- Email: [email protected]
Re: Prostate Cancer Incidence and PSA Testing Patterns in Relation to USPSTF Screening Recommendations
EURURO-6745; No. of Pages 6 3
EUROPEAN UROLOGY XXX (2016) XXX–XXX
olaparib for more than 6 mo. Anemia (10 patients) and fatigue (six patients) were the most common Grade 3/4 adverse events. Targeted next-generation sequencing, exome and transcription analysis, and polymerase-chain-reaction testing were performed on samples from tumor biopsies. As a result, homozygous deletions, and/or deleterious mutations, or both in DNA repair genes (BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2) were identified in 16/49 patients who could be evaluated. Of these 16 patients, 14 had a response to olaparib, including all patients with BRCA2 loss and 4/5 with ATM mutations. Expert’s opinion: The interpatient heterogeneity of CRPC is well recognized. Prognostic tests such as prostate-specific antigen and commercially available gene panels as Prolaris, Oncotype DX, and Decipher are used, in addition to other clinical parameters and nomograms, to help decide for active surveillance or treatment with curative intent [2]. However, contrary to other diseases such as chronic myeloid leukemia, breast cancer, lung cancer, and colorectal cancer, personalized precision medicine (PPM) with a treatment based on molecular biomarkers is currently not yet available for CRPC [3]. Twenty-three percent to 30% of metastatic CRCP patients have genomic aberrations that interfere with DNA repair [4,5]. Some of these aberrations have been associated with sensitivity to platinum, also in bladder cancer, and poly(adenosine diphosphate-ribose) polymerase inhibitors, suggesting that poly(adenosine diphosphate-ribose) polymerase inhibition may lead to cell death [6]. The results of this phase 2 trial with olaparib, which has recently been approved for treating ovarian cancer with BRCA1/2 mutations, suggests that a subset of metastatic CRPC can be molecularly stratified for PPM. Six of
Re: Prostate Cancer Incidence and PSA Testing Patterns in Relation to USPSTF Screening Recommendations Jemal A, Fedewa SA, Ma J, et al JAMA 2015;314:2054–61 Experts’ summary: In 2008, the US Preventive Services Task Force (USPSTF) discouraged prostate-specific antigen (PSA)–based screening for prostate cancer (PCa) for men aged 75 yr. In 2012, this recommendation was extended to all men, based on the evidence that the PSA test often produces false-positive results, leading to negative psychological effects in addition to unnecessary complementary testing [1]. Because these recommendations were in contrast to those of the American Urological Association and the American Cancer Society, they triggered a large debate in the medical community and in society in general regarding PCa screening. Jemal et al reported on recent changes in PCa incidence and PSA screening rates in the United States following the USPSTF recommendations. Using data from 18 populationbased Surveillance, Epidemiology, and End Results (SEER) registries and questionnaires from the National Health Interview Survey, they found that overall PCa incidence
the 32 patients with measurable disease (Response Assessment in Solid Tumors 1.1) in this trial had a confirmed radiologic partial response and 14/49 patients had impressive falls in circulating tumor-cell counts. However, it is too early to determine whether survival is prolonged in this specific group of patients. If future research confirms these results, this is an important step towards PPM in CRPC. Conflicts of interest: The author has nothing to disclose.
References [1] Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015;373:1697–708. [2] Bostro¨m PJ, Bjartell AS, Catto JWF, et al. Genomic predictors of outcome in prostate cancer. Eur Urol 2015;68:1033–44. [3] Schneider D, Bianchini G, Horgan D, et al. Establishing the evidence bar for molecular diagnostics in personalized cancer care. Public Health Genomics 2015;18:349–58. [4] Grasso CS, Wu Y-M, Robinson DR, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012;487:239–43. [5] Robinson D, Van Allen EM, Wu Y-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215–28. [6] Plimack ER, Dunbrack RL, Brennan TA, et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle invasive bladder cancer. Eur Urol 2015;68:959–68. Wim P.J. Witjes* EAU Research Foundation, EAU Central Office, Arnhem, The Netherlands *EAU Research Foundation, EAU Central Office, Mr. E.N. van Kleffensstraat 5, Arnhem 6842CV, The Netherlands. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2016.03.059
decreased progressively since 2007, with the largest decline registered in 2011–2012 (relative decrease of 16%). Interestingly, the incidence of distant-stage disease increased significantly for patients aged 75 yr between 2011 and 2012, whereas it remained unchanged for all other patient groups. PSA screening rates remained relatively stable until 2013, at which time they decreased significantly for men aged 50 yr. Because of the short follow-up, no data were reported on the effect of these shifts in PCa incidence and stage. Experts’ comments: The benefits and harms of PSA screening for PCa in men aged 50 yr have been passionately debated for many years [2]. Defenders of PSA screening believe in the benefit of early detection of PCa, which, if localized, might be controlled, at least lowering the metastatic cascade. Others consider PSA an avoidable test due to the unacceptable risk of overdiagnosis and overtreatment. Data on both the benefits and the harms of PSA screening are still insufficient to make a final decision about its future. However, one cannot deny that PSA screening has led to the decrease in the rate of PCa metastasis and mortality—at what cost remains to be determined.
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EUROPEAN UROLOGY XXX (2016) XXX–XXX
The worry of many of us is that the ‘‘hard-earned’’ survival benefit for men will be lost because of a non–patientcentered, politically and financially driven health policy. As both sides have a point, we need to explore the middle ground, that is, how can we make PSA screening more tailored and precise for individual men? Vickers has proposed a smart screening approach based on the lesson of the past 10 yr [3]. He proposes to focus PSA screening on younger men; to select only men with a high risk of PCa for biopsy; to treat at high-volume centers, if deemed necessary; and to encourage active surveillance for low-risk PCa.
Carlsson, et al. Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Eur Urol 2012;62:745–52, Eur Urol 2012;62:e90–1. [3] Vickers AJ. Four flawed arguments against prostate-specific antigen screening (and 1 good one). Urology 2015;85:491–4. Ilaria Luccaa,b, Shahrokh F. Shariata,* a
Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
b
Department of Urology, Centre hospitalier universitaire vaudois, Lausanne, Switzerland
Conflicts of interest: The authors have nothing to disclose.
References [1] Moyer VA, US Preventive Services Task Force. Screening for prostate
*Corresponding author. Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Wa¨hringer Gu¨rtel 18-20, A-1090 Vienna, Austria.
cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157:120–34.
E-mail address: [email protected] (S.F. Shariat).
[2] Schro¨der FH, Roobol MJ. Reply to Alain Braillon and Ge´rard Dubois’ letter to the editor re: Fritz H. Schro¨der, Jonas Hugosson, Sigrid
Re: Mental Health Outcomes in Elderly Men with Prostate Cancer Ravi P, Karakiewicz PI, Roghmann F, et al Urol Oncol 2014;32:1333–40 Experts’ summary: This study investigated the potential burden of mental health issues on prostate cancer (PCa) patients by analyzing the relationship between diagnosis of localized PCa and subsequent development of anxiety, depressive disorders, and suicide. Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare database (1992–2005), Ravi et al identified 50 856 men between 65 and 80 yr of age diagnosed with localized PCa without a prior history of mental health issues. The authors found that 20.4% of men diagnosed with PCa subsequently developed mental health issues. Using multivariable Cox regression analysis, significant risk factors for mental health issues included age 75 yr (hazard ratio [HR]: 1.29); higher comorbidity (Charlson comorbidity index 3, HR: 1.63); rural hospital location (HR: 1.14); being single, divorced, or widowed (HR: 1.12); later year of diagnosis (HR: 1.05); and urinary incontinence (HR: 1.47). Protective factors for developing mental health issues included black race (HR: 0.79), very high income status (HR: 0.87), and erectile dysfunction (HR: 0.90). In addition, the risk of developing mental health issues for patients undergoing radical prostatectomy (RP) or radiation therapy (RT) was significantly lower than for patients electing for watchful waiting (RP, HR: 0.79; RT, HR: 0.85). The authors concluded that mental health issues are a significant burden on patients diagnosed with localized PCa, with a significantly higher risk among men who do not undergo definitive therapy. Experts’ comments: Because the majority of men diagnosed with localized PCa will not die of their disease, quality-of-life outcomes are important
http://dx.doi.org/10.1016/j.eururo.2016.03.060
when considering treatment options. Ravi et al hypothesized that definitive treatment of localized PCa may provide men with finality and peace of mind, whereas watchful waiting may lead to anxiety and fear and contribute to the development of mental health issues. Of note, a limitation of the SEER–Medicare database is that the cohort is restricted to patients aged 65 yr (the Medicare-eligible age in the United States) and may not be generalizable to younger patients diagnosed with PCa. Findings from previous studies may contradict the authors’ conclusions. Punnen et al [1], for example, found no difference in distress or anxiety levels between patients treated with RP and active surveillance. Instead, post-treatment functional decline in urinary or sexual function after RP was the most significant predictor of increased mental health burden [1]. Furthermore, Parker et al [2] reported no significant change in fear of disease progression over time in patients undergoing active surveillance. Interestingly, they found that uncertainty and anxiety scores actually decreased over a 2.5-yr period of active surveillance [2]. Considering that a number of patients with PCa will develop mental health issues, the succeeding concern is for personal safety and suicidal risk of these patients. Indeed, a number of recent studies have demonstrated an increased risk of suicide in patients with PCa compared with the general population [3–5]. The same demographic risk factors for mental health issues outlined by Ravi et al, namely unmarried status, white race, and older age, are also risk factors for suicide [4,5]. Furthermore, PCa patients have increased risk for suicide with time from diagnosis [4], potentially highlighting the importance of functional outcomes and long-term quality of life. A high index of suspicion, an ability to identify high-risk patients, and early psychologic or psychiatric referral should be required for all health care providers treating PCa patients. Conflicts of interest: The authors have nothing to disclose.
EUROPEAN UROLOGY XXX (2016) XXX–XXX
olaparib for more than 6 mo. Anemia (10 patients) and fatigue (six patients) were the most common Grade 3/4 adverse events. Targeted next-generation sequencing, exome and transcription analysis, and polymerase-chain-reaction testing were performed on samples from tumor biopsies. As a result, homozygous deletions, and/or deleterious mutations, or both in DNA repair genes (BRCA1/2, ATM, Fanconi’s anemia genes, and CHEK2) were identified in 16/49 patients who could be evaluated. Of these 16 patients, 14 had a response to olaparib, including all patients with BRCA2 loss and 4/5 with ATM mutations. Expert’s opinion: The interpatient heterogeneity of CRPC is well recognized. Prognostic tests such as prostate-specific antigen and commercially available gene panels as Prolaris, Oncotype DX, and Decipher are used, in addition to other clinical parameters and nomograms, to help decide for active surveillance or treatment with curative intent [2]. However, contrary to other diseases such as chronic myeloid leukemia, breast cancer, lung cancer, and colorectal cancer, personalized precision medicine (PPM) with a treatment based on molecular biomarkers is currently not yet available for CRPC [3]. Twenty-three percent to 30% of metastatic CRCP patients have genomic aberrations that interfere with DNA repair [4,5]. Some of these aberrations have been associated with sensitivity to platinum, also in bladder cancer, and poly(adenosine diphosphate-ribose) polymerase inhibitors, suggesting that poly(adenosine diphosphate-ribose) polymerase inhibition may lead to cell death [6]. The results of this phase 2 trial with olaparib, which has recently been approved for treating ovarian cancer with BRCA1/2 mutations, suggests that a subset of metastatic CRPC can be molecularly stratified for PPM. Six of
Re: Prostate Cancer Incidence and PSA Testing Patterns in Relation to USPSTF Screening Recommendations Jemal A, Fedewa SA, Ma J, et al JAMA 2015;314:2054–61 Experts’ summary: In 2008, the US Preventive Services Task Force (USPSTF) discouraged prostate-specific antigen (PSA)–based screening for prostate cancer (PCa) for men aged 75 yr. In 2012, this recommendation was extended to all men, based on the evidence that the PSA test often produces false-positive results, leading to negative psychological effects in addition to unnecessary complementary testing [1]. Because these recommendations were in contrast to those of the American Urological Association and the American Cancer Society, they triggered a large debate in the medical community and in society in general regarding PCa screening. Jemal et al reported on recent changes in PCa incidence and PSA screening rates in the United States following the USPSTF recommendations. Using data from 18 populationbased Surveillance, Epidemiology, and End Results (SEER) registries and questionnaires from the National Health Interview Survey, they found that overall PCa incidence
the 32 patients with measurable disease (Response Assessment in Solid Tumors 1.1) in this trial had a confirmed radiologic partial response and 14/49 patients had impressive falls in circulating tumor-cell counts. However, it is too early to determine whether survival is prolonged in this specific group of patients. If future research confirms these results, this is an important step towards PPM in CRPC. Conflicts of interest: The author has nothing to disclose.
References [1] Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015;373:1697–708. [2] Bostro¨m PJ, Bjartell AS, Catto JWF, et al. Genomic predictors of outcome in prostate cancer. Eur Urol 2015;68:1033–44. [3] Schneider D, Bianchini G, Horgan D, et al. Establishing the evidence bar for molecular diagnostics in personalized cancer care. Public Health Genomics 2015;18:349–58. [4] Grasso CS, Wu Y-M, Robinson DR, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012;487:239–43. [5] Robinson D, Van Allen EM, Wu Y-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215–28. [6] Plimack ER, Dunbrack RL, Brennan TA, et al. Defects in DNA repair genes predict response to neoadjuvant cisplatin-based chemotherapy in muscle invasive bladder cancer. Eur Urol 2015;68:959–68. Wim P.J. Witjes* EAU Research Foundation, EAU Central Office, Arnhem, The Netherlands *EAU Research Foundation, EAU Central Office, Mr. E.N. van Kleffensstraat 5, Arnhem 6842CV, The Netherlands. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2016.03.059
decreased progressively since 2007, with the largest decline registered in 2011–2012 (relative decrease of 16%). Interestingly, the incidence of distant-stage disease increased significantly for patients aged 75 yr between 2011 and 2012, whereas it remained unchanged for all other patient groups. PSA screening rates remained relatively stable until 2013, at which time they decreased significantly for men aged 50 yr. Because of the short follow-up, no data were reported on the effect of these shifts in PCa incidence and stage. Experts’ comments: The benefits and harms of PSA screening for PCa in men aged 50 yr have been passionately debated for many years [2]. Defenders of PSA screening believe in the benefit of early detection of PCa, which, if localized, might be controlled, at least lowering the metastatic cascade. Others consider PSA an avoidable test due to the unacceptable risk of overdiagnosis and overtreatment. Data on both the benefits and the harms of PSA screening are still insufficient to make a final decision about its future. However, one cannot deny that PSA screening has led to the decrease in the rate of PCa metastasis and mortality—at what cost remains to be determined.
EURURO-6745; No. of Pages 6 4
EUROPEAN UROLOGY XXX (2016) XXX–XXX
The worry of many of us is that the ‘‘hard-earned’’ survival benefit for men will be lost because of a non–patientcentered, politically and financially driven health policy. As both sides have a point, we need to explore the middle ground, that is, how can we make PSA screening more tailored and precise for individual men? Vickers has proposed a smart screening approach based on the lesson of the past 10 yr [3]. He proposes to focus PSA screening on younger men; to select only men with a high risk of PCa for biopsy; to treat at high-volume centers, if deemed necessary; and to encourage active surveillance for low-risk PCa.
Carlsson, et al. Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC). Eur Urol 2012;62:745–52, Eur Urol 2012;62:e90–1. [3] Vickers AJ. Four flawed arguments against prostate-specific antigen screening (and 1 good one). Urology 2015;85:491–4. Ilaria Luccaa,b, Shahrokh F. Shariata,* a
Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
b
Department of Urology, Centre hospitalier universitaire vaudois, Lausanne, Switzerland
Conflicts of interest: The authors have nothing to disclose.
References [1] Moyer VA, US Preventive Services Task Force. Screening for prostate
*Corresponding author. Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Wa¨hringer Gu¨rtel 18-20, A-1090 Vienna, Austria.
cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157:120–34.
E-mail address: [email protected] (S.F. Shariat).
[2] Schro¨der FH, Roobol MJ. Reply to Alain Braillon and Ge´rard Dubois’ letter to the editor re: Fritz H. Schro¨der, Jonas Hugosson, Sigrid
Re: Mental Health Outcomes in Elderly Men with Prostate Cancer Ravi P, Karakiewicz PI, Roghmann F, et al Urol Oncol 2014;32:1333–40 Experts’ summary: This study investigated the potential burden of mental health issues on prostate cancer (PCa) patients by analyzing the relationship between diagnosis of localized PCa and subsequent development of anxiety, depressive disorders, and suicide. Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare database (1992–2005), Ravi et al identified 50 856 men between 65 and 80 yr of age diagnosed with localized PCa without a prior history of mental health issues. The authors found that 20.4% of men diagnosed with PCa subsequently developed mental health issues. Using multivariable Cox regression analysis, significant risk factors for mental health issues included age 75 yr (hazard ratio [HR]: 1.29); higher comorbidity (Charlson comorbidity index 3, HR: 1.63); rural hospital location (HR: 1.14); being single, divorced, or widowed (HR: 1.12); later year of diagnosis (HR: 1.05); and urinary incontinence (HR: 1.47). Protective factors for developing mental health issues included black race (HR: 0.79), very high income status (HR: 0.87), and erectile dysfunction (HR: 0.90). In addition, the risk of developing mental health issues for patients undergoing radical prostatectomy (RP) or radiation therapy (RT) was significantly lower than for patients electing for watchful waiting (RP, HR: 0.79; RT, HR: 0.85). The authors concluded that mental health issues are a significant burden on patients diagnosed with localized PCa, with a significantly higher risk among men who do not undergo definitive therapy. Experts’ comments: Because the majority of men diagnosed with localized PCa will not die of their disease, quality-of-life outcomes are important
http://dx.doi.org/10.1016/j.eururo.2016.03.060
when considering treatment options. Ravi et al hypothesized that definitive treatment of localized PCa may provide men with finality and peace of mind, whereas watchful waiting may lead to anxiety and fear and contribute to the development of mental health issues. Of note, a limitation of the SEER–Medicare database is that the cohort is restricted to patients aged 65 yr (the Medicare-eligible age in the United States) and may not be generalizable to younger patients diagnosed with PCa. Findings from previous studies may contradict the authors’ conclusions. Punnen et al [1], for example, found no difference in distress or anxiety levels between patients treated with RP and active surveillance. Instead, post-treatment functional decline in urinary or sexual function after RP was the most significant predictor of increased mental health burden [1]. Furthermore, Parker et al [2] reported no significant change in fear of disease progression over time in patients undergoing active surveillance. Interestingly, they found that uncertainty and anxiety scores actually decreased over a 2.5-yr period of active surveillance [2]. Considering that a number of patients with PCa will develop mental health issues, the succeeding concern is for personal safety and suicidal risk of these patients. Indeed, a number of recent studies have demonstrated an increased risk of suicide in patients with PCa compared with the general population [3–5]. The same demographic risk factors for mental health issues outlined by Ravi et al, namely unmarried status, white race, and older age, are also risk factors for suicide [4,5]. Furthermore, PCa patients have increased risk for suicide with time from diagnosis [4], potentially highlighting the importance of functional outcomes and long-term quality of life. A high index of suspicion, an ability to identify high-risk patients, and early psychologic or psychiatric referral should be required for all health care providers treating PCa patients. Conflicts of interest: The authors have nothing to disclose.