Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context

Abstract

Background: The time by which prostate-specific antigen (PSA) screening advances prostate cancer diagnosis, called the lead time, has been reported by several studies, but results have varied widely, with mean lead times ranging from 3 to 12 years. A quantity that is closely linked with the lead time is the overdiagnosis frequency, which is the fraction of screen-detected cancers that would not have been diagnosed in the absence of screening. Reported overdiagnosis estimates have also been variable, ranging from 25% to greater than 80% of screen-detected cancers.

Methods: We used three independently developed mathematical models of prostate cancer progression and detection that were calibrated to incidence data from the Surveillance, Epidemiology, and End Results program to estimate lead times and the fraction of overdiagnosed cancers due to PSA screening among US men aged 54-80 years in 1985-2000. Lead times were estimated by use of three definitions. We also compared US and earlier estimates from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) that were calculated by use of a microsimulation screening analysis (MISCAN) model.

Results: The models yielded similar estimates for each definition of lead time, but estimates differed across definitions. Among screen-detected cancers that would have been diagnosed in the patients' lifetimes, the estimated mean lead time ranged from 5.4 to 6.9 years across models, and overdiagnosis ranged from 23% to 42% of all screen-detected cancers. The original MISCAN model fitted to ERSPC Rotterdam data predicted a mean lead time of 7.9 years and an overdiagnosis estimate of 66%; in the model that was calibrated to the US data, these were 6.9 years and 42%, respectively.

Conclusion: The precise definition and the population used to estimate lead time and overdiagnosis can be important drivers of study results and should be clearly specified.

Figure 1

Lead time, sojourn time, and overdiagnosis. A) Non-overdiagnosed prostate cancers. B) Overdiagnosed prostate cancers. A non-overdiagnosed cancer patient is clinically diagnosed (CD) before dying from any cause (AC Death), whereas an overdiagnosed cancer patient dies of other causes (OC Death) before being clinically diagnosed. Lead times (L) begin at screen detection (SD), and sojourn times (S) begin at disease onset (Onset). Non-overdiagnosed lead and sojourn times (L_N and S_N) are calculated only for non-overdiagnosed cancers. Censored lead and sojourn times (L_C and S_C) are calculated for both non-overdiagnosed cancers and overdiagnosed cancers, with times for overdiagnosed cancers censored at OC death. Uncensored lead and sojourn times (L_U and S_U) are also calculated for both non-overdiagnosed cancers and overdiagnosed cancers, with times for overdiagnosed cancers uncensored at OC Death. Note that the overdiagnosed cancers might include nonprogressive cancer or “insignificant” cancer, for which clinical diagnosis would “never” happen, even in the absence of other-cause mortality. CD = clinical diagnosis; SD = screen detection; AC Death = death from any cause; OC Death = death from other causes; Onset = disease onset time, when the tumor becomes detectable by screening.

Figure 2

Dissemination of PSA screening. The graph presents the age-adjusted [to the US standard million (21)] frequency of first PSA tests and repeat tests in men aged 50–84 years. Rates are based on the results of Mariotto et al. (19). PSA = prostate-specific antigen.

Figure 3

Age-adjusted [to the US standard million (21)] incidence of prostate cancer in men aged 50–84 years as observed in SEER 9 and predicted by each of the models. Predicted incidence is separated into screen-detected (SD) and clinically diagnosed (CD) components. A) The MISCAN model. B) The FHCRC model. C) The UMich model. SEER 9 = the nine core catchment areas in the Surveillance, Epidemiology, and End Results program of the National Cancer Institute; MISCAN = microsimulation screening analysis model based on ERSPC Rotterdam, calibrated to SEER 9 incidence; FHCRC = microsimulation model developed at the Fred Hutchinson Cancer Research Center, explicitly linking PSA levels and prostate cancer development; UMich = analytic model developed by A. Tsodikov (University of Michigan); PSA = prostate-specific antigen; ERSPC = European Randomized Study of Screening for Prostate Cancer.

Figure 4

Age-adjusted [to the US standard million (21)] incidence in men aged 50–84 years of local–regional-stage and distant-stage prostate cancer as observed (SEER 9) and predicted by each of the models. A) Local–regional-stage prostate cancer. B) Distant-stage prostate cancer. SEER 9 = the nine core catchment areas in the Surveillance, Epidemiology, and End Results program of the National Cancer Institute; MISCAN = microsimulation screening analysis model based on ERSPC Rotterdam, calibrated to SEER 9 incidence; FHCRC = microsimulation model developed at the Fred Hutchinson Cancer Research Center, explicitly linking PSA levels and prostate cancer development; UMich = analytic model developed by A. Tsodikov (University of Michigan); PSA = prostate-specific antigen; ERSPC = European Randomized Study of Screening for Prostate Cancer.

Figure 5

Age-adjusted [to the US standard million (21)] incidence of prostate cancer in men aged 50–84 years as observed in SEER 9 and predicted by the calibrated* and uncalibrated† MISCAN models. *Model calibrated to SEER 9 incidence, with risk of clinical diagnosis and test sensitivity estimated from SEER 9 incidence. †Original, uncalibrated model with parameters estimated from incidence in the Netherlands in 1991 and cancer rates observed in the Rotterdam section of ERSPC. SEER 9 = the nine core catchment areas in the Surveillance, Epidemiology, and End Results program of the National Cancer Institute; ERSPC = European Randomized Study of Screening for Prostate Cancer; MISCAN = microsimulation screening analysis.