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The Ongoing Need for Improved Risk Stratification and Monitoring for Those on Active Surveillance for Early Stage Prostate Cancer
EUROPEAN UROLOGY 65 (2014) 1032–1033
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 1023–1031 of this issue
The Ongoing Need for Improved Risk Stratification and Monitoring for Those on Active Surveillance for Early Stage Prostate Cancer Christopher J. Welty *, Peter R. Carroll Department of Urology, University of California, San Francisco, San Francisco, CA, USA
With the recognition of the prevalence of clinically indolent prostate cancer (PCa), the goal of PCa care has shifted from detection and treatment of all men with PCa to identifying and treating only men with clinically significant disease, disease that would put them at risk if left undiagnosed. However, current risk stratification schemes are not perfect. The parameters traditionally used to stratify pretreatment PCa risk (e.g., prostate-specific antigen [PSA], Gleason score (GS), T stage, tumor volume) misclassify some patients [1,2]. As a result, current active surveillance (AS) protocols call for monitoring all patients, even those with very favorable disease characteristics, with serial PSAs, examination, selective use of imaging, and periodic prostate biopsy. However, such a strategy for all patients may neither be safe nor necessary. The potential morbidity and cost of repeat biopsy, as well as other repeated evaluations, is leading clinicians (and their patients) in search of new, more refined markers of risk and the need for eventual treatment. In this month’s issue of European Urology, van den Bergh and colleagues provide an excellent summary of the studies to date examining novel markers in AS for PCa [3]. The authors identified 30 original articles for review assessing a variety of potential markers including magnetic resonance imaging, serum and urinary tests, histopathologic panels, and germline genetic markers. As the authors note, MRI has been the most commonly studied test to date and currently has the most utility in AS. The reported ability of MRI to predict future biopsy results or surgical pathology results has varied depending on magnet strength, imaging technique, and cohort used. In several
studies, high-quality multiparametric magnetic resonance imaging (MP-MRI) has been associated with a high negative predictive value pathologic upgrading in men with favorable MRI findings and the ability to detect higher risk lesions in some studies [4,5]. Regular use of MP-MRI in AS may be able to reduce or eliminate repeat biopsy in men with favorable results, although this approach requires additional, more rigorous validation. Serum and urinary markers have been associated with higher GS and increased disease burden on follow-up. However, the use of these markers in AS has been limited by a high degree of overlap between men who do and do not progress. More precision is required if these markers are to be effective adjuncts to a surveillance protocol. It appears that genetic- and expression-level biomarkers hold promise for improving risk stratification in AS, but they are still early in their development. The authors discuss the Oncotype Dx Genomic Prostate Score (GPS; Genomic Health, Inc.) and the Cell Cycle Progression (CCP) score. When applied to biopsy specimens, the GPS was better able to predict the likelihood of T3 disease or predominant Gleason pattern 4 or 5 disease compared with standard pathologic features. The GPS has been tested and validated in low- and intermediate-risk patients in whom surveillance is an option [6]. The CCP score was a stronger predictor of eventual PCa death following a positive biopsy than PSA or GS but has not been validated as yet in patients who are candidates for AS [7]. Improving technology has made individual tumor sequencing possible and increasingly available. Such improved molecular characterization
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.01.027. * Corresponding author. University of California, San Francisco, 1600 Divisadero Street, A630, San Francisco, CA 94143-1695, USA. Tel. +1 415 885 7748; Fax: +1 415 353 9932. E-mail addresses: [email protected], [email protected] (C.J. Welty). http://dx.doi.org/10.1016/j.eururo.2014.02.044 0302-2838/# 2014 Published by Elsevier B.V. on behalf of European Association of Urology.
EUROPEAN UROLOGY 65 (2014) 1032–1033
may eventually lead to a genetic signature that differentiates a potentially lethal tumor from a clinically indolent one [8]. One common weakness of the studies to date is the use of pathologic upgrading or treatment as the primary outcome measure for AS. Progression is not an unexpected outcome because surveillance for many men is about timing of treatment. Treatment does not signify a failure of AS but rather a natural consequence of this approach in at least a third of men at 5 yr. The true oncologic outcome of patients on AS is best assessed by overall survival, cancer-specific survival, and metastasis-free survival. More morbid treatment at the time of progression (as compared with immediate treatment) as well as cancer recurrence after definitive treatment are other potential adverse outcomes, although their utility may be limited due to selection bias. Given the rarity of death and metastases among men with low-risk PCa, one recent study estimates a 2–3% mortality rate at 20 yr among men currently eligible for AS. It is understandable why these outcomes are not commonly assessed as yet [9]. However, it is likely that novel technology, as reviewed in this paper and that under development, will replace standard surveillance regimens and end points for treatment. Such technology is currently being assessed in many prospectively accrued AS cohorts [10].
1033
References [1] Cooperberg MR, Pasta DJ, Elkin EP, et al. The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy. J Urol 2005;173:1938–42. [2] Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011;364:1708–17. [3] van den Bergh RCN, Ahmed HU, Bangma CH, Cooperberg MR, Villers A, Parker CC. Novel tools to improve patient selection and monitoring on active surveillance for low-risk prostate cancer: a systematic review. Eur Urol 2014;65:1023–31. [4] Fradet V, Kurhanewicz J, Cowan JE, et al. Prostate cancer managed with active surveillance: role of anatomic MR imaging and MR spectroscopic imaging. Radiology 2010;256:176–83. [5] Mullins JK, Bonekamp D, Landis P, et al. Multiparametric magnetic resonance imaging findings in men with low-risk prostate cancer followed using active surveillance. BJU Int 2013;111:1037–45. [6] Klein EA. A genomic approach to active surveillance: a step toward precision medicine. Asian J Androl 2013;15:340–1. [7] Cuzick J, Berney DM, Fisher G, et al. Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer 2012;106: 1095–9. [8] Barbieri CE, Demichelis F, Rubin MA. The lethal clone in prostate cancer: redefining the index. Eur Urol. In press. http://dx.doi.org/ 10.1016/j.eururo.2013.12.052. [9] Xia J, Trock BJ, Cooperberg MR, et al. Prostate cancer mortality following active surveillance versus immediate radical prostatec-
Conflicts of interest: Peter R. Carroll receives research funding from
tomy. Clin Cancer Res 2012;18:5471–8.
Genomic Health, Inc. and Myriad Genetics, Inc., and is an advisor to
[10] Newcomb LF, Brooks JD, Carroll PR, et al. Canary prostate active
and receives speaker honoraria from Genomic Health, Inc. Christopher
surveillance study: design of a multi-institutional active surveil-
J. Welty has nothing to disclose.
lance cohort and biorepository. Urology 2010;75:407–13.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 1023–1031 of this issue
The Ongoing Need for Improved Risk Stratification and Monitoring for Those on Active Surveillance for Early Stage Prostate Cancer Christopher J. Welty *, Peter R. Carroll Department of Urology, University of California, San Francisco, San Francisco, CA, USA
With the recognition of the prevalence of clinically indolent prostate cancer (PCa), the goal of PCa care has shifted from detection and treatment of all men with PCa to identifying and treating only men with clinically significant disease, disease that would put them at risk if left undiagnosed. However, current risk stratification schemes are not perfect. The parameters traditionally used to stratify pretreatment PCa risk (e.g., prostate-specific antigen [PSA], Gleason score (GS), T stage, tumor volume) misclassify some patients [1,2]. As a result, current active surveillance (AS) protocols call for monitoring all patients, even those with very favorable disease characteristics, with serial PSAs, examination, selective use of imaging, and periodic prostate biopsy. However, such a strategy for all patients may neither be safe nor necessary. The potential morbidity and cost of repeat biopsy, as well as other repeated evaluations, is leading clinicians (and their patients) in search of new, more refined markers of risk and the need for eventual treatment. In this month’s issue of European Urology, van den Bergh and colleagues provide an excellent summary of the studies to date examining novel markers in AS for PCa [3]. The authors identified 30 original articles for review assessing a variety of potential markers including magnetic resonance imaging, serum and urinary tests, histopathologic panels, and germline genetic markers. As the authors note, MRI has been the most commonly studied test to date and currently has the most utility in AS. The reported ability of MRI to predict future biopsy results or surgical pathology results has varied depending on magnet strength, imaging technique, and cohort used. In several
studies, high-quality multiparametric magnetic resonance imaging (MP-MRI) has been associated with a high negative predictive value pathologic upgrading in men with favorable MRI findings and the ability to detect higher risk lesions in some studies [4,5]. Regular use of MP-MRI in AS may be able to reduce or eliminate repeat biopsy in men with favorable results, although this approach requires additional, more rigorous validation. Serum and urinary markers have been associated with higher GS and increased disease burden on follow-up. However, the use of these markers in AS has been limited by a high degree of overlap between men who do and do not progress. More precision is required if these markers are to be effective adjuncts to a surveillance protocol. It appears that genetic- and expression-level biomarkers hold promise for improving risk stratification in AS, but they are still early in their development. The authors discuss the Oncotype Dx Genomic Prostate Score (GPS; Genomic Health, Inc.) and the Cell Cycle Progression (CCP) score. When applied to biopsy specimens, the GPS was better able to predict the likelihood of T3 disease or predominant Gleason pattern 4 or 5 disease compared with standard pathologic features. The GPS has been tested and validated in low- and intermediate-risk patients in whom surveillance is an option [6]. The CCP score was a stronger predictor of eventual PCa death following a positive biopsy than PSA or GS but has not been validated as yet in patients who are candidates for AS [7]. Improving technology has made individual tumor sequencing possible and increasingly available. Such improved molecular characterization
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2014.01.027. * Corresponding author. University of California, San Francisco, 1600 Divisadero Street, A630, San Francisco, CA 94143-1695, USA. Tel. +1 415 885 7748; Fax: +1 415 353 9932. E-mail addresses: [email protected], [email protected] (C.J. Welty). http://dx.doi.org/10.1016/j.eururo.2014.02.044 0302-2838/# 2014 Published by Elsevier B.V. on behalf of European Association of Urology.
EUROPEAN UROLOGY 65 (2014) 1032–1033
may eventually lead to a genetic signature that differentiates a potentially lethal tumor from a clinically indolent one [8]. One common weakness of the studies to date is the use of pathologic upgrading or treatment as the primary outcome measure for AS. Progression is not an unexpected outcome because surveillance for many men is about timing of treatment. Treatment does not signify a failure of AS but rather a natural consequence of this approach in at least a third of men at 5 yr. The true oncologic outcome of patients on AS is best assessed by overall survival, cancer-specific survival, and metastasis-free survival. More morbid treatment at the time of progression (as compared with immediate treatment) as well as cancer recurrence after definitive treatment are other potential adverse outcomes, although their utility may be limited due to selection bias. Given the rarity of death and metastases among men with low-risk PCa, one recent study estimates a 2–3% mortality rate at 20 yr among men currently eligible for AS. It is understandable why these outcomes are not commonly assessed as yet [9]. However, it is likely that novel technology, as reviewed in this paper and that under development, will replace standard surveillance regimens and end points for treatment. Such technology is currently being assessed in many prospectively accrued AS cohorts [10].
1033
References [1] Cooperberg MR, Pasta DJ, Elkin EP, et al. The University of California, San Francisco Cancer of the Prostate Risk Assessment score: a straightforward and reliable preoperative predictor of disease recurrence after radical prostatectomy. J Urol 2005;173:1938–42. [2] Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2011;364:1708–17. [3] van den Bergh RCN, Ahmed HU, Bangma CH, Cooperberg MR, Villers A, Parker CC. Novel tools to improve patient selection and monitoring on active surveillance for low-risk prostate cancer: a systematic review. Eur Urol 2014;65:1023–31. [4] Fradet V, Kurhanewicz J, Cowan JE, et al. Prostate cancer managed with active surveillance: role of anatomic MR imaging and MR spectroscopic imaging. Radiology 2010;256:176–83. [5] Mullins JK, Bonekamp D, Landis P, et al. Multiparametric magnetic resonance imaging findings in men with low-risk prostate cancer followed using active surveillance. BJU Int 2013;111:1037–45. [6] Klein EA. A genomic approach to active surveillance: a step toward precision medicine. Asian J Androl 2013;15:340–1. [7] Cuzick J, Berney DM, Fisher G, et al. Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer 2012;106: 1095–9. [8] Barbieri CE, Demichelis F, Rubin MA. The lethal clone in prostate cancer: redefining the index. Eur Urol. In press. http://dx.doi.org/ 10.1016/j.eururo.2013.12.052. [9] Xia J, Trock BJ, Cooperberg MR, et al. Prostate cancer mortality following active surveillance versus immediate radical prostatec-
Conflicts of interest: Peter R. Carroll receives research funding from
tomy. Clin Cancer Res 2012;18:5471–8.
Genomic Health, Inc. and Myriad Genetics, Inc., and is an advisor to
[10] Newcomb LF, Brooks JD, Carroll PR, et al. Canary prostate active
and receives speaker honoraria from Genomic Health, Inc. Christopher
surveillance study: design of a multi-institutional active surveil-
J. Welty has nothing to disclose.
lance cohort and biorepository. Urology 2010;75:407–13.