0

The full content of Annals is available to subscribers

Subscribe/Learn More  >
Original Research |

Comparative Effectiveness of Alternative Prostate-Specific Antigen–Based Prostate Cancer Screening Strategies: Model Estimates of Potential Benefits and Harms

Roman Gulati, MS; John L. Gore, MD; and Ruth Etzioni, PhD
[+] Article and Author Information

From the Fred Hutchinson Cancer Research Center and University of Washington, Seattle, Washington.

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, rgulati@fhcrc.org). 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, retzioni@fhcrc.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.


Ann Intern Med. 2013;158(3):145-153. doi:10.7326/0003-4819-158-3-201302050-00003
Text Size: A A A

Chinese translation

Background: The U.S. Preventive Services Task Force recently concluded that the harms of existing prostate-specific antigen (PSA) screening strategies outweigh the benefits.

Objective: To evaluate comparative effectiveness of alternative PSA screening strategies.

Design: Microsimulation model of prostate cancer incidence and mortality quantifying harms and lives saved for alternative PSA screening strategies.

Data Sources: National and trial data on PSA growth, screening and biopsy patterns, incidence, treatment distributions, treatment efficacy, and mortality.

Target Population: A contemporary cohort of U.S. men.

Time Horizon: Lifetime.

Perspective: Societal.

Intervention: 35 screening strategies that vary by start and stop ages, screening intervals, and thresholds for biopsy referral.

Outcome Measures: PSA tests, false-positive test results, cancer detected, overdiagnoses, prostate cancer deaths, lives saved, and months of life saved.

Results of Base-Case Analysis: 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%.

Results of Sensitivity Analysis: Varying incidence inputs or reducing the survival improvement due to screening did not change conclusions.

Limitation: The model is a simplification of the natural history of prostate cancer, and improvement in survival due to screening is uncertain.

Conclusion: 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.

Primary Funding Source: National Cancer Institute and Centers for Disease Control and Prevention.

Figures

Grahic Jump Location
Figure 1.

Fred Hutchinson Cancer Research Center prostate cancer incidence model: underlying PSA growth before and after onset of tumors with a Gleason score of 2 through 7 and 8 through 10.

The dashed and dotted lines are PSA trajectories by age for the 2 categories of Gleason score. Shaded bands around those lines illustrate between-person variability in PSA values based on interquartile ranges. The jagged line illustrates an example PSA trajectory for a man who develops a tumor with a Gleason score of 2 through 7. In this example, PSA exceeds the threshold for biopsy referral on the fifth test of a schematic screening strategy. PSA = prostate-specific antigen.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Fred Hutchinson Cancer Research Center prostate cancer incidence model: healthy, preclinical, clinical, prostate cancer mortality, and other-cause mortality states in the absence of screening.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 1.

Effect of screening on prostate cancer survival based on the stage-shift model and a scheme for considering more modest effects in a sensitivity analysis.

The effect of early detection on prostate cancer survival is assumed to follow a stage-shift model; that is, when nonoverdiagnosed patients are shifted from distant to local–regional stage at diagnosis, they receive a corresponding survival improvement. This figure represents a nonoverdiagnosed patient whose prostate cancer would have been detected in distant stage in the absence of PSA screening. His prostate cancer survival in the absence of PSA screening is represented by the curve labeled “no PSA.” In the presence of PSA, his prostate cancer is detected in local–regional stage, and his prostate cancer survival follows a more favorable distribution, namely that for local–regional stage cases. This prostate cancer survival is represented by the curve labeled “PSA.” The new survival begins at his original date of clinical diagnosis because, as a nonoverdiagnosed patient, by definition he cannot die during his lead time. In a sensitivity analysis, we considered a more modest effect of screening on prostate cancer survival. To implement this, the age at prostate cancer death consists of a weighted average of the age at prostate cancer death in the absence of screening and the age at prostate cancer death in the presence of screening: [Death (actual)] = w × [Death (no PSA)] + (1 − w) × [Death (PSA)], where the weight (w = e−αλ) depends on lead time λ = [Diagnosis (no PSA)] − [Diagnosis (PSA)] and on a variable reflecting the effect of screening on survival α. Consequently, when α is small, the weight is approximately 1, and the actual age at prostate cancer death is the same as that projected in the absence of screening. In contrast, when α is large, the weight is approximately 0, and the actual age at prostate cancer death is the same as that projected in the presence of screening. For values of α between these extremes, weight depends on the lead time, with longer lead times leading to more weight being placed on age at prostate cancer death in the presence of screening. We use 4 values of α to achieve mortality reductions due to screening, ranging from 0 to the full effect expected under the stage-shift model. PSA = prostate-specific antigen.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.

Observed and projected age-adjusted prostate cancer incidence rates per 100 000 men aged 50 to 84 years, by stage at diagnosis.

In the absence of PSA screening, the model projects constant prostate cancer incidence at approximately the level observed in the core 9 catchment areas of SEER in 1985. In the presence of observed PSA screening (39), the model projects prostate cancer incidence that closely replicates the observed rapid increase and subsequent stabilization in local–regional stage incidence and much of the observed decline in distant stage incidence because of early detection. PSA = prostate-specific antigen; SEER = Surveillance, Epidemiology, and End Results.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.

Effect of varying individual screening strategy components on projected lifetime harms and benefits relative to the reference strategy.

Only the reference strategy (strategy 8) and strategies that differ from the reference strategy in a single variable are shown. Strategies are identified by the strategy number shown in the Table, and varied screening strategy components are in bold. In strategy 9, the screening interval is biennial if the PSA level is <2.5 µg/L and annual if the PSA level is ≥2.5 µg/L. In strategy 20, the threshold for biopsy referral is a PSA level of 3.5, 4.5, and 6.5 µg/L for ages 50–59, 60–69, and 70–74 y, respectively (21). Strategies are sorted in decreasing order by probability of life saved. NA = not applicable; PSA = prostate-specific antigen.

Grahic Jump Location
Grahic Jump Location
Figure 3.

Tradeoff between lifetime probabilities of life saved by screening and overdiagnosis for selected screening strategies.

Each point represents the tradeoff for 10 of the 35 screening strategies examined in this study: the reference strategy (strategy 8); strategies that differ from the reference by a single screening variable (strategies 3, 5, 6, 9, 18, 20, and 26 [Appendix Figure 3]); and strategies based on recommendations by the National Comprehensive Cancer Network (strategy 1), the American Cancer Society (strategy 9), and Vickers and Lilja (strategy 22) (8) (see the Table for strategy details). The assumed effects of screening on prostate cancer survival correspond to mortality reductions of 29% (the reduction observed in the ERSPC trial after correction for noncompliance), 20%, 10%, and 0% projected in a simulated version of the ERSPC after 11 years of follow-up. Probability of life saved by screening corresponding to a mortality reduction of 29% is based on the assumption that a patient whose stage was shifted from distant to local–regional by screening receives the survival of the earlier stage. Probability of life saved by screening corresponding to mortality reductions of 20%, 10%, and 0% in the simulated version of the ERSPC are based on a generalization of this stage-shift assumption that projects prostate cancer survival on a continuum between no effect for patients with short lead times and the full stage shift for patients with long lead times. Probability of overdiagnosis is based on model-projected competing risks for prostate cancer detection and other-cause mortality. Lines connect projections under the same mortality reduction. The additional NND to prevent 1 prostate cancer death is an established summary measure of the harm–benefit tradeoff in prostate cancer screening compared with no screening, defined as the overdiagnoses divided by lives saved by screening. The NND corresponding to any point in the figure is obtained as the ratio of the probability of overdiagnosis to the probability of life saved. For reference, dashed lines radiating from the origin (representing no screening) illustrate fixed NND values of 5, 10, and 20. For a given probability of overdiagnosis, as the probability of life saved by screening decreases, the corresponding NND increases. For the mortality reduction of 29%, NNDs range from 7.1 (strategy 1) to 3.6 (strategy 26), and for the mortality reduction of 10%, NNDs range from 16.5 (strategy 1) to 9.9 (strategy 26). A strategy that falls between 2 NND lines (for example, “NND = 5” and “NND = 10”) has an NND between those NND values. Different strategies will be preferred depending on relative weighting of the probabilities of life saved and overdiagnosis. Among the strategies considered, strategy 1 maximizes the probability of life saved and will be the preferred strategy if survival is the highest priority. Strategy 26 minimizes the probability of overdiagnosis and will be preferred if the morbidity associated with treatment is the greatest concern. For priorities between these extremes, the preferred strategy will be based on the most favorable balance between probabilities of life saved and overdiagnosis. For example, assuming the mortality reduction of 29%, a target tradeoff of 5 or fewer overdiagnoses per life saved (that is, NND ≤5) would identify strategies above and to the left of the “NND = 5” line. Assuming a mortality reduction of 20%, a target tradeoff of 5 or fewer overdiagnoses per life saved identifies strategy 20 as the only option. No strategy satisfies a target tradeoff of NND ≤3. No strategy satisfies a target tradeoff constraint of NND ≤10 under a mortality reduction assumption of 10%. ERSPC = European Randomized Study of Screening for Prostate Cancer; NND = number needed to detect.

Grahic Jump Location

Tables

References

Letters

NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Comments

Submit a Comment
What is the lifetime risk of prostate cancer with and without screening?
Posted on March 22, 2013
Michel Labrecque, MD
Hopital Saint Francis d'Assisse
Conflict of Interest: None Declared

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.

Author's Response
Posted on March 29, 2013
Roman Gulati, MS, Ruth Etzioni, PhD
Fred Hutchinson Cancer Research Center
Conflict of Interest: None Declared

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%).

 

  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):145-153.
  2. 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):778-784.
  3. 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.
  4. Mariotto AB, Etzioni R, Krapcho M, Feuer EJ. Reconstructing PSA testing patterns between black and white men in the US from Medicare claims and the National Health Interview Survey. Cancer. 2007;109(9):1877-1886.
Submit a Comment

Summary for Patients

Screening Smarter, Not Harder, for Prostate Cancer

The full report is titled “Comparative Effectiveness of Alternative Prostate-Specific Antigen–Based Prostate Cancer Screening Strategies. Model Estimates of Potential Benefits and Harms.” It is in the 5 February 2013 issue of Annals of Internal Medicine (volume 158, pages 145-153). The authors are R. Gulati, J.L. Gore, and R. Etzioni.

Read More...

Clinical Slide Sets

Terms of Use

The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-for-profit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets will constitute copyright infringement.

Toolkit

Buy Now

to gain full access to the content and tools.

Want to Subscribe?

Learn more about subscription options

Advertisement
Related Articles
Related Point of Care
Topic Collections
PubMed Articles
Forgot your password?
Enter your username and email address. We'll send you a reminder to the email address on record.
(Required)
(Required)