Roman Gulati, MS; John L. Gore, MD; Ruth Etzioni, PhD
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, the National Institutes of Health, or the Centers for Disease Control and Prevention.
Acknowledgment: The authors thank Jeffrey Katcher for developing a flexible interface for specifying candidate PSA screening strategies and Drs. Jeanne Mandelblatt and Andrew Vickers for helpful comments on an earlier draft of the manuscript.
Grant Support: By awards R01 CA131874 and U01 CA88160 (National Cancer Institute) and U01 CA157224 (National Cancer Institute and the Centers for Disease Control and Prevention).
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M12-1645.
Reproducible Research Statement: Study protocol, statistical code, and data set: Available from Mr. Gulati (e-mail, email@example.com). A detailed model description is available at http://cisnet.cancer.gov/prostate/profiles.html.
Requests for Single Reprints: Ruth Etzioni, PhD, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M2-B230, PO Box 19024, Seattle, WA 98109-1024; e-mail, firstname.lastname@example.org.
Current Author Addresses: Mr. Gulati and Dr. Etzioni: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M2-B230, PO Box 19024, Seattle, WA 98109-1024.
Dr. Gore: Department of Urology, University of Washington, 1959 Northeast Pacific Street, Box 356510, Seattle, WA 98195-6510.
Author Contributions: Conception and design: R. Gulati, R. Etzioni.
Analysis and interpretation of the data: R. Gulati, J.L. Gore, R. Etzioni.
Drafting of the article: R. Gulati, R. Etzioni.
Critical revision of the article for important intellectual content: R. Gulati, J.L. Gore, R. Etzioni.
Final approval of the article: R. Gulati, J.L. Gore, R. Etzioni.
Statistical expertise: R. Gulati, R. Etzioni.
Obtaining of funding: R. Gulati, R. Etzioni.
Administrative, technical, or logistic support: R. Gulati.
Collection and assembly of data: R. Gulati, R. Etzioni.
Gulati R., Gore J., Etzioni R.; Comparative Effectiveness of Alternative Prostate-Specific Antigen–Based Prostate Cancer Screening Strategies: Model Estimates of Potential Benefits and Harms. Ann Intern Med. 2013;158:145-153. doi: 10.7326/0003-4819-158-3-201302050-00003
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Published: Ann Intern Med. 2013;158(3):145-153.
The U.S. Preventive Services Task Force recently concluded that the harms of existing prostate-specific antigen (PSA) screening strategies outweigh the benefits.
To evaluate comparative effectiveness of alternative PSA screening strategies.
Microsimulation model of prostate cancer incidence and mortality quantifying harms and lives saved for alternative PSA screening strategies.
National and trial data on PSA growth, screening and biopsy patterns, incidence, treatment distributions, treatment efficacy, and mortality.
A contemporary cohort of U.S. men.
35 screening strategies that vary by start and stop ages, screening intervals, and thresholds for biopsy referral.
PSA tests, false-positive test results, cancer detected, overdiagnoses, prostate cancer deaths, lives saved, and months of life saved.
Without screening, the risk for prostate cancer death is 2.86%. A reference strategy that screens men aged 50 to 74 years annually with a PSA threshold for biopsy referral of 4 µg/L reduces the risk for prostate cancer death to 2.15%, with risk for overdiagnosis of 3.3%. A strategy that uses higher PSA thresholds for biopsy referral in older men achieves a similar risk for prostate cancer death (2.23%) but reduces the risk for overdiagnosis to 2.3%. A strategy that screens biennially with longer screening intervals for men with low PSA levels achieves similar risks for prostate cancer death (2.27%) and overdiagnosis (2.4%), but reduces total tests by 59% and false-positive results by 50%.
Varying incidence inputs or reducing the survival improvement due to screening did not change conclusions.
The model is a simplification of the natural history of prostate cancer, and improvement in survival due to screening is uncertain.
Compared with standard screening, PSA screening strategies that use higher thresholds for biopsy referral for older men and that screen men with low PSA levels less frequently can reduce harms while preserving lives.
National Cancer Institute and Centers for Disease Control and Prevention.
Michel Labrecque, MD
Hopital Saint Francis d'Assisse
March 22, 2013
What is the lifetime risk of prostate cancer with and without screening?
Gulati and al(1) propose estimates of lifetime risk of prostate cancer for 35 strategies of screening vs. no screening. Based on their analysis, the lifetime risk of prostate cancer diagnosis in a 50 year old man undergoing annual PSA screening until the age of 69 with a 4.0 µg/l PSA threshold for referral to further investigate (the most effective strategy to minimize overdiagnosis according to the authors) would be 13.8% while the lifetime risk of a 50 year old man not undergoing screening would be 12% (difference in risk: 1.8%). These numbers appear surprisingly low considering that:1) The estimate of the lifetime risk of prostate cancer based on US 2007-2009 SEER data(2) is 16.15%. Given that that not all US men have routine screening between 50 and 69 years of age, one would expect a modeled estimate that assumes 100% uptake of screening to be higher. 2) Earlier models of lifetime risk of prostate cancer yielded two different estimates. Wever et al(3) estimated that the lifetime risk of prostate cancer would be 21% and 14% in a cohort of 50 year old men undergoing annual screening until age 69 and a cohort of men of the same age not undergoing screening, respectively (difference in risk: 7%). Heijnsdijk et al(4) estimated that the lifetime risk would be 15.7% with annual screening between ages 50 and 69 and 11.2% without annual screening (difference in risk: 4.5%). These latter estimates were based on a population aged 0-100 (meaning that some men were already beyond recommended screening age ranges) and, when running the model in a cohort of men aged 50, the lifetime risk of those who were screened was 20.8% (difference in risk: 9.6%) (Heijnsdijk EAM, personal communication).Precise estimates of the risk of prostate cancer with and without screening are essential pieces of information to share with men to help them making informed decisions about undergoing prostate screening or not. It is unclear from the available data which is the appropriate information to provide.
1. Gulati R, Gore JL, Etzioni R. Comparative effectiveness of alternative prostate-specific antigen-based prostate cancer screening strategies: model estimates of potential benefits and harms. Ann Intern Med. 2013;158(3):145-53.
2. National Cancer Institute. DevCan-Probability of Developing or Dying of Cancer. 2012. Accessed at http://surveillance.cancer.gov/devcan/ on 13 March 2013.
3. Wever EM, Hugosson J, Heijnsdijk EA, Bangma CH, Draisma G, de Koning HJ. To be screened or not to be screened? Modeling the consequences of PSA screening for the individual. Br J Cancer. 2012;107(5):778-84.
4. Heijnsdijk EA, Wever EM, Auvinen A, Hugosson J, Ciatto S, Nelen V, et al. Quality-of-life effects of prostate-specific antigen screening. N Engl J Med. 2012;367(7):595-605.
Roman Gulati, MS, Ruth Etzioni, PhD
Fred Hutchinson Cancer Research Center
March 29, 2013
The lifetime risk of prostate cancer diagnosis under PSA screening depends critically on the screening and biopsy practice setting. The FHCRC model in Gulati et al. (1) is designed to represent US clinical practice, and it estimates that this risk ranges from 13.5% to 18.2% depending on screening ages, intervals, and biopsy referral criteria. In contrast, the MISCAN model in Wever et al. (2) and Heijnsdijk et al. (3) represents practice in the European Randomized Study of Screening for Prostate Cancer (ERSPC) and, partly due to this different setting, gives higher estimates.
Consider annual screening for men ages 50–69. Assuming biopsy referral when PSA exceeds 4.0 μg/L and frequency of biopsy (41%) after a positive PSA test observed in the Prostate, Lung, Colorectal, and Ovarian cancer screening trial, the FHCRC model estimates that the lifetime risk of diagnosis under this strategy would be 13.8%. This risk is lower than that under recent US practice because, under recent practice, screening detected many cancers among men 70 years and older. Using screening ages and intervals for the US population (4), the FHCRC estimate (16.7%) is close to the SEER estimate (16.2%).
The MISCAN model estimates that the lifetime risk under annual screening for ages 50–69 is 17.4%, with continued screening to age 74 increasing this to 20.8% (Heijnsdijk EAM, personal communication). One reason the MISCAN estimate is higher than the FHCRC estimate is it assumes biopsy referral when PSA exceeds 3.0 μg/L and biopsy frequency (86%) as in the ERSPC. Using this lower PSA threshold and higher biopsy frequency, the FHCRC estimate increases to 15.2%.
The remaining difference between estimates (17.4%−15.2%=2.2%) is due to differences in the ways the models represent natural history and screening outcomes. The FHCRC model explicitly models individual PSA growth, which is linked to cancer progression and detection, while the MISCAN model estimates PSA sensitivity for different clinical T-stages and Gleason scores. Both models reproduce observed incidence patterns in their settings and are consistent with the current state of knowledge about prostate cancer natural history.
Note that restricting screening to ages 50–69 is not the most effective strategy to minimize overdiagnosis—stopping screening entirely would better achieve that goal. Rather, this is an example of a screening strategy that substantially reduces the lifetime risk of overdiagnosis (from 4.4% under current screening to 1.8%) while retaining the same lifetime risk of prostate cancer death (2.3%).
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Hematology/Oncology, High Value Care, Prostate Cancer, Cancer Screening/Prevention, Prevention/Screening.
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