- Email: [email protected]
Re: Intermittent Androgen Suppression for Rising PSA Level After Radiotherapy
1129
EUROPEAN UROLOGY 63 (2013) 1128–1133
Conflicts of interest: The authors have nothing to disclose.
[7] Trasino SE, Kim YS, Wang TT. Ligand, receptor, and cell typedependent regulation of ABCA1 and ABCG1 mRNA in prostate
References [1] Swyer G. The cholesterol content of normal and enlarged prostates. Cancer Res 1942;2:372–5. [2] Pelton K, Freeman MR, Solomon KR. Cholesterol and prostate cancer. Curr Opin Pharmacol 2012;12:751–9.
cancer epithelial cells. Mol Cancer Ther 2009;8:1934–45. [8] Leon CG, Locke JA, Adomat HH, et al. Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model. Prostate 2010;70:390–400.
[3] Schaffner CP. Prostatic cholesterol metabolism: regulation and alteration. Prog Clin Biol Res 1981;75A:279–324. [4] Kim J, Di Vizio D, Kim TK, et al. The response of the prostate to circulating cholesterol: activating transcription factor 3 (ATF3) as a
Keith R. Solomon, Emma H. Allott, Michael R. Freeman, Stephen J. Freedland*
prominent node in a cholesterol-sensing network. PloS One 2012;
Duke University School of Medicine, Durham, NC, USA
7:e39448. [5] Solomon KR, Pelton K, Boucher K, et al. Ezetimibe is an inhibitor of tumor angiogenesis. Am J Pathol 2009;174:1017–26.
*Corresponding author. E-mail address: [email protected] (S.J. Freedland).
[6] Pommier AJ, Alves G, Viennois E, et al. Liver X receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells. Oncogene 2010;29:2712–23.
Re: Intermittent Androgen Suppression for Rising PSA Level After Radiotherapy Crook JM, O’Callaghan CJ, Duncan G, et al. N Engl J Med 2012;367:895–903 Experts’ summary: Intermittent androgen-deprivation therapy (IADT) has been proposed as an alternative to continuous androgendeprivation therapy (CADT), based on the hypothesis that IADT improves quality of life without increasing mortality in men with advanced prostate cancer (PCa). To evaluate this hypothesis, Crook et al. designed this noninferiority trial randomizing 1386 men with biochemically recurrent nonmetastatic PCa to either CADT or IADT. Results were reported after a median of 6.9 yr of follow-up and after 524 deaths occurred. Overall survival was 8.8 yr for men undergoing IADT, compared with 9.1 yr for men undergoing CADT. Overall and disease-specific survival were not different between the two arms: hazard ratio [HR]: 1.02 (95% confidence interval [CI], 0.86–1.21) and HR: 1.18 (95% CI, 0.90–1.55), respectively. Analysis for noninferiority was statistically significant ( p = 0.009). It is important to note that 59% of deaths were unrelated to PCa, and only two deaths were directly attributable to androgen-deprivation therapy (ADT). Men undergoing IADT had fewer symptomatic complaints and mildly, but not significantly, improved functional status compared with men on CADT.
http://dx.doi.org/10.1016/j.eururo.2013.03.017
This important study by Crook et al. provides additional support for IADT in men with nonmetastatic disease. The findings are consistent with those of Calais da Silva et al. [3]; higher PCa mortality in the IADT cohort was offset by higher non-PCa mortality in the CADT cohort. While these results clearly support the use of IADT, there are a few caveats. First, many of the men on intermittent therapy never attained eugonadal levels of testosterone and thus, in reality, may have been biologically on CADT. The median age of men in the study was >74 yr, and most deaths were unrelated to PCa. Follow-up was only 7 yr, somewhat less than the estimated 10 yr before development of castration-resistant disease [4]. Because of these limitations, the safety of IADT remains unproven for younger men with longer life expectancy, and young men are exactly those most interested in IADT. Finally, this trial examined patients without metastatic disease. Recent data suggest that IADT may be inferior in men with metastatic disease [5]. Therefore, at the current time, we advise cautious use of IADT in carefully selected individuals. Conflicts of interest: The authors have nothing to disclose.
References [1] Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol 2009;181:1998–2006. [2] Akakura K, Bruchovsky N, Goldenberg SL, Rennie PS, Buckley AR, Sullivan LD. Effects of intermittent androgen suppression on
Experts’ comments: IADT has been embraced because of the potential for cost savings and improved quality of life. Based on data from preclinical and observational studies, it had been suggested that IADT could reduce cardiometabolic toxicity [1] or even delay progression to castration-resistant disease [2]. Calais da Silva et al. randomized 626 men with locally advanced or metastatic disease to IADT or CADT. They found no difference in overall survival. IADT was associated with higher PCaspecific mortality, while CADT was associated with higher cardiovascular mortality [3].
androgen-dependent tumors: apoptosis and serum prostate-specific antigen. Cancer 1993;71:2782–90. [3] Calais da Silva FEC, Bono AV, Whelan P, et al. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol 2009;55:1269–77. [4] Crook JM, O’Callaghan CJ, Ding K, et al. A phase III randomized trial of intermittent versus continuous androgen suppression for PSA progression after radical therapy [abstract 4514]. J Clin Oncol 2011;29(Suppl). [5] Hussain M, Tangen CM, Higano CS, et al. Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive
1130
EUROPEAN UROLOGY 63 (2013) 1128–1133
metastatic prostate cancer (HSM1PC) patients: results of S9346
*Corresponding author. Brigham and Women’s Hospital, Urology,
(INT-0162), an international phase III trial [abstract 4]. J Clin Oncol
45 Francis Street, Boston, MA 02115, USA.
2012;30(Suppl).
E-mail address: [email protected] (A.S. Kibel). Ravi Kackera, Adam S. Kibela,b,* a
Brigham and Women’s Hospital, Boston, MA, USA b
Harvard Medical School, Boston, MA, USA
Re: Quality-of-life Effects of Prostate-specific Antigen Screening Heijnsdijk EAM, Wever EM, Auvinen A, et al. N Engl J Med 2012;367:595–605 Expert’s summary: Heijnsdijk et al. used a simulation model to adjust the mortality benefit demonstrated for prostate-specific antigen (PSA)–based screening in the European Randomized Study of Screening for Prostate Cancer (ERSPC) by accounting for the potential negative effects of screening, diagnosis, and treatment on quality of life (QOL). The analysis is based on a treatment algorithm in which men can be screened, biopsied, and diagnosed, after which they can receive treatment or active surveillance and then might progress to advanced and terminal illness. Adverse effects of irradiation and surgery both last for 12 mo, and stress incontinence and erectile dysfunction are the only QOL domains considered. Utility weights assigned to each treatment and health state are referenced from the literature, but these weights are not well validated, and varying the utility assumptions has a major effect on the model outcomes. The authors conclude that their study quantifies the extent to which the observed mortality reduction achievable by screening in ERSPC is attenuated by the QOL impact. Expert’s comments: Substantial challenges clearly exist in developing a qualityadjusted life-year (QALY) model calculated with a lifetime horizon from time of screening. The clinical model—the possible treatments and health states—is substantially oversimplified [1], and the authors acknowledge some of the limitations associated with their selection of utility values in the model. The broad message of the paper—that harms should be considered in evaluating the impact of screening—is clearly true, but the model is nowhere close to robust enough for the specific quantitative findings reported to be considered reliable or clinically useful.
Re: Radical Prostatectomy Versus Observation for Localized Prostate Cancer Wilt TJ, Brawer MK, Jones KM, et al., Prostate Cancer Intervention Versus Observation Trial (PIVOT) Study Group N Engl J Med 2012;367:203–13 Experts’ summary: This paper reports a randomized trial of radical prostatectomy (RP) versus observation for men with localized prostate cancer (PCa) in the prostate-specific antigen (PSA) era.
http://dx.doi.org/10.1016/j.eururo.2013.03.018
Perhaps the most important philosophical flaw in the utility analysis is the false assumption that the ‘‘perfect’’ health state—the one assigned a utility of 1.0—is the naive, unscreened state. In the authors’ analysis, the simple drawing of a PSA test causes an immediate decline in utility attributed to anxiety, and no utility following biopsy is ever >0.97. In reality, the majority of men screened are found to have a very low PSA [2] and, therefore, a negligible risk of prostate cancer mortality. In prior studies among men without cancer, the overwhelming majority of men prefer, and thus have a higher utility for, the state of being ‘‘normal by screening’’ compared with the state of unknown status without screening [3]. In other words, men perceive much value in reassurance [4], and ignoring this QOL gain in a decision analytic framework will unfairly reduce the QALY benefit associated with screening. Conflicts of interest: The author has nothing to disclose.
References [1] Cooperberg MR, Ramakrishna NR, Duff SB. et al. Primary treatments for clinically localised prostate cancer a comprehensive lifetime cost-utility analysis BJU Int 2013;111:437–50. [2] Vickers AJ, Cronin AM, Bjo¨rk T, et al. Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study. BMJ 2010;341:c4521. [3] Cantor SB, Volk RJ, Cass AR, Gilani J, Spann SJ. Psychological benefits of prostate cancer screening: the role of reassurance. Health Expect 2002;5:104–13. [4] Detsky AS. Underestimating the value of reassurance. JAMA 2012;307:1035–6. Matthew R. Cooperberg University of California, San Francisco, Urology, 3025 Scott St., San Francisco, CA 94123, USA E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2013.03.019
Men with untreated PCa were recruited over 8 yr, mostly from US Department of Veterans Affairs facilities across the United States. The men were medically fit to undergo RP and had clinical stage T2 or lower, PSA <50 ng/ml, age <75 yr, negative bone scan, any Gleason grade, and life expectancy of at least 10 yr. Subjects were randomized to RP or observation. The primary and secondary outcome measures were all-cause mortality (ACM) and PCa-specific mortality (PCSM). The study was originally designed to accrue 2000 patients, but due to recruiting difficulties, the goal was modified to 740.
EUROPEAN UROLOGY 63 (2013) 1128–1133
Conflicts of interest: The authors have nothing to disclose.
[7] Trasino SE, Kim YS, Wang TT. Ligand, receptor, and cell typedependent regulation of ABCA1 and ABCG1 mRNA in prostate
References [1] Swyer G. The cholesterol content of normal and enlarged prostates. Cancer Res 1942;2:372–5. [2] Pelton K, Freeman MR, Solomon KR. Cholesterol and prostate cancer. Curr Opin Pharmacol 2012;12:751–9.
cancer epithelial cells. Mol Cancer Ther 2009;8:1934–45. [8] Leon CG, Locke JA, Adomat HH, et al. Alterations in cholesterol regulation contribute to the production of intratumoral androgens during progression to castration-resistant prostate cancer in a mouse xenograft model. Prostate 2010;70:390–400.
[3] Schaffner CP. Prostatic cholesterol metabolism: regulation and alteration. Prog Clin Biol Res 1981;75A:279–324. [4] Kim J, Di Vizio D, Kim TK, et al. The response of the prostate to circulating cholesterol: activating transcription factor 3 (ATF3) as a
Keith R. Solomon, Emma H. Allott, Michael R. Freeman, Stephen J. Freedland*
prominent node in a cholesterol-sensing network. PloS One 2012;
Duke University School of Medicine, Durham, NC, USA
7:e39448. [5] Solomon KR, Pelton K, Boucher K, et al. Ezetimibe is an inhibitor of tumor angiogenesis. Am J Pathol 2009;174:1017–26.
*Corresponding author. E-mail address: [email protected] (S.J. Freedland).
[6] Pommier AJ, Alves G, Viennois E, et al. Liver X receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells. Oncogene 2010;29:2712–23.
Re: Intermittent Androgen Suppression for Rising PSA Level After Radiotherapy Crook JM, O’Callaghan CJ, Duncan G, et al. N Engl J Med 2012;367:895–903 Experts’ summary: Intermittent androgen-deprivation therapy (IADT) has been proposed as an alternative to continuous androgendeprivation therapy (CADT), based on the hypothesis that IADT improves quality of life without increasing mortality in men with advanced prostate cancer (PCa). To evaluate this hypothesis, Crook et al. designed this noninferiority trial randomizing 1386 men with biochemically recurrent nonmetastatic PCa to either CADT or IADT. Results were reported after a median of 6.9 yr of follow-up and after 524 deaths occurred. Overall survival was 8.8 yr for men undergoing IADT, compared with 9.1 yr for men undergoing CADT. Overall and disease-specific survival were not different between the two arms: hazard ratio [HR]: 1.02 (95% confidence interval [CI], 0.86–1.21) and HR: 1.18 (95% CI, 0.90–1.55), respectively. Analysis for noninferiority was statistically significant ( p = 0.009). It is important to note that 59% of deaths were unrelated to PCa, and only two deaths were directly attributable to androgen-deprivation therapy (ADT). Men undergoing IADT had fewer symptomatic complaints and mildly, but not significantly, improved functional status compared with men on CADT.
http://dx.doi.org/10.1016/j.eururo.2013.03.017
This important study by Crook et al. provides additional support for IADT in men with nonmetastatic disease. The findings are consistent with those of Calais da Silva et al. [3]; higher PCa mortality in the IADT cohort was offset by higher non-PCa mortality in the CADT cohort. While these results clearly support the use of IADT, there are a few caveats. First, many of the men on intermittent therapy never attained eugonadal levels of testosterone and thus, in reality, may have been biologically on CADT. The median age of men in the study was >74 yr, and most deaths were unrelated to PCa. Follow-up was only 7 yr, somewhat less than the estimated 10 yr before development of castration-resistant disease [4]. Because of these limitations, the safety of IADT remains unproven for younger men with longer life expectancy, and young men are exactly those most interested in IADT. Finally, this trial examined patients without metastatic disease. Recent data suggest that IADT may be inferior in men with metastatic disease [5]. Therefore, at the current time, we advise cautious use of IADT in carefully selected individuals. Conflicts of interest: The authors have nothing to disclose.
References [1] Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol 2009;181:1998–2006. [2] Akakura K, Bruchovsky N, Goldenberg SL, Rennie PS, Buckley AR, Sullivan LD. Effects of intermittent androgen suppression on
Experts’ comments: IADT has been embraced because of the potential for cost savings and improved quality of life. Based on data from preclinical and observational studies, it had been suggested that IADT could reduce cardiometabolic toxicity [1] or even delay progression to castration-resistant disease [2]. Calais da Silva et al. randomized 626 men with locally advanced or metastatic disease to IADT or CADT. They found no difference in overall survival. IADT was associated with higher PCaspecific mortality, while CADT was associated with higher cardiovascular mortality [3].
androgen-dependent tumors: apoptosis and serum prostate-specific antigen. Cancer 1993;71:2782–90. [3] Calais da Silva FEC, Bono AV, Whelan P, et al. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol 2009;55:1269–77. [4] Crook JM, O’Callaghan CJ, Ding K, et al. A phase III randomized trial of intermittent versus continuous androgen suppression for PSA progression after radical therapy [abstract 4514]. J Clin Oncol 2011;29(Suppl). [5] Hussain M, Tangen CM, Higano CS, et al. Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive
1130
EUROPEAN UROLOGY 63 (2013) 1128–1133
metastatic prostate cancer (HSM1PC) patients: results of S9346
*Corresponding author. Brigham and Women’s Hospital, Urology,
(INT-0162), an international phase III trial [abstract 4]. J Clin Oncol
45 Francis Street, Boston, MA 02115, USA.
2012;30(Suppl).
E-mail address: [email protected] (A.S. Kibel). Ravi Kackera, Adam S. Kibela,b,* a
Brigham and Women’s Hospital, Boston, MA, USA b
Harvard Medical School, Boston, MA, USA
Re: Quality-of-life Effects of Prostate-specific Antigen Screening Heijnsdijk EAM, Wever EM, Auvinen A, et al. N Engl J Med 2012;367:595–605 Expert’s summary: Heijnsdijk et al. used a simulation model to adjust the mortality benefit demonstrated for prostate-specific antigen (PSA)–based screening in the European Randomized Study of Screening for Prostate Cancer (ERSPC) by accounting for the potential negative effects of screening, diagnosis, and treatment on quality of life (QOL). The analysis is based on a treatment algorithm in which men can be screened, biopsied, and diagnosed, after which they can receive treatment or active surveillance and then might progress to advanced and terminal illness. Adverse effects of irradiation and surgery both last for 12 mo, and stress incontinence and erectile dysfunction are the only QOL domains considered. Utility weights assigned to each treatment and health state are referenced from the literature, but these weights are not well validated, and varying the utility assumptions has a major effect on the model outcomes. The authors conclude that their study quantifies the extent to which the observed mortality reduction achievable by screening in ERSPC is attenuated by the QOL impact. Expert’s comments: Substantial challenges clearly exist in developing a qualityadjusted life-year (QALY) model calculated with a lifetime horizon from time of screening. The clinical model—the possible treatments and health states—is substantially oversimplified [1], and the authors acknowledge some of the limitations associated with their selection of utility values in the model. The broad message of the paper—that harms should be considered in evaluating the impact of screening—is clearly true, but the model is nowhere close to robust enough for the specific quantitative findings reported to be considered reliable or clinically useful.
Re: Radical Prostatectomy Versus Observation for Localized Prostate Cancer Wilt TJ, Brawer MK, Jones KM, et al., Prostate Cancer Intervention Versus Observation Trial (PIVOT) Study Group N Engl J Med 2012;367:203–13 Experts’ summary: This paper reports a randomized trial of radical prostatectomy (RP) versus observation for men with localized prostate cancer (PCa) in the prostate-specific antigen (PSA) era.
http://dx.doi.org/10.1016/j.eururo.2013.03.018
Perhaps the most important philosophical flaw in the utility analysis is the false assumption that the ‘‘perfect’’ health state—the one assigned a utility of 1.0—is the naive, unscreened state. In the authors’ analysis, the simple drawing of a PSA test causes an immediate decline in utility attributed to anxiety, and no utility following biopsy is ever >0.97. In reality, the majority of men screened are found to have a very low PSA [2] and, therefore, a negligible risk of prostate cancer mortality. In prior studies among men without cancer, the overwhelming majority of men prefer, and thus have a higher utility for, the state of being ‘‘normal by screening’’ compared with the state of unknown status without screening [3]. In other words, men perceive much value in reassurance [4], and ignoring this QOL gain in a decision analytic framework will unfairly reduce the QALY benefit associated with screening. Conflicts of interest: The author has nothing to disclose.
References [1] Cooperberg MR, Ramakrishna NR, Duff SB. et al. Primary treatments for clinically localised prostate cancer a comprehensive lifetime cost-utility analysis BJU Int 2013;111:437–50. [2] Vickers AJ, Cronin AM, Bjo¨rk T, et al. Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study. BMJ 2010;341:c4521. [3] Cantor SB, Volk RJ, Cass AR, Gilani J, Spann SJ. Psychological benefits of prostate cancer screening: the role of reassurance. Health Expect 2002;5:104–13. [4] Detsky AS. Underestimating the value of reassurance. JAMA 2012;307:1035–6. Matthew R. Cooperberg University of California, San Francisco, Urology, 3025 Scott St., San Francisco, CA 94123, USA E-mail address: [email protected]. http://dx.doi.org/10.1016/j.eururo.2013.03.019
Men with untreated PCa were recruited over 8 yr, mostly from US Department of Veterans Affairs facilities across the United States. The men were medically fit to undergo RP and had clinical stage T2 or lower, PSA <50 ng/ml, age <75 yr, negative bone scan, any Gleason grade, and life expectancy of at least 10 yr. Subjects were randomized to RP or observation. The primary and secondary outcome measures were all-cause mortality (ACM) and PCa-specific mortality (PCSM). The study was originally designed to accrue 2000 patients, but due to recruiting difficulties, the goal was modified to 740.