- Email: [email protected]
The Future of Prostate Cancer Diagnosis: Biomarkers, Biopsy, Both, or Neither?
EUROPEAN UROLOGY FOCUS 1 (2015) 97–98
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Editorial
The Future of Prostate Cancer Diagnosis: Biomarkers, Biopsy, Both, or Neither? Alberto Briganti a,*, Gianluca Giannarini b, Tobias Klatte c, James W. Catto d, Shahrokh F. Shariat c a
Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; b Urology Unit, Academic Medical Centre Hospital ‘‘Santa Maria della
Misericordia’’, Udine, Italy; c Department of Urology, Comprehensive Cancer Centre, Medical University of Vienna, Vienna General Hospital, Vienna, Austria; d
Academic Urology Unit, University of Sheffield, The Medical School, Beech Hill Road, Sheffield, UK
Approximately 45 yr after the discovery of prostatespecific antigen (PSA) by Richard J. Ablin [1], benefits and harms of PSA-based prostate cancer (PCa) screening still represent a matter of debate [2,3]. However, the constant and endless discussion about PSA-based screening efficacy currently seems somehow anachronistic. Although early detection may reduce PCa mortality, PSAbased screening—as currently practiced—is not actually exerting its highest efficacy on mortality reduction and, even worse, is fuelling overdetection and overtreatment [4]. The major concern related to this diagnostic approach is that PSA-based screening is currently widespread among older men with limited life expectancy [5]. Moreover, too many men with low-risk disease still receive curative treatment upfront, whereas a significant proportion of high-risk patients do not receive appropriate therapy [6]. Finally, curative treatments are still offered in lowvolume centres, for which outcomes are probably inferior compared with higher volume hospitals [7]. To reverse this process, there is a need to evolve towards a more individualised and multidisciplinary approach to cancer diagnosis and management. To do so, we should abandon the old concept of simplistic risk-stratification methods and embrace integrated, personalised diagnostic modalities. These include novel tools such as biomarkers and integrated imaging approaches, which can help in assessing the risk profile of each patient. The time has come to conceptually change the idea of prostate biopsy (PB). Although the conventional practice has always been to perform PB as blinded, systematic, template-based sampling under transrectal ultrasound guidance, this practice has several inherent
drawbacks. These include the risk of missing many PCas, undersampling of significant disease, and oversampling insignificant disease in many men. How can we improve our diagnostic ability to detect (significant) PCa in men who are most likely to benefit from curative treatment? To reach this goal, several key points need to be stressed. First, PCa screening should be restricted in men with limited life expectancy, who are most prone to overdiagnosis. Urologists and, more important, family doctors should carefully identify patients who would benefit the most from PSA screening by evaluating their risk factors, comorbidity profiles, performance status, and life expectancy [8]. In other words, screening should be personalised by performance status rather than by chronological age. Second, only men who have a certain risk of harbouring clinically significant disease should be referred for PB. Several recently identified biomarkers (ie, urinary PCa antigen 3 [PCA3], serum [ 2]proPSA, and the four-kallikrein panel) have been shown to increase the accuracy of PSA and its derivatives for the detection of significant PCa at both initial and repeat biopsies. For these reasons, these tools should be seen as complementary to PSA for reducing the number of unnecessary biopsies (and thus overdiagnosis) [9–13]. However, despite their use, 10–30% of patients receiving initial PB are found to have low-grade PCa [9–13]. Having said this, it has to be acknowledged that many of these studies are focused on statistical abstractions, such as area under the curve and specificity, that have questionable clinical interpretability. On the contrary, biomarker studies should follow simple principles for statistical reporting and interpretation [14]:
* Corresponding author. Division of Oncology/Unit of Urology, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Via Olgettina, 60, 20132 Milan, Italy. Tel. +39 02 2643 7286; Fax: +39 02 2643 7298. E-mail address: [email protected] (A. Briganti). http://dx.doi.org/10.1016/j.euf.2015.07.007 2405-4569/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
98
EUROPEAN UROLOGY FOCUS 1 (2015) 97–98
The dichotomisation of the biomarker test represents the first typical statistical error: There is no reason why a quantitative test, especially one based on a sophisticated algorithm, should be turned into a binary yes/no test on the basis of a cut point. Conversely, the quantitative test should be added to a base predictive model, evaluating the gain in accuracy and in clinical net-benefit with its inclusion. The evaluated outcome is crucial: High-grade or clinically significant PCa should be the end point, not any grade of cancer. A clinical implications report is essential: The number of biopsies that would have been avoided and the number of high-grade cancers that would have been missed give the reader direct information about clinical implications. In this context, it is likely that the future of biomarkers will be led by genomic signatures, which entail a personalised approach by definition. Ideally, they should be used both in the initial clinical decision-making process and in disease monitoring after initial treatment, given the well-known heterogeneity of PCa over its entire course. Issues to be solved are certainly related to tissue processing and costs. Third, the capability of prostate magnetic resonance imaging (MRI), with the increasing use of functional sequences (so-called multiparametric MRI [mpMRI]) and advances in technology, protocols, and data-reporting standardisation in localising PCa, has revolutionised the conventional practice of PB. Data available so far seem to show that sampling mpMRI-derived targets results in detection of a higher proportion of clinically significant cancers using fewer cores compared with conventional sampling [15,16]. Whether this is true in all patients is still under debate [17]. What is still unknown is the optimal diagnostic strategy and sequence, which may include both novel biomarkers and mpMRI. In this context, the collaboration between urologists and radiologists would be necessary to engage the challenging issue of PCa detection. In conclusion, biomarkers and targeted PB might play an important role in reducing PSA-based PCa overdetection. The diagnostic process should represent a multidisciplinary field in which different professionals have to cooperate for optimal identification of those men who harbour potentially aggressive disease and thus benefit the most from curative treatment.
[2] Schro¨der FH, Hugosson J, Roobol MJ, et al. Screening and prostatecancer mortality in a randomized European study. N Engl J Med 2009;360:1320–8. [3] Andriole GL, Crawford ED, Grubb III RL, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009; 360:1310–9. [4] Loeb S, Bjurlin MA, Nicholson J, et al. Overdiagnosis and overtreatment of prostate cancer. Eur Urol 2014;65:1046–55. [5] Drazer MW, Prasad SM, Huo D, et al. National trends in prostate cancer screening among older American men with limited 9-year life expectancies: evidence of an increased need for shared decision making. Cancer 2014;120:1491–8. [6] Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 2010;28:1117–23. [7] Savage CJ, Vickers AJ. Low annual caseloads of United States surgeons conducting radical prostatectomy. J Urol 2009;182: 2677–9. [8] Period life table, 2010. US Social Security Administration Web site. http://www.ssa.gov/OACT/STATS/table4c6.html. Accessed April 5, 2015. [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] Guazzoni G, Nava L, Lazzeri M, et al. Prostate-specific antigen (PSA) isoform p2PSA significantly improves the prediction of prostate cancer at initial extended prostate biopsies in patients with total PSA between 2.0 and 10 ng/ml: results of a prospective study in a clinical setting. Eur Urol 2011;60:214–22. [11] Lughezzani G, Lazzeri M, Larcher A, et al. Development and internal validation of a Prostate Health Index based nomogram for predicting prostate cancer at extended biopsy. J Urol 2012;188: 1144–50. [12] Vickers A, Cronin A, Roobol M, et al. Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol 2010;28:2493–8. [13] Wei JT, Feng Z, Partin AW, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol 2014;32: 4066–72. [14] Vickers AJ. Markers for the early detection of prostate cancer: some principles for statistical reporting and interpretation. J Clin Oncol 2014;32:4033–4. [15] Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA 2015;313: 390–7. [16] Fu¨tterer JJ, Briganti A, De Visschere P, et al. Can clinically significant prostate cancer be detected with multiparametric magnetic resonance imaging? A systematic review of the literature. Eur Urol. In
Conflicts of interest: The authors have nothing to disclose.
press. doi:10.1016/j.eururo.2015.01.013 [17] Tonttila PP, Lantto J, Pa¨a¨kko¨ E, et al. Prebiopsy multiparametric
References
magnetic resonance imaging for prostate cancer diagnosis in biopsy-naive men with suspected prostate cancer based on elevated
[1] Ablin RJ. The great prostate mistake. New York Times. March 9,
prostate-specific antigen values: results from a randomized pro-
2010. http://www.nytimes.com/2010/03/10/opinion/10Ablin.
spective blinded controlled trial. Eur Urol. In press. doi:10.1016/j.
html?_r=0. Accessed July 25, 2013.
eururo.2015.05.024
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Editorial
The Future of Prostate Cancer Diagnosis: Biomarkers, Biopsy, Both, or Neither? Alberto Briganti a,*, Gianluca Giannarini b, Tobias Klatte c, James W. Catto d, Shahrokh F. Shariat c a
Division of Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy; b Urology Unit, Academic Medical Centre Hospital ‘‘Santa Maria della
Misericordia’’, Udine, Italy; c Department of Urology, Comprehensive Cancer Centre, Medical University of Vienna, Vienna General Hospital, Vienna, Austria; d
Academic Urology Unit, University of Sheffield, The Medical School, Beech Hill Road, Sheffield, UK
Approximately 45 yr after the discovery of prostatespecific antigen (PSA) by Richard J. Ablin [1], benefits and harms of PSA-based prostate cancer (PCa) screening still represent a matter of debate [2,3]. However, the constant and endless discussion about PSA-based screening efficacy currently seems somehow anachronistic. Although early detection may reduce PCa mortality, PSAbased screening—as currently practiced—is not actually exerting its highest efficacy on mortality reduction and, even worse, is fuelling overdetection and overtreatment [4]. The major concern related to this diagnostic approach is that PSA-based screening is currently widespread among older men with limited life expectancy [5]. Moreover, too many men with low-risk disease still receive curative treatment upfront, whereas a significant proportion of high-risk patients do not receive appropriate therapy [6]. Finally, curative treatments are still offered in lowvolume centres, for which outcomes are probably inferior compared with higher volume hospitals [7]. To reverse this process, there is a need to evolve towards a more individualised and multidisciplinary approach to cancer diagnosis and management. To do so, we should abandon the old concept of simplistic risk-stratification methods and embrace integrated, personalised diagnostic modalities. These include novel tools such as biomarkers and integrated imaging approaches, which can help in assessing the risk profile of each patient. The time has come to conceptually change the idea of prostate biopsy (PB). Although the conventional practice has always been to perform PB as blinded, systematic, template-based sampling under transrectal ultrasound guidance, this practice has several inherent
drawbacks. These include the risk of missing many PCas, undersampling of significant disease, and oversampling insignificant disease in many men. How can we improve our diagnostic ability to detect (significant) PCa in men who are most likely to benefit from curative treatment? To reach this goal, several key points need to be stressed. First, PCa screening should be restricted in men with limited life expectancy, who are most prone to overdiagnosis. Urologists and, more important, family doctors should carefully identify patients who would benefit the most from PSA screening by evaluating their risk factors, comorbidity profiles, performance status, and life expectancy [8]. In other words, screening should be personalised by performance status rather than by chronological age. Second, only men who have a certain risk of harbouring clinically significant disease should be referred for PB. Several recently identified biomarkers (ie, urinary PCa antigen 3 [PCA3], serum [ 2]proPSA, and the four-kallikrein panel) have been shown to increase the accuracy of PSA and its derivatives for the detection of significant PCa at both initial and repeat biopsies. For these reasons, these tools should be seen as complementary to PSA for reducing the number of unnecessary biopsies (and thus overdiagnosis) [9–13]. However, despite their use, 10–30% of patients receiving initial PB are found to have low-grade PCa [9–13]. Having said this, it has to be acknowledged that many of these studies are focused on statistical abstractions, such as area under the curve and specificity, that have questionable clinical interpretability. On the contrary, biomarker studies should follow simple principles for statistical reporting and interpretation [14]:
* Corresponding author. Division of Oncology/Unit of Urology, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Via Olgettina, 60, 20132 Milan, Italy. Tel. +39 02 2643 7286; Fax: +39 02 2643 7298. E-mail address: [email protected] (A. Briganti). http://dx.doi.org/10.1016/j.euf.2015.07.007 2405-4569/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
98
EUROPEAN UROLOGY FOCUS 1 (2015) 97–98
The dichotomisation of the biomarker test represents the first typical statistical error: There is no reason why a quantitative test, especially one based on a sophisticated algorithm, should be turned into a binary yes/no test on the basis of a cut point. Conversely, the quantitative test should be added to a base predictive model, evaluating the gain in accuracy and in clinical net-benefit with its inclusion. The evaluated outcome is crucial: High-grade or clinically significant PCa should be the end point, not any grade of cancer. A clinical implications report is essential: The number of biopsies that would have been avoided and the number of high-grade cancers that would have been missed give the reader direct information about clinical implications. In this context, it is likely that the future of biomarkers will be led by genomic signatures, which entail a personalised approach by definition. Ideally, they should be used both in the initial clinical decision-making process and in disease monitoring after initial treatment, given the well-known heterogeneity of PCa over its entire course. Issues to be solved are certainly related to tissue processing and costs. Third, the capability of prostate magnetic resonance imaging (MRI), with the increasing use of functional sequences (so-called multiparametric MRI [mpMRI]) and advances in technology, protocols, and data-reporting standardisation in localising PCa, has revolutionised the conventional practice of PB. Data available so far seem to show that sampling mpMRI-derived targets results in detection of a higher proportion of clinically significant cancers using fewer cores compared with conventional sampling [15,16]. Whether this is true in all patients is still under debate [17]. What is still unknown is the optimal diagnostic strategy and sequence, which may include both novel biomarkers and mpMRI. In this context, the collaboration between urologists and radiologists would be necessary to engage the challenging issue of PCa detection. In conclusion, biomarkers and targeted PB might play an important role in reducing PSA-based PCa overdetection. The diagnostic process should represent a multidisciplinary field in which different professionals have to cooperate for optimal identification of those men who harbour potentially aggressive disease and thus benefit the most from curative treatment.
[2] Schro¨der FH, Hugosson J, Roobol MJ, et al. Screening and prostatecancer mortality in a randomized European study. N Engl J Med 2009;360:1320–8. [3] Andriole GL, Crawford ED, Grubb III RL, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009; 360:1310–9. [4] Loeb S, Bjurlin MA, Nicholson J, et al. Overdiagnosis and overtreatment of prostate cancer. Eur Urol 2014;65:1046–55. [5] Drazer MW, Prasad SM, Huo D, et al. National trends in prostate cancer screening among older American men with limited 9-year life expectancies: evidence of an increased need for shared decision making. Cancer 2014;120:1491–8. [6] Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 2010;28:1117–23. [7] Savage CJ, Vickers AJ. Low annual caseloads of United States surgeons conducting radical prostatectomy. J Urol 2009;182: 2677–9. [8] Period life table, 2010. US Social Security Administration Web site. http://www.ssa.gov/OACT/STATS/table4c6.html. Accessed April 5, 2015. [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] Guazzoni G, Nava L, Lazzeri M, et al. Prostate-specific antigen (PSA) isoform p2PSA significantly improves the prediction of prostate cancer at initial extended prostate biopsies in patients with total PSA between 2.0 and 10 ng/ml: results of a prospective study in a clinical setting. Eur Urol 2011;60:214–22. [11] Lughezzani G, Lazzeri M, Larcher A, et al. Development and internal validation of a Prostate Health Index based nomogram for predicting prostate cancer at extended biopsy. J Urol 2012;188: 1144–50. [12] Vickers A, Cronin A, Roobol M, et al. Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol 2010;28:2493–8. [13] Wei JT, Feng Z, Partin AW, et al. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J Clin Oncol 2014;32: 4066–72. [14] Vickers AJ. Markers for the early detection of prostate cancer: some principles for statistical reporting and interpretation. J Clin Oncol 2014;32:4033–4. [15] Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. JAMA 2015;313: 390–7. [16] Fu¨tterer JJ, Briganti A, De Visschere P, et al. Can clinically significant prostate cancer be detected with multiparametric magnetic resonance imaging? A systematic review of the literature. Eur Urol. In
Conflicts of interest: The authors have nothing to disclose.
press. doi:10.1016/j.eururo.2015.01.013 [17] Tonttila PP, Lantto J, Pa¨a¨kko¨ E, et al. Prebiopsy multiparametric
References
magnetic resonance imaging for prostate cancer diagnosis in biopsy-naive men with suspected prostate cancer based on elevated
[1] Ablin RJ. The great prostate mistake. New York Times. March 9,
prostate-specific antigen values: results from a randomized pro-
2010. http://www.nytimes.com/2010/03/10/opinion/10Ablin.
spective blinded controlled trial. Eur Urol. In press. doi:10.1016/j.
html?_r=0. Accessed July 25, 2013.
eururo.2015.05.024