us that the pool of men with subclinical disease is considerably greater than the pool of men who present with obstructive symptoms or prostate nodules [8]. As a consequence, repeated PSA testing is uncovering large numbers of patients who never would have presented with localized disease similar to the cohort assembled by Adolfsson et al. It may be true that some of the men identified by PSA testing are destined to develop metastatic disease if left untreated, but there is a much higher probability that a significant number of men identified by PSA testing are not destined to suffer effects of their disease at all. PSA testing also leads to the diagnosis of prostate cancer in men at much younger ages than was common during the era when the Adolfsson et al cohort was assembled. Do we actually alter the course of this disease by finding and treating it earlier or are we just witnessing the typical effects of lead time that have been estimated by Draisma et al [9] to be at least 10 yr among men diagnosed in their fifties and >5 yr among men diagnosed in their seventies? Randomized trials are currently underway that will help provide important insights into these uncertainties. The European Randomized Trial of
949
Screening for Prostate Cancer is soon expected to present results concerning the efficacy of population-based PSA testing. The Prostate, Lung, Colorectal, Ovary (PLCO) trial being conducted in the United States will provide some insights concerning the actual impact of PSA testing in a primary care setting. The Prostate Cancer Intervention versus Observation Trial (PIVOT) being conducted in the United States by the Veterans Affairs Administration should provide information concerning the efficacy of radical prostatectomy in a population of men whose cancers have been identified by PSA testing. Finally, the Prostate Testing for Cancer and Treatment (ProTeCT) trial being conducted in the United Kingdom should provide answers concerning the impact of both screening and treatment with either surgery or radiation. Unfortunately, many of these trials are still several years away from reporting results. How should we manage this disease in the interim? Although still controversial, a growing number of researchers have begun to advocate a policy of active surveillance for men with localized, lowgrade, small-volume disease [10]. Urologists practicing in countries where widespread PSA testing has occurred for many years have noticed an increasing number of men diagnosed with minute quantities of Gleason 6 disease. One or two cores of 10 or 12 obtained often have <20% involvement with disease. This is clearly not the disease described in the present paper by Adolfsson et al. Furthermore, these patients are likely to have a prognosis that is much better than those described in that paper. In fact, there is a high probability that this disease will progress very slowly over the next several decades. No protocol has been established to monitor men on an active surveillance program, but those proposed are similar to the one outlined by Adolfsson et al. Most researchers suggest periodic PSA testing, possibly every 4–6 mo. Most researchers also suggest a repeat biopsy, usually between 1 and 2 yr following the initial diagnosis. After that most protocols suggest periodic prostate biopsy every 1–3 yr. Active surveillance is continued provided a patient’s serum PSA remains stable and there is no evidence of disease progression either by volume or by increased grade. Early reports suggest that a number of men will progress during the first few years based on these strict criteria, but a significant number will not. Hopefully this approach will match aggressive treatments with those men who have aggressive disease and no treatment for those men who harbor indolent disease. Whitmore’s saying ‘‘Is treatment possible, when it is necessary and is it necessary when it is
950
european urology 52 (2007) 948–950
possible?’’ has become an axiom among urologists. By publishing their results, Adolfsson et al remind us that this challenge is still very real. All men diagnosed with prostate cancer following PSA testing are not destined to die from their disease just as all men in Sweden who presented with prostate symptoms or a nodule in 1978–1982 did not die of theirs. Data from these historical series should provide contemporary clinicians with the courage to recommend active surveillance for some of their patients. Advising all men with newly diagnosed, localized prostate cancer to undergo surgery or radiation would have been wrong in 1980 just as it is wrong today. Similarly, advising all men to undergo watchful waiting was wrong in 38% of cases in 1980 as it would be today. In contemporary practice we have only two tools, serum PSA and tissue histology. We should try to use them to their best advantage until research into genetic markers provides us with better alternatives.
References [1] Adolfsson J, Tribukait B, Levitt S. The 20-yr outcome in patients with well- or moderately differentiated clinically localized prostate cancer diagnosed in the pre-PSA era: the prognostic value of tumor ploidy and comorbidity. Eur Urol 2007;52:1028–35.
[2] Johansson JE, Andren O, Andersson SO, et al. Natural history of early localized prostate cancer. JAMA 2004; 291:2713–9. [3] Albertsen PC, Hanley JA, Fine J. 20 year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005;293:2095–101. [4] Tribukait B. Flow cytometry in assessing the clinical aggressiveness of genito-urinary neoplasms. World J Urol 1987;5:108–22. [5] Albertsen PC, Hanley JA, Barrows GH, et al. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005;97:1236–7. [6] Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Eng J Med 2005;352:1977–84. [7] Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer: a phase III randomized trial. Lancet 2002;360:103–6. [8] Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or = 4.0 ng per millilitre. N Eng J Med 2004;350: 2239–46. [9] Draisma G, Boer R, Otto SJ, et al. Lead times and overdetection due to prostate specific antigen screening: estimates from the European randomized study of screening for prostate cancer. J Natl Cancer Inst 2003; 95:868–78. [10] Warlick C, Trock BJ, Landis P, et al. Delayed versus immediate surgical intervention and prostate cancer outcome. J Natl Cancer Inst 2006;98:355–7.