- Email: [email protected]
Re: Radical Prostatectomy Versus Observation for Localized Prostate Cancer
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.
1131
EUROPEAN UROLOGY 63 (2013) 1128–1133
A total of 731 men agreed to participate in the trial; 364 were randomized to RP, and 367 were randomized to observation. At median follow-up of 10.0 yr, RP provided no benefit with respect to ACM (hazard ratio [HR]: 0.88; 95% confidence interval [CI], 0.71–1.08; p = 0.22; absolute risk reduction, 2.9 percentage points) or PCSM (HR: 0.63; 95% CI, 0.36–1.09; p = 0.09; absolute risk reduction, 2.6 percentage points). For men with PSA >10 ng/ml, subgroup analysis demonstrated that RP was associated with decreased ACM (HR: 0.67; 95% CI, 0.48–0.94) and PCSM (HR: 0.36; 95% CI, 0.15–0.89).
overall and PCa-specific survival. The study also demonstrated higher rates of non-PCSM than had been previously suggested by other studies over similar time frames [2]. Such information is crucial when counseling men about the benefits of treatment. This study adds to mounting evidence that low-risk tumors may safely be observed and high-risk tumors should be treated. Conflicts of interest: The authors have nothing to disclose.
References Experts’ comments: This study is truly pivotal because it is the first randomized trial to assess the impact of RP versus observation in the PSA era, an issue that remains important and unclear >17 yr after the study first opened. A prior Scandinavian trial largely performed in the pre-PSA era demonstrated improved PCa-specific survival [1] and, with longer follow-up, improved overall survival [2] in patients who received RP. However, the generalizability of this Scandinavian trial has been questioned because >80% of study participants were diagnosed by digital rectal examination. Although the PIVOT study is flawed (accrual goals were not met, and the investigators failed to account for differences in outcomes based on provider [3]), Wilt et al. report their results with 10 yr of median follow-up and demonstrate clearly that men with lower-risk cancers do not benefit from RP, a finding that is largely consistent with active surveillance trials [4]. Although this result is not surprising, several important findings are worth noting. Men with higher-risk PCa benefited from RP. Bone metastases were lower in the RP group than in the observation group, and patients with PSA >10ng/ml had improved
Re: Postoperative Radiotherapy After Radical Prostatectomy for High-risk Prostate Cancer: Long-term Results of a Randomised Controlled Trial (EORTC Trial 22911) Bolla M, van Poppel H, Tombal B, et al. Lancet 2012;380:2018–27 Experts’ summary: This paper reports on the third large randomized trial exploring the value of adjuvant radiotherapy following radical prostatectomy for prostate cancer [1,2]. A total of 1005 patients from 37 European institutions were randomized. Eligible patients had pT2N0M0 or pT3N0M0 disease after surgery and at least one of the following additional risk factors: extracapsular extension, positive surgical margins, or seminal vesicle invasion. In total, 502 patients were assigned to immediate irradiation (60 Gy). For the 503 patients in the wait-andsee group, irradiation was deferred until biochemical progression had occurred. After 10 yr, 227 patients (45.1%) remained biochemically and clinically recurrence-free. Only
[1] Holmberg L, Bill-Axelson A, Helgesen F, et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002;347:781–9. [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] Vickers AJ, Bianco FJ, Serio AM, et al. The surgical learning curve for prostate cancer control after radical prostatectomy. J Natl Cancer Inst 2007;99:1171–7. [4] Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 2010;28:126–31. Jonathan L. Silberstein*, James A. Eastham Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA *Corresponding author. Memorial Sloan-Kettering Cancer Center, Urology Service, Department of Surgery, 1275 York Ave., New York, NY 10021, USA. E-mail address: [email protected] (J.L. Silberstein). http://dx.doi.org/10.1016/j.eururo.2013.03.020
155 patients (30.8%) received salvage irradiation. Biochemical progression was more common in the wait-and-see group than the immediate irradiation group (61.8% compared with 39.4%), but this reduced risk did not translate into a survival benefit, as the two treatment groups did not differ with respect to progression-free survival (PFS), distant metastasis–free survival, or overall survival. Experts’ comments: It is already apparent that this important paper will be interpreted in two quite opposite ways. Radiation oncologists will highlight the improved biochemical-free survival in the immediate irradiation group and argue in favor of adjuvant therapy for patients with high-risk features after radical prostatectomy. Urologists will point to the lack of improvement in overall survival, clinical PFS, or distant metastasis, as well as the higher rate of late adverse effects in the patients randomized to immediate irradiation. What are we to conclude? Clearly, there is a population of patients who will benefit from early administration of radiotherapy after radical prostatectomy, that is, patients with extracapsular disease and positive margins. However,
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.
1131
EUROPEAN UROLOGY 63 (2013) 1128–1133
A total of 731 men agreed to participate in the trial; 364 were randomized to RP, and 367 were randomized to observation. At median follow-up of 10.0 yr, RP provided no benefit with respect to ACM (hazard ratio [HR]: 0.88; 95% confidence interval [CI], 0.71–1.08; p = 0.22; absolute risk reduction, 2.9 percentage points) or PCSM (HR: 0.63; 95% CI, 0.36–1.09; p = 0.09; absolute risk reduction, 2.6 percentage points). For men with PSA >10 ng/ml, subgroup analysis demonstrated that RP was associated with decreased ACM (HR: 0.67; 95% CI, 0.48–0.94) and PCSM (HR: 0.36; 95% CI, 0.15–0.89).
overall and PCa-specific survival. The study also demonstrated higher rates of non-PCSM than had been previously suggested by other studies over similar time frames [2]. Such information is crucial when counseling men about the benefits of treatment. This study adds to mounting evidence that low-risk tumors may safely be observed and high-risk tumors should be treated. Conflicts of interest: The authors have nothing to disclose.
References Experts’ comments: This study is truly pivotal because it is the first randomized trial to assess the impact of RP versus observation in the PSA era, an issue that remains important and unclear >17 yr after the study first opened. A prior Scandinavian trial largely performed in the pre-PSA era demonstrated improved PCa-specific survival [1] and, with longer follow-up, improved overall survival [2] in patients who received RP. However, the generalizability of this Scandinavian trial has been questioned because >80% of study participants were diagnosed by digital rectal examination. Although the PIVOT study is flawed (accrual goals were not met, and the investigators failed to account for differences in outcomes based on provider [3]), Wilt et al. report their results with 10 yr of median follow-up and demonstrate clearly that men with lower-risk cancers do not benefit from RP, a finding that is largely consistent with active surveillance trials [4]. Although this result is not surprising, several important findings are worth noting. Men with higher-risk PCa benefited from RP. Bone metastases were lower in the RP group than in the observation group, and patients with PSA >10ng/ml had improved
Re: Postoperative Radiotherapy After Radical Prostatectomy for High-risk Prostate Cancer: Long-term Results of a Randomised Controlled Trial (EORTC Trial 22911) Bolla M, van Poppel H, Tombal B, et al. Lancet 2012;380:2018–27 Experts’ summary: This paper reports on the third large randomized trial exploring the value of adjuvant radiotherapy following radical prostatectomy for prostate cancer [1,2]. A total of 1005 patients from 37 European institutions were randomized. Eligible patients had pT2N0M0 or pT3N0M0 disease after surgery and at least one of the following additional risk factors: extracapsular extension, positive surgical margins, or seminal vesicle invasion. In total, 502 patients were assigned to immediate irradiation (60 Gy). For the 503 patients in the wait-andsee group, irradiation was deferred until biochemical progression had occurred. After 10 yr, 227 patients (45.1%) remained biochemically and clinically recurrence-free. Only
[1] Holmberg L, Bill-Axelson A, Helgesen F, et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002;347:781–9. [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] Vickers AJ, Bianco FJ, Serio AM, et al. The surgical learning curve for prostate cancer control after radical prostatectomy. J Natl Cancer Inst 2007;99:1171–7. [4] Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol 2010;28:126–31. Jonathan L. Silberstein*, James A. Eastham Urology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA *Corresponding author. Memorial Sloan-Kettering Cancer Center, Urology Service, Department of Surgery, 1275 York Ave., New York, NY 10021, USA. E-mail address: [email protected] (J.L. Silberstein). http://dx.doi.org/10.1016/j.eururo.2013.03.020
155 patients (30.8%) received salvage irradiation. Biochemical progression was more common in the wait-and-see group than the immediate irradiation group (61.8% compared with 39.4%), but this reduced risk did not translate into a survival benefit, as the two treatment groups did not differ with respect to progression-free survival (PFS), distant metastasis–free survival, or overall survival. Experts’ comments: It is already apparent that this important paper will be interpreted in two quite opposite ways. Radiation oncologists will highlight the improved biochemical-free survival in the immediate irradiation group and argue in favor of adjuvant therapy for patients with high-risk features after radical prostatectomy. Urologists will point to the lack of improvement in overall survival, clinical PFS, or distant metastasis, as well as the higher rate of late adverse effects in the patients randomized to immediate irradiation. What are we to conclude? Clearly, there is a population of patients who will benefit from early administration of radiotherapy after radical prostatectomy, that is, patients with extracapsular disease and positive margins. However,