EUROPEAN UROLOGY 67 (2015) 1006–1008
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 993–1005 of this issue
Active Surveillance for Prostate Cancer: Debate over the Application, Not the Concept Laurence Klotz * Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
The concept of conservative management of low-risk prostate cancer is not new. The approach, however, has evolved substantially over the last 40 yr, and continues to do so. For many years there was widespread skepticism about the impact of definitive therapy on the natural history of prostate cancer. Whitmore articulated this with his famous rhetorical question, ‘‘Is cure possible when it is necessary, or necessary when it is possible?’’, the inference for both being, probably not. The term watchful waiting was used to describe expectant management with intervention for symptomatic metastatic disease, and indeed some argued that this was optimal management for all men with prostate cancer. The first paper to use the term active surveillance (AS) in the management of prostate cancer, published in 1990, advocated this approach [1], which was essentially no treatment beyond delayed hormonal therapy. However, at least in North America, this was considered nihilistic and not widely adopted. The prostate-specific antigen (PSA) revolution of the late 1980s, along with the advent of transrectal ultrasoundguided biopsy and the biopsy gun, the adoption of nervesparing prostatectomy, and the development of improved radiation techniques, resulted in a widespread change to definitive management for all newly diagnosed patients with localized disease. Radical treatment was considered de rigueur for eligible patients, including those with low-grade disease. This commitment to radical treatment was powerfully enhanced by the milestone Scandinavian randomized trial of surgery versus watchful waiting, which showed a 50% reduction in cause-specific mortality [2], recently updated [3]. However, the idea that radical treatment represented overtreatment for low-grade disease did not die completely.
Many groups were concerned about this. The challenge was to develop an approach representing a middle ground between watchful waiting (no treatment until metastatic disease) and definitive therapy for all patients. A key concept that had not been articulated previously was the profound value of observing patients over time as a component of decision-making for patients with localized cancer. Over time, some patients would exhibit a change in risk parameters, affording an opportunity to identify the ‘‘wolf in sheep’s clothing’’ while the patient was still curable. Since most men with advanced prostate cancer had high PSA, and most men with low-risk early prostate cancer had low PSA, it seemed obvious that stable PSA might identify patients with clinically insignificant disease, and rapidly rising PSA might identify those who would benefit from treatment. Thus, the modern concept of AS, with close monitoring and selective delayed intervention for those who were reclassified as higher-risk patients, was born. The first report of a cohort of patients (n = 253) managed explicitly in this fashion was published in 2002 [4]. Since then, there has been an explosion of interest in this approach. The authors of the systematic review published in this issue [5] identified 3781 unique articles on the topic of AS in prostate cancer. Indeed, the concept has crossed disciplines, and is being adopted in breast cancer for management of ductal carcinoma in situ, for example, with explicit reference to the success of this approach in prostate cancer. The article in this issue of European Urology by Simpkin et al [5] is a significant contribution to the literature. It represents a detailed summary of AS experience to date, with a focus on the indications for radical intervention. The
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2015.01.004. * Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, #MG 408, Toronto, Ontario M4N 3M5, Canada. Tel. +1 416 4804673; Fax: +1 416 4806121. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2015.01.007 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
EUROPEAN UROLOGY 67 (2015) 1006–1008
authors identified 26 AS cohorts involving 7627 men. They used several novel techniques to address concerns about publication bias and small-study effects. As one might expect, given regional differences in the approach to cancer around the world, these cohorts differed in their eligibility criteria and triggers for intervention. The overall radical treatment rate was 8.8% per year, or approximately one-third at 4 yr. What is striking, however, is that the intervention rate varied 20-fold, from 1.1% per year (ref. [10] in the article) to 22.2% per year (ref. [18] in the article). Studies that included men with Gleason >6 had a lower rate of radical treatment overall, although men with Gleason 7 had a twofold higher rate of treatment. This seemingly paradoxical observation can be explained. That Gleason 4 pattern confers a more aggressive phenotype is supported by numerous studies. However, some experts believe that not all patients with Gleason 4 necessarily require treatment, particularly those found to have only small amounts. (A recent autopsy study of men dying of other causes revealed that more than 50% of the incidental cancers in Asian men were Gleason 7 [6]). These physicians are likely to have a more risk-tolerant view of volume and grade progression. Investigators who use an inclusive approach, including some intermediate-risk patients, for example, are likely to be less ‘‘trigger happy’’; in other words, they will require more substantial evidence of risk reclassification before advising the patient to have treatment. Investigators who are restrictive about patient eligibility for surveillance undoubtedly have a more riskaverse view of the implications of volume and grade increase, and are more likely to advise treatment for increase in Gleason 6 volume or the finding of Gleason 4 disease. These approaches are both legitimate. A more inclusive approach to surveillance and a higher bar before treatment is advised will provide many more patients with the benefits of avoiding intervention, but are also likely to result in a small increase in the number of men who progress to metastatic disease. We recently published our updated surveillance experience (too recent to be included in this overview), which was based on an inclusive approach. The proportion of patients managed with initial surveillance who had late progression to metastatic disease (beyond 7 yr), and therefore may have been cured by initial radical therapy, was 2.5% at 15 yr [7]. A more restrictive approach, as taken by the Hopkins group, for example, (ref. [19] in the article) will reduce the number of patients who avoid treatment, but may reduce this already low mortality rate further. The 26 series reviewed in this meta-analysis did not use magnetic resonance imaging as a parameter for decision-making. The ability to image prostate cancer accurately, and particularly the ability to exclude clinically significant disease with high probability, is a game changer. Other developments in the field that have not been captured include the move away from PSA kinetics as a trigger for intervention (owing to the lack of specificity of a rise in PSA); a clearer appreciation of the characteristics of the cancer in patients harboring worse
1007
disease (usually large anterior cancers); convincing evidence that Gleason pattern 3 has no metastatic potential; evidence that the main significance of higher Gleason 6 volume is a greater likelihood of coexistent higher-grade cancer; the emerging role of predictive molecular biomarkers; and data supporting the use of 5-a-reductase inhibitors in men on surveillance [8]. Incorporation of these developments is likely to result in a more consistent approach to men on AS. The overview reported that 20% of patients receiving treatment did so because of patient choice or anxiety. This figure seems high. Patient anxiety is very amenable to reassurance and accurate information about the indolent natural history of low-risk prostate cancer. My experience is that many patients who are categorized as being treated because of patient choice made decisions based on a change in risk that did not reach the threshold for intervention; for example, a PSA doubling time of 4 yr (whereas most groups required a threshold of 3 yr) or a significant increase in volume of Gleason 6 at centers that require grade progression. The authors rightfully identify that detailed information about the indications for intervention in prospective trials should be more meticulously collected. The median follow-up in the 26 studies was only 3.5 yr (range 1.5–7.5 yr). This short follow-up duration is somewhat misleading, in that as AS became legitimized, all of the cohorts began to accrue larger numbers of patients, reducing the median follow-up duration. However, the most mature cohorts now have substantial numbers of patients followed for more than 10–15 yr. Within another 5 yr, there will be hundreds of patients managed with AS with 15–20-yr follow-up, which should provide important information about long-term outcomes in AS patients. AS is an effective antidote to the overdiagnosis and potential for overtreatment resulting from PSA screening. Indeed, widespread adoption of AS will almost certainly result in a sharp decrease in the number needed to treat. The heterogeneity of the approach used by various groups around the world and the large number of important outstanding research questions described by the authors only reinforce the robust state of this field, and should in no way undermine the value that AS brings to patients. Conflicts of interest: The author has nothing to disclose.
References [1] Smith PH. The case for no initial treatment of localized prostate cancer. Urol Clin North Am 1990;17:827–34. [2] Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 2014;370:932–42. [3] Holmberg L, Bill-Axelson A, Helgesen F, et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002;347:781–9. [4] Choo R, Klotz L, Danjoux C, et al. Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression. J Urol 2002;167: 1664–9.
1008
EUROPEAN UROLOGY 67 (2015) 1006–1008
[5] Simpkin AJ, Tilling K, Martin RM, et al. Systematic review and meta-
[7] Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a
analysis of factors determining change to radical treatment in
large active surveillance cohort of patients with prostate cancer. J
active surveillance for localized prostate cancer. Eur Urol 2015; 67:993–1005.
Clin Oncol 2015;33:272–7. [8] Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in
[6] Zlotta AR, Egawa S, Pushkar D, et al. Prevalence of prostate cancer on
localised prostate cancer management: the REDEEM random-
autopsy: cross-sectional study on unscreened Caucasian and Asian
ised, double-blind, placebo-controlled trial. Lancet 2012;379:
men. J Natl Cancer Inst 2013;105:1050–8.
1103–11.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 993–1005 of this issue
Active Surveillance for Prostate Cancer: Debate over the Application, Not the Concept Laurence Klotz * Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
The concept of conservative management of low-risk prostate cancer is not new. The approach, however, has evolved substantially over the last 40 yr, and continues to do so. For many years there was widespread skepticism about the impact of definitive therapy on the natural history of prostate cancer. Whitmore articulated this with his famous rhetorical question, ‘‘Is cure possible when it is necessary, or necessary when it is possible?’’, the inference for both being, probably not. The term watchful waiting was used to describe expectant management with intervention for symptomatic metastatic disease, and indeed some argued that this was optimal management for all men with prostate cancer. The first paper to use the term active surveillance (AS) in the management of prostate cancer, published in 1990, advocated this approach [1], which was essentially no treatment beyond delayed hormonal therapy. However, at least in North America, this was considered nihilistic and not widely adopted. The prostate-specific antigen (PSA) revolution of the late 1980s, along with the advent of transrectal ultrasoundguided biopsy and the biopsy gun, the adoption of nervesparing prostatectomy, and the development of improved radiation techniques, resulted in a widespread change to definitive management for all newly diagnosed patients with localized disease. Radical treatment was considered de rigueur for eligible patients, including those with low-grade disease. This commitment to radical treatment was powerfully enhanced by the milestone Scandinavian randomized trial of surgery versus watchful waiting, which showed a 50% reduction in cause-specific mortality [2], recently updated [3]. However, the idea that radical treatment represented overtreatment for low-grade disease did not die completely.
Many groups were concerned about this. The challenge was to develop an approach representing a middle ground between watchful waiting (no treatment until metastatic disease) and definitive therapy for all patients. A key concept that had not been articulated previously was the profound value of observing patients over time as a component of decision-making for patients with localized cancer. Over time, some patients would exhibit a change in risk parameters, affording an opportunity to identify the ‘‘wolf in sheep’s clothing’’ while the patient was still curable. Since most men with advanced prostate cancer had high PSA, and most men with low-risk early prostate cancer had low PSA, it seemed obvious that stable PSA might identify patients with clinically insignificant disease, and rapidly rising PSA might identify those who would benefit from treatment. Thus, the modern concept of AS, with close monitoring and selective delayed intervention for those who were reclassified as higher-risk patients, was born. The first report of a cohort of patients (n = 253) managed explicitly in this fashion was published in 2002 [4]. Since then, there has been an explosion of interest in this approach. The authors of the systematic review published in this issue [5] identified 3781 unique articles on the topic of AS in prostate cancer. Indeed, the concept has crossed disciplines, and is being adopted in breast cancer for management of ductal carcinoma in situ, for example, with explicit reference to the success of this approach in prostate cancer. The article in this issue of European Urology by Simpkin et al [5] is a significant contribution to the literature. It represents a detailed summary of AS experience to date, with a focus on the indications for radical intervention. The
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2015.01.004. * Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, #MG 408, Toronto, Ontario M4N 3M5, Canada. Tel. +1 416 4804673; Fax: +1 416 4806121. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2015.01.007 0302-2838/# 2015 Published by Elsevier B.V. on behalf of European Association of Urology.
EUROPEAN UROLOGY 67 (2015) 1006–1008
authors identified 26 AS cohorts involving 7627 men. They used several novel techniques to address concerns about publication bias and small-study effects. As one might expect, given regional differences in the approach to cancer around the world, these cohorts differed in their eligibility criteria and triggers for intervention. The overall radical treatment rate was 8.8% per year, or approximately one-third at 4 yr. What is striking, however, is that the intervention rate varied 20-fold, from 1.1% per year (ref. [10] in the article) to 22.2% per year (ref. [18] in the article). Studies that included men with Gleason >6 had a lower rate of radical treatment overall, although men with Gleason 7 had a twofold higher rate of treatment. This seemingly paradoxical observation can be explained. That Gleason 4 pattern confers a more aggressive phenotype is supported by numerous studies. However, some experts believe that not all patients with Gleason 4 necessarily require treatment, particularly those found to have only small amounts. (A recent autopsy study of men dying of other causes revealed that more than 50% of the incidental cancers in Asian men were Gleason 7 [6]). These physicians are likely to have a more risk-tolerant view of volume and grade progression. Investigators who use an inclusive approach, including some intermediate-risk patients, for example, are likely to be less ‘‘trigger happy’’; in other words, they will require more substantial evidence of risk reclassification before advising the patient to have treatment. Investigators who are restrictive about patient eligibility for surveillance undoubtedly have a more riskaverse view of the implications of volume and grade increase, and are more likely to advise treatment for increase in Gleason 6 volume or the finding of Gleason 4 disease. These approaches are both legitimate. A more inclusive approach to surveillance and a higher bar before treatment is advised will provide many more patients with the benefits of avoiding intervention, but are also likely to result in a small increase in the number of men who progress to metastatic disease. We recently published our updated surveillance experience (too recent to be included in this overview), which was based on an inclusive approach. The proportion of patients managed with initial surveillance who had late progression to metastatic disease (beyond 7 yr), and therefore may have been cured by initial radical therapy, was 2.5% at 15 yr [7]. A more restrictive approach, as taken by the Hopkins group, for example, (ref. [19] in the article) will reduce the number of patients who avoid treatment, but may reduce this already low mortality rate further. The 26 series reviewed in this meta-analysis did not use magnetic resonance imaging as a parameter for decision-making. The ability to image prostate cancer accurately, and particularly the ability to exclude clinically significant disease with high probability, is a game changer. Other developments in the field that have not been captured include the move away from PSA kinetics as a trigger for intervention (owing to the lack of specificity of a rise in PSA); a clearer appreciation of the characteristics of the cancer in patients harboring worse
1007
disease (usually large anterior cancers); convincing evidence that Gleason pattern 3 has no metastatic potential; evidence that the main significance of higher Gleason 6 volume is a greater likelihood of coexistent higher-grade cancer; the emerging role of predictive molecular biomarkers; and data supporting the use of 5-a-reductase inhibitors in men on surveillance [8]. Incorporation of these developments is likely to result in a more consistent approach to men on AS. The overview reported that 20% of patients receiving treatment did so because of patient choice or anxiety. This figure seems high. Patient anxiety is very amenable to reassurance and accurate information about the indolent natural history of low-risk prostate cancer. My experience is that many patients who are categorized as being treated because of patient choice made decisions based on a change in risk that did not reach the threshold for intervention; for example, a PSA doubling time of 4 yr (whereas most groups required a threshold of 3 yr) or a significant increase in volume of Gleason 6 at centers that require grade progression. The authors rightfully identify that detailed information about the indications for intervention in prospective trials should be more meticulously collected. The median follow-up in the 26 studies was only 3.5 yr (range 1.5–7.5 yr). This short follow-up duration is somewhat misleading, in that as AS became legitimized, all of the cohorts began to accrue larger numbers of patients, reducing the median follow-up duration. However, the most mature cohorts now have substantial numbers of patients followed for more than 10–15 yr. Within another 5 yr, there will be hundreds of patients managed with AS with 15–20-yr follow-up, which should provide important information about long-term outcomes in AS patients. AS is an effective antidote to the overdiagnosis and potential for overtreatment resulting from PSA screening. Indeed, widespread adoption of AS will almost certainly result in a sharp decrease in the number needed to treat. The heterogeneity of the approach used by various groups around the world and the large number of important outstanding research questions described by the authors only reinforce the robust state of this field, and should in no way undermine the value that AS brings to patients. Conflicts of interest: The author has nothing to disclose.
References [1] Smith PH. The case for no initial treatment of localized prostate cancer. Urol Clin North Am 1990;17:827–34. [2] Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 2014;370:932–42. [3] Holmberg L, Bill-Axelson A, Helgesen F, et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002;347:781–9. [4] Choo R, Klotz L, Danjoux C, et al. Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression. J Urol 2002;167: 1664–9.
1008
EUROPEAN UROLOGY 67 (2015) 1006–1008
[5] Simpkin AJ, Tilling K, Martin RM, et al. Systematic review and meta-
[7] Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a
analysis of factors determining change to radical treatment in
large active surveillance cohort of patients with prostate cancer. J
active surveillance for localized prostate cancer. Eur Urol 2015; 67:993–1005.
Clin Oncol 2015;33:272–7. [8] Fleshner NE, Lucia MS, Egerdie B, et al. Dutasteride in
[6] Zlotta AR, Egawa S, Pushkar D, et al. Prevalence of prostate cancer on
localised prostate cancer management: the REDEEM random-
autopsy: cross-sectional study on unscreened Caucasian and Asian
ised, double-blind, placebo-controlled trial. Lancet 2012;379:
men. J Natl Cancer Inst 2013;105:1050–8.
1103–11.
![[Active surveillance for prostate cancer].](/assets/img/hold.png)
