- Email: [email protected]
Active Surveillance for Low-risk Prostate Cancer: Developments to Date
EUROPEAN UROLOGY 67 (2015) 646–648
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the articles published on pp. 619–626, pp. 627–636 and pp. 637–645 of this issue
Active Surveillance for Low-risk Prostate Cancer: Developments to Date Chris H. Bangma a,*, Riccardo Valdagni b, Peter R. Carroll c, Hein van Poppel d, Laurence Klotz e, Jonas Hugosson f a
Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands; b Prostate Program, Scientific Directorate, Fondazione IRCSS Instituto Nazionale
dei Tumori, Milan, Italy; c Department of Urology, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; d University Hospitals Leuven, Department of Urology, Leuven, Belgium; e Division of Urology, Sunnybrook and Women’s Health Science Centre, Toronto, Ontario, Canada; f Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Active surveillance (AS) for low-risk prostate cancer (PCa) is attracting increased scientific interest due to better understanding of the natural course of PCa and to rapid technological developments in the diagnosis and treatment of early disease. There is no consensus on the optimal method of selecting men for AS with traditional markers and the role of new histologic, proteomic, or genetic markers. The role of new imaging modalities also remains unclear. The measurement of quality of life, the selection of men based on psychological assessments, and the methods of optimal support of patients during AS are areas requiring further development. These issues are highlighted in a series of papers within this issue of European Urology [1–3], as a result of discussions during the second Inside Track Conference, ‘‘Active Surveillance for Low Risk Prostate Cancer,’’ organized by the European School of Oncology and the European Association of Urology, in Amsterdam, The Netherlands, February 22–24, 2014. In addition, the papers address new methods of risk stratification, the changing definition of indolent cancer, and AS-related biopsy complications.
During the first 2 yr of AS, there is a shift from an expectant stance toward definitive therapy in 20–30% of patients. This effect is largely due to diagnostic resampling of higher grade tumors, an effect that is reduced over time. An unmet need is to identify those tumors destined to progress over time. New tools based on serum and urinary markers are being added to the histologic characteristics to improve our definition of low-risk cancers. Visualization of prostatic tumors, predominantly with multiparametric magnetic resonance imaging, permits more accurate assessment of cancer by targeted biopsy. Validation of the new modalities for diagnosis and prognosis is in progress. The introduction of new and complex risk parameters now and in the near future will require probabilistic approaches, instead of the current simple rule-based protocols, to include men into an AS program. Because similar methods are being used for individual PCa screening, it is likely that such approaches will meet acceptance. Such methods have been shown to reduce overdiagnosis of low-risk cancers while identifying the cancers at risk for progression while still asymptomatic [1].
1.
2. The definition of indolent cancer: our understanding of biology and clinic
Risk stratification
Analysis of studies on AS over the past decade show the pivotal role of regular repeated biopsies to redefine the risk of the tumors under observation and to reclassify the patient to continue AS or to switch to active treatment.
The aggressiveness of a tumor is best characterized by biological parameters. The clinical decision to offer AS is also dependent on host factors. Histologic parameters
DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2014.10.010, http://dx.doi.org/10.1016/j.eururo.2014.10.028, http://dx.doi.org/10.1016/ j.eururo.2014.10.050. * Corresponding author. Erasmus MC, Department of Urology - H1096, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Tel. +31 10 70 336 07; Fax: +31 10 70 35025. E-mail address: [email protected] (C.H. Bangma). http://dx.doi.org/10.1016/j.eururo.2014.11.004 0302-2838/# 2014 Published by Elsevier B.V. on behalf of European Association of Urology.
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EUROPEAN UROLOGY 67 (2015) 646–648
including Gleason score, the number of positive biopsies, and percentage of cancerous tissue as surrogates for cancer volume are likely to be combined with, or maybe replaced by, genomic analysis and tumor imaging. Biological characterization mandates direct acquisition of tissue directly from the tumor by targeted biopsy. At present, it is not known how much Gleason 4 tumor may be present while maintaining a patient on AS. Although some restrictive protocols exclude all patients with any fraction of Gleason grade 4 or 5 and patients with multiple positive cores of grade 3, other more inclusive protocols aim to avoid overtreatment by managing such patients with AS. The latter approach might result in a larger number of shifts toward active treatment. The restrictive versus inclusive approach is estimated to show 20% versus 50% inclusion of newly screened patients at the cost of 1% versus 3% mortality over 15 yr [4]. So far, the difference in genomic fingerprint between Gleason 3 and Gleason 4 has not led to a dichotomous attitude with which Gleason 3 is always harmless and Gleason 4 is always aggressive. Ten genetic tests are currently under development, and new prognostic parameters, such as noncoding long RNAs, are expected.
antibiotic resistance toward fluoroquines and subsequently serious infections after prostatic biopsy have been reported since 2003. Bacteremia has been observed in 12.7–19.0%, whereas bacteriuria and urinary tract infections are present in 3.7–14.8% and 3.3–9.0%, respectively. Severe infectious episodes needing clinical treatment were seen in 0–6.3% [5]. The increase in ciprofloxacin resistance in outpatient clinics to 15% is in contrast to the more gradual increase of resistance of cotrimoxazol to 5% between 2000 and 2010. Remarkably, this appears to be an overall phenomenon, as no predictive factors were observed in these data sets [5]. Prevention of infection was addressed in a number of evaluations analyzing the bioflora in the rectum at the time of biopsy, reporting up to 20% quinolone resistance in Escherichia coli by rectal swab. In other words, 38 men would have to be swabbed to prevent one infection by targeted antibiotic prevention. Tailored prophylaxis after individual rectal screen appears to be a cost-effective option, but another might be reducing the number of repeated biopsies using information from imaging or tumor markers. 4.
3.
Further challenges
Active surveillance–related biopsy complications
Repeated biopsies under prophylactic antibiotics currently form the core for reclassification. However, growing [(Fig._1)TD$IG]
With the increasing awareness of AS, the number of observations within databases has increased over the years (Fig. 1a), but within these databases, growth has appeared
4500
(a)
No. of men included in PRIAS
4000 3500 3000 2500 2000 1500 1000 500 0 2006
2007
2008
2009
2010
2011
2012
2013
Year of diagnosis Annual increase, n
Total
Europe
Japan
Australia/New Zealand
Canada
1000
(b) 500 0 2006
2007
2008
2009
2010
2011
2012
2013
Year of diagnosis Total
Europe
Japan
Australia/New Zealand
Canada
Fig. 1 – Participants in the observational Prostate Cancer Research International: Active Surveillance (PRIAS) database during 2006–2013 per continent [6]. (a) Absolute number of men included in the PRIAS study. (b) Annual increase in number of men included in the PRIAS study, reflecting growth.
648
EUROPEAN UROLOGY 67 (2015) 646–648
to stabilize (Fig. 1b) [6]. It takes many years to obtain sufficient data to design the optimal protocols for selection and monitoring and to convince all physicians and patients of the value of this treatment approach. In the absence of long-term follow-up and mortality data, the efficacy of current AS strategies has been judged on surrogate outcomes, including the number of men shifting toward active treatment, and on the pathologic outcome and shortterm follow-up of those that underwent radical prostatectomy. Only very limited data on 4- to 7-yr follow-up are currently available, and the recent numbers from Toronto show 10-year cancer-specific mortality of 2–5% due to disease progression toward incurable stages during followup [4]. Direct comparison of data on patients included in the various protocols worldwide will enhance resolution of current questions regarding monitoring of patients on AS. This task requires the construction of a database from very different data sources—an ambitious but not impossible project. The Amsterdam meeting enhanced the understanding of maturing data, forming the basis for further shared activities on new developments in the field of markers, imaging, and quality of life.
Acknowledgment: Graphs provided by L.P. Bokhorst, doctoral candidate, Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands.
References [1] Loeb S, Bruinsma SM, Nicholson J, et al. Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. Eur Urol 2015;67: 619–26. [2] Schoots IG, Petrides N, Giganti F, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. Eur Urol 2015;67:627–36. [3] Bellardita L, Valdagni R, van den Bergh R, et al. How does active surveillance for prostate cancer affect quality of life?. A systematic review. Eur Urol 2015;67:637–45. [4] Klotz L. Triggers for reclassification in ongoing studies. Presented at: 2nd Inside Track Conference; February 22–24, 2014; Amsterdam, The Netherlands. [5] Ranniko A. Repeated biopsies: complications. Presented at: 2nd Inside Track Conference; February 22–24, 2014; Amsterdam, The Netherlands. [6] Roobol MJ, Steyerberg EW, Kranse R, et al. A risk-based strategy improves prostate-specific antigen-driven detection of prostate can-
Conflicts of interest: The authors have nothing to disclose.
cer. Eur Urol 2010;57:79–85.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the articles published on pp. 619–626, pp. 627–636 and pp. 637–645 of this issue
Active Surveillance for Low-risk Prostate Cancer: Developments to Date Chris H. Bangma a,*, Riccardo Valdagni b, Peter R. Carroll c, Hein van Poppel d, Laurence Klotz e, Jonas Hugosson f a
Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands; b Prostate Program, Scientific Directorate, Fondazione IRCSS Instituto Nazionale
dei Tumori, Milan, Italy; c Department of Urology, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; d University Hospitals Leuven, Department of Urology, Leuven, Belgium; e Division of Urology, Sunnybrook and Women’s Health Science Centre, Toronto, Ontario, Canada; f Department of Urology, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Active surveillance (AS) for low-risk prostate cancer (PCa) is attracting increased scientific interest due to better understanding of the natural course of PCa and to rapid technological developments in the diagnosis and treatment of early disease. There is no consensus on the optimal method of selecting men for AS with traditional markers and the role of new histologic, proteomic, or genetic markers. The role of new imaging modalities also remains unclear. The measurement of quality of life, the selection of men based on psychological assessments, and the methods of optimal support of patients during AS are areas requiring further development. These issues are highlighted in a series of papers within this issue of European Urology [1–3], as a result of discussions during the second Inside Track Conference, ‘‘Active Surveillance for Low Risk Prostate Cancer,’’ organized by the European School of Oncology and the European Association of Urology, in Amsterdam, The Netherlands, February 22–24, 2014. In addition, the papers address new methods of risk stratification, the changing definition of indolent cancer, and AS-related biopsy complications.
During the first 2 yr of AS, there is a shift from an expectant stance toward definitive therapy in 20–30% of patients. This effect is largely due to diagnostic resampling of higher grade tumors, an effect that is reduced over time. An unmet need is to identify those tumors destined to progress over time. New tools based on serum and urinary markers are being added to the histologic characteristics to improve our definition of low-risk cancers. Visualization of prostatic tumors, predominantly with multiparametric magnetic resonance imaging, permits more accurate assessment of cancer by targeted biopsy. Validation of the new modalities for diagnosis and prognosis is in progress. The introduction of new and complex risk parameters now and in the near future will require probabilistic approaches, instead of the current simple rule-based protocols, to include men into an AS program. Because similar methods are being used for individual PCa screening, it is likely that such approaches will meet acceptance. Such methods have been shown to reduce overdiagnosis of low-risk cancers while identifying the cancers at risk for progression while still asymptomatic [1].
1.
2. The definition of indolent cancer: our understanding of biology and clinic
Risk stratification
Analysis of studies on AS over the past decade show the pivotal role of regular repeated biopsies to redefine the risk of the tumors under observation and to reclassify the patient to continue AS or to switch to active treatment.
The aggressiveness of a tumor is best characterized by biological parameters. The clinical decision to offer AS is also dependent on host factors. Histologic parameters
DOIs of original articles: http://dx.doi.org/10.1016/j.eururo.2014.10.010, http://dx.doi.org/10.1016/j.eururo.2014.10.028, http://dx.doi.org/10.1016/ j.eururo.2014.10.050. * Corresponding author. Erasmus MC, Department of Urology - H1096, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Tel. +31 10 70 336 07; Fax: +31 10 70 35025. E-mail address: [email protected] (C.H. Bangma). http://dx.doi.org/10.1016/j.eururo.2014.11.004 0302-2838/# 2014 Published by Elsevier B.V. on behalf of European Association of Urology.
647
EUROPEAN UROLOGY 67 (2015) 646–648
including Gleason score, the number of positive biopsies, and percentage of cancerous tissue as surrogates for cancer volume are likely to be combined with, or maybe replaced by, genomic analysis and tumor imaging. Biological characterization mandates direct acquisition of tissue directly from the tumor by targeted biopsy. At present, it is not known how much Gleason 4 tumor may be present while maintaining a patient on AS. Although some restrictive protocols exclude all patients with any fraction of Gleason grade 4 or 5 and patients with multiple positive cores of grade 3, other more inclusive protocols aim to avoid overtreatment by managing such patients with AS. The latter approach might result in a larger number of shifts toward active treatment. The restrictive versus inclusive approach is estimated to show 20% versus 50% inclusion of newly screened patients at the cost of 1% versus 3% mortality over 15 yr [4]. So far, the difference in genomic fingerprint between Gleason 3 and Gleason 4 has not led to a dichotomous attitude with which Gleason 3 is always harmless and Gleason 4 is always aggressive. Ten genetic tests are currently under development, and new prognostic parameters, such as noncoding long RNAs, are expected.
antibiotic resistance toward fluoroquines and subsequently serious infections after prostatic biopsy have been reported since 2003. Bacteremia has been observed in 12.7–19.0%, whereas bacteriuria and urinary tract infections are present in 3.7–14.8% and 3.3–9.0%, respectively. Severe infectious episodes needing clinical treatment were seen in 0–6.3% [5]. The increase in ciprofloxacin resistance in outpatient clinics to 15% is in contrast to the more gradual increase of resistance of cotrimoxazol to 5% between 2000 and 2010. Remarkably, this appears to be an overall phenomenon, as no predictive factors were observed in these data sets [5]. Prevention of infection was addressed in a number of evaluations analyzing the bioflora in the rectum at the time of biopsy, reporting up to 20% quinolone resistance in Escherichia coli by rectal swab. In other words, 38 men would have to be swabbed to prevent one infection by targeted antibiotic prevention. Tailored prophylaxis after individual rectal screen appears to be a cost-effective option, but another might be reducing the number of repeated biopsies using information from imaging or tumor markers. 4.
3.
Further challenges
Active surveillance–related biopsy complications
Repeated biopsies under prophylactic antibiotics currently form the core for reclassification. However, growing [(Fig._1)TD$IG]
With the increasing awareness of AS, the number of observations within databases has increased over the years (Fig. 1a), but within these databases, growth has appeared
4500
(a)
No. of men included in PRIAS
4000 3500 3000 2500 2000 1500 1000 500 0 2006
2007
2008
2009
2010
2011
2012
2013
Year of diagnosis Annual increase, n
Total
Europe
Japan
Australia/New Zealand
Canada
1000
(b) 500 0 2006
2007
2008
2009
2010
2011
2012
2013
Year of diagnosis Total
Europe
Japan
Australia/New Zealand
Canada
Fig. 1 – Participants in the observational Prostate Cancer Research International: Active Surveillance (PRIAS) database during 2006–2013 per continent [6]. (a) Absolute number of men included in the PRIAS study. (b) Annual increase in number of men included in the PRIAS study, reflecting growth.
648
EUROPEAN UROLOGY 67 (2015) 646–648
to stabilize (Fig. 1b) [6]. It takes many years to obtain sufficient data to design the optimal protocols for selection and monitoring and to convince all physicians and patients of the value of this treatment approach. In the absence of long-term follow-up and mortality data, the efficacy of current AS strategies has been judged on surrogate outcomes, including the number of men shifting toward active treatment, and on the pathologic outcome and shortterm follow-up of those that underwent radical prostatectomy. Only very limited data on 4- to 7-yr follow-up are currently available, and the recent numbers from Toronto show 10-year cancer-specific mortality of 2–5% due to disease progression toward incurable stages during followup [4]. Direct comparison of data on patients included in the various protocols worldwide will enhance resolution of current questions regarding monitoring of patients on AS. This task requires the construction of a database from very different data sources—an ambitious but not impossible project. The Amsterdam meeting enhanced the understanding of maturing data, forming the basis for further shared activities on new developments in the field of markers, imaging, and quality of life.
Acknowledgment: Graphs provided by L.P. Bokhorst, doctoral candidate, Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands.
References [1] Loeb S, Bruinsma SM, Nicholson J, et al. Active surveillance for prostate cancer: a systematic review of clinicopathologic variables and biomarkers for risk stratification. Eur Urol 2015;67: 619–26. [2] Schoots IG, Petrides N, Giganti F, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. Eur Urol 2015;67:627–36. [3] Bellardita L, Valdagni R, van den Bergh R, et al. How does active surveillance for prostate cancer affect quality of life?. A systematic review. Eur Urol 2015;67:637–45. [4] Klotz L. Triggers for reclassification in ongoing studies. Presented at: 2nd Inside Track Conference; February 22–24, 2014; Amsterdam, The Netherlands. [5] Ranniko A. Repeated biopsies: complications. Presented at: 2nd Inside Track Conference; February 22–24, 2014; Amsterdam, The Netherlands. [6] Roobol MJ, Steyerberg EW, Kranse R, et al. A risk-based strategy improves prostate-specific antigen-driven detection of prostate can-
Conflicts of interest: The authors have nothing to disclose.
cer. Eur Urol 2010;57:79–85.