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A Matched Cohort Analysis of Prostate Cancer Screening in Younger Men in Sweden
EURURO-6771; No. of Pages 2 EUROPEAN UROLOGY XXX (2016) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
A Matched Cohort Analysis of Prostate Cancer Screening in Younger Men in Sweden Roman Gulati *, Ruth Etzioni Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
In this month’s issue of European Urology, Carlsson et al reported on a matched cohort analysis of screening for prostate cancer (PCa) in Swedish men aged 50–54 yr [1]. Their analysis compared incidence and mortality in the youngest subgroup of men aged 50–64 yr who were invited to prostate-specific antigen (PSA) screening as part of the Go¨teborg randomized screening trial in the mid-1990s versus age-matched men who contributed blood samples to the Malmo¨ Preventive Project a decade earlier. The Go¨teborg trial is the most favorable PSA screening trial to date, with a 44% reduction in the risk of PCa death after 14 yr [2]. Even among the subset of participants who were included in the European Randomized Study of Screening for Prostate Cancer analysis of men aged 55–69 yr, a 38% reduction in mortality was reported after 13 yr [3]. The observed magnitude of benefit easily satisfies any reasonable definition of an efficacious test. To more closely examine the evidence for starting screening at age 50 yr instead of age 54 yr, the authors could have undertaken a subgroup analysis of the Go¨teborg trial. Instead, they conducted a nonrandomized comparison with a historical control group in a different geographical region and in which many of the cancer cases were diagnosed before the Go¨teborg trial even began. Why? The authors argued that because opportunistic screening among men randomized to the control arm in Go¨teborg increased significantly in later years, a conventional intention-to-screen analysis no longer reflected the effect of screening versus no screening [1]. Because there was negligible screening in the historical population, using this population as a control group could provide a more pure comparison. Indeed, the results are consistent with this
idea, yielding mortality reduction (71%) greater than even the value most recently reported by trial investigators for this age group when comparing the screening and control arms (50%) [4]. Which estimate is more reliable and should be cited in future studies and policy deliberations? This question takes us to the heart of the debate over what constitutes evidence in medical decision making. One of the first principles in policy development is that randomized trials are preferred over observational studies because they can avoid confounding and other biases [5]. Indeed, we cling to trials even when they are clearly inadequate or outdated. Recent mammography screening guidelines still cite historical mammography trials over more contemporary service-screening studies even though the trials were conducted decades ago. And the most recent prostate screening recommendation from the US Preventive Services Task Force included the null result of the Prostate, Lung, Colorectal, and Ovarian cancer screening trial in the range of efficacy of PSA screening even though the extreme contamination on the control arm of this trial renders it uninformative about the efficacy of screening versus no screening [6]. In such settings, we naturally seek to clarify the evidence by turning to nonrandomized studies, including cohort, case–control, and modeling studies [7,8]. Each is subject to well-known limitations, but when a randomized trial is not available or can give only a tainted answer, a nonrandomized study may offer important insights, although tied to its own mix of strengths and weaknesses [9]. How tainted is the Go¨teborg trial, and how believable is the Malmo¨ comparison? A recent analysis of opportunistic screening in the control arm of the trial found incidence significantly higher than expected but no associated
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2016.03.026. * Corresponding author. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M2-B230, PO Box 19024, Seattle, WA 98109-1024, USA. Tel. +1 206 667 7795; Fax: +1 206 667 7264. E-mail address: [email protected] (R. Gulati). http://dx.doi.org/10.1016/j.eururo.2016.04.006 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Gulati R, Etzioni R. A Matched Cohort Analysis of Prostate Cancer Screening in Younger Men in Sweden. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.04.006
EURURO-6771; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2016) XXX–XXX
reduction in PCa mortality [10]. On the one hand, the problem of opportunistic screening affecting mortality reduction seems modest. This modest effect is consistent with the close agreement between the authors’ estimated number needed to invite (NNI) to prevent one PCa death (NNI: 176) compared with the trial estimate for men aged 50–64 yr (NNI: 190). On the other hand, the higher-thanexpected incidence artificially narrows the incidence gap between arms, potentially leading to an underestimate of the number needed to diagnose (NND) to prevent one PCa death. Indeed, the authors’ estimate of this number (NND: 16) is nearly double that for the trial estimate for men aged 50–64 yr (NND: 9). The validity of the Malmo¨ comparison depends on the comparability of the two cohorts in terms of both baseline risk and treatment practices. The authors assessed comparability and presented some encouraging findings. They observed, for example, similar overall mortality between the two cohorts, suggesting comparable risks of noncancer death. They also noted that age-standardized PCa mortality rates in Sweden were stable over the years of the study, suggesting that improved treatment is an unlikely explanation for differential risks of cancerspecific death. These checks are supportive of internal validity but are not conclusive. It is possible, for example, that national trends in PCa mortality rates are not representative of the Malmo¨ cohort, that receipt of radical treatment or quality of follow-up care was different between cohorts, or that unknown factors associated with selection for the Malmo¨ cohort could have predisposed these men to different risks of cancer incidence or death. Unfortunately, none of the results presented allow us to compare the baseline risk in the Malmo¨ cohort with that in the control arm of the trial, a comparison that could have been quite informative. In conclusion, if we imagine ourselves tasked with formulating screening policies for men aged 50–54 yr, we still find ourselves trusting the Go¨teborg trial results regarding relative and absolute reductions in PCa mortality; however, there is little doubt that the trial results understate the increase in incidence due to screening. Although overdiagnosis is only imperfectly reflected in increased incidence, the matched cohorts may, in theory, be better positioned to estimate it. In general, we believe that
nontraditional studies, with due recognition of their caveats, can provide useful insights that complement randomized trial results and present a more complete picture of screening benefits and harms. Conflicts of interest: The authors have nothing to disclose. Funding support: This work was supported by awards R01 CA192402 and U01 CA199338 from the US National Cancer Institute (NCI). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI.
References [1] Carlsson S, Assel M, Ulmert D, et al. Screening for prostate cancer starting at age 50–54 years. A population-based cohort study. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2016.03.026 [2] Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010;11:725–32. [3] Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014;384:2027–35. [4] Arnsrud Godtman R, Carlsson S, Grenabo Bergdahl A et al., 18-year follow up of the Gothenburg randomized population-based prostate cancer screening trial. Presented at: European Association of Urology congress; March 11–15, 2016; Munich, Germany. [5] Rochon PA, Gurwitz JH, Sykora K, et al. Reader’s guide to critical appraisal of cohort studies: 1. Role and design. BMJ 2005;330:895–7. [6] Melnikow J, LeFevre ML, Wilt TJ, Moyer VA. Counterpoint: randomized trials provide the strongest evidence for clinical guidelines: the US Preventive Services Task Force and prostate cancer screening. Med Care 2013;51:301–3. [7] Etzioni R, Gulati R, Cooperberg MR, Penson DM, Weiss NS, Thompson IM. Limitations of basing screening policies on screening trials: the US Preventive Services Task Force and prostate cancer screening. Med Care 2013;51:295–300. [8] Etzioni R, Gulati R. Response: reading between the lines of cancer screening trials: using modeling to understand the evidence. Med Care 2013;51:304–6. [9] Rawlins M. De Testimonio: on the evidence for decisions about the use of therapeutic interventions. Clin Med (Lond) 2008;8:579–88. [10] Arnsrud Godtman R, Holmberg E, Lilja H, Stranne J, Hugosson J. Opportunistic testing versus organized prostate-specific antigen screening: outcome after 18 years in the Goteborg randomized population-based prostate cancer screening trial. Eur Urol 2015; 68:354–60.
Please cite this article in press as: Gulati R, Etzioni R. A Matched Cohort Analysis of Prostate Cancer Screening in Younger Men in Sweden. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.04.006
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. x–y of this issue
A Matched Cohort Analysis of Prostate Cancer Screening in Younger Men in Sweden Roman Gulati *, Ruth Etzioni Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
In this month’s issue of European Urology, Carlsson et al reported on a matched cohort analysis of screening for prostate cancer (PCa) in Swedish men aged 50–54 yr [1]. Their analysis compared incidence and mortality in the youngest subgroup of men aged 50–64 yr who were invited to prostate-specific antigen (PSA) screening as part of the Go¨teborg randomized screening trial in the mid-1990s versus age-matched men who contributed blood samples to the Malmo¨ Preventive Project a decade earlier. The Go¨teborg trial is the most favorable PSA screening trial to date, with a 44% reduction in the risk of PCa death after 14 yr [2]. Even among the subset of participants who were included in the European Randomized Study of Screening for Prostate Cancer analysis of men aged 55–69 yr, a 38% reduction in mortality was reported after 13 yr [3]. The observed magnitude of benefit easily satisfies any reasonable definition of an efficacious test. To more closely examine the evidence for starting screening at age 50 yr instead of age 54 yr, the authors could have undertaken a subgroup analysis of the Go¨teborg trial. Instead, they conducted a nonrandomized comparison with a historical control group in a different geographical region and in which many of the cancer cases were diagnosed before the Go¨teborg trial even began. Why? The authors argued that because opportunistic screening among men randomized to the control arm in Go¨teborg increased significantly in later years, a conventional intention-to-screen analysis no longer reflected the effect of screening versus no screening [1]. Because there was negligible screening in the historical population, using this population as a control group could provide a more pure comparison. Indeed, the results are consistent with this
idea, yielding mortality reduction (71%) greater than even the value most recently reported by trial investigators for this age group when comparing the screening and control arms (50%) [4]. Which estimate is more reliable and should be cited in future studies and policy deliberations? This question takes us to the heart of the debate over what constitutes evidence in medical decision making. One of the first principles in policy development is that randomized trials are preferred over observational studies because they can avoid confounding and other biases [5]. Indeed, we cling to trials even when they are clearly inadequate or outdated. Recent mammography screening guidelines still cite historical mammography trials over more contemporary service-screening studies even though the trials were conducted decades ago. And the most recent prostate screening recommendation from the US Preventive Services Task Force included the null result of the Prostate, Lung, Colorectal, and Ovarian cancer screening trial in the range of efficacy of PSA screening even though the extreme contamination on the control arm of this trial renders it uninformative about the efficacy of screening versus no screening [6]. In such settings, we naturally seek to clarify the evidence by turning to nonrandomized studies, including cohort, case–control, and modeling studies [7,8]. Each is subject to well-known limitations, but when a randomized trial is not available or can give only a tainted answer, a nonrandomized study may offer important insights, although tied to its own mix of strengths and weaknesses [9]. How tainted is the Go¨teborg trial, and how believable is the Malmo¨ comparison? A recent analysis of opportunistic screening in the control arm of the trial found incidence significantly higher than expected but no associated
DOI of original article: http://dx.doi.org/10.1016/j.eururo.2016.03.026. * Corresponding author. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M2-B230, PO Box 19024, Seattle, WA 98109-1024, USA. Tel. +1 206 667 7795; Fax: +1 206 667 7264. E-mail address: [email protected] (R. Gulati). http://dx.doi.org/10.1016/j.eururo.2016.04.006 0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Gulati R, Etzioni R. A Matched Cohort Analysis of Prostate Cancer Screening in Younger Men in Sweden. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.04.006
EURURO-6771; No. of Pages 2 2
EUROPEAN UROLOGY XXX (2016) XXX–XXX
reduction in PCa mortality [10]. On the one hand, the problem of opportunistic screening affecting mortality reduction seems modest. This modest effect is consistent with the close agreement between the authors’ estimated number needed to invite (NNI) to prevent one PCa death (NNI: 176) compared with the trial estimate for men aged 50–64 yr (NNI: 190). On the other hand, the higher-thanexpected incidence artificially narrows the incidence gap between arms, potentially leading to an underestimate of the number needed to diagnose (NND) to prevent one PCa death. Indeed, the authors’ estimate of this number (NND: 16) is nearly double that for the trial estimate for men aged 50–64 yr (NND: 9). The validity of the Malmo¨ comparison depends on the comparability of the two cohorts in terms of both baseline risk and treatment practices. The authors assessed comparability and presented some encouraging findings. They observed, for example, similar overall mortality between the two cohorts, suggesting comparable risks of noncancer death. They also noted that age-standardized PCa mortality rates in Sweden were stable over the years of the study, suggesting that improved treatment is an unlikely explanation for differential risks of cancerspecific death. These checks are supportive of internal validity but are not conclusive. It is possible, for example, that national trends in PCa mortality rates are not representative of the Malmo¨ cohort, that receipt of radical treatment or quality of follow-up care was different between cohorts, or that unknown factors associated with selection for the Malmo¨ cohort could have predisposed these men to different risks of cancer incidence or death. Unfortunately, none of the results presented allow us to compare the baseline risk in the Malmo¨ cohort with that in the control arm of the trial, a comparison that could have been quite informative. In conclusion, if we imagine ourselves tasked with formulating screening policies for men aged 50–54 yr, we still find ourselves trusting the Go¨teborg trial results regarding relative and absolute reductions in PCa mortality; however, there is little doubt that the trial results understate the increase in incidence due to screening. Although overdiagnosis is only imperfectly reflected in increased incidence, the matched cohorts may, in theory, be better positioned to estimate it. In general, we believe that
nontraditional studies, with due recognition of their caveats, can provide useful insights that complement randomized trial results and present a more complete picture of screening benefits and harms. Conflicts of interest: The authors have nothing to disclose. Funding support: This work was supported by awards R01 CA192402 and U01 CA199338 from the US National Cancer Institute (NCI). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI.
References [1] Carlsson S, Assel M, Ulmert D, et al. Screening for prostate cancer starting at age 50–54 years. A population-based cohort study. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2016.03.026 [2] Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010;11:725–32. [3] Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014;384:2027–35. [4] Arnsrud Godtman R, Carlsson S, Grenabo Bergdahl A et al., 18-year follow up of the Gothenburg randomized population-based prostate cancer screening trial. Presented at: European Association of Urology congress; March 11–15, 2016; Munich, Germany. [5] Rochon PA, Gurwitz JH, Sykora K, et al. Reader’s guide to critical appraisal of cohort studies: 1. Role and design. BMJ 2005;330:895–7. [6] Melnikow J, LeFevre ML, Wilt TJ, Moyer VA. Counterpoint: randomized trials provide the strongest evidence for clinical guidelines: the US Preventive Services Task Force and prostate cancer screening. Med Care 2013;51:301–3. [7] Etzioni R, Gulati R, Cooperberg MR, Penson DM, Weiss NS, Thompson IM. Limitations of basing screening policies on screening trials: the US Preventive Services Task Force and prostate cancer screening. Med Care 2013;51:295–300. [8] Etzioni R, Gulati R. Response: reading between the lines of cancer screening trials: using modeling to understand the evidence. Med Care 2013;51:304–6. [9] Rawlins M. De Testimonio: on the evidence for decisions about the use of therapeutic interventions. Clin Med (Lond) 2008;8:579–88. [10] Arnsrud Godtman R, Holmberg E, Lilja H, Stranne J, Hugosson J. Opportunistic testing versus organized prostate-specific antigen screening: outcome after 18 years in the Goteborg randomized population-based prostate cancer screening trial. Eur Urol 2015; 68:354–60.
Please cite this article in press as: Gulati R, Etzioni R. A Matched Cohort Analysis of Prostate Cancer Screening in Younger Men in Sweden. Eur Urol (2016), http://dx.doi.org/10.1016/j.eururo.2016.04.006