Papers

Natural experiment examining impact of aggressive screening and treatment on prostate cancer mortality in two fixed cohorts from Seattle area and Connecticut

Grace Lu-Yao, director ^a, Peter C Albertsen, professor of surgery ^b, Janet L Stanford, member and head, Program in Prostate Cancer Research ^c, Therese A Stukel, professor of biostatistics ^d, Elizabeth S Walker-Corkery, research coordinator ^e, Michael J Barry, associate professor of medicine, Harvard Medical School ^e. 

^a HealthStat, PO Box 7501, Princeton, NJ 08543, USA, ^b Division of Urology, Department of Surgery, University of Connecticut Health Center, MC 3955, Farmington, CT 06030, USA, ^c Division of Public Health Sciences, Programs in Epidemiology and Prostate Cancer Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, MW-814, Seattle, WA 98109, USA, ^d Center for the Evaluative Clinical Sciences, Dartmouth Medical School, 7251 Strasenburgh, Hanover, NH 03755, USA, ^e Medical Practices Evaluation Center, Massachusetts General Hospital, 50 Staniford Street, 9th floor, Boston, MA 02114, USA

Correspondence to: M J Barry mbarry{at}partners.org

	Abstract

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Objective: To determine whether the more intensive screening and treatment for prostate cancer in the Seattle-Puget Sound area in 1987-90 led to lower mortality from prostate cancer than in Connecticut.
Design: Natural experiment comparing two fixed cohorts from 1987 to 1997.
Setting: Seattle-Puget Sound and Connecticut surveillance, epidemiology, and end results areas.
Participants: Population based cohorts of male Medicare beneficiaries aged 65-79 drawn from the Seattle (n=94 900) and Connecticut (n=120 621) areas.
Main outcome measures: Rates of screening for prostate cancer, treatment with radical prostatectomy and external beam radiotherapy, and prostate cancer specific mortality.
Results: The prostate specific antigen testing rate in Seattle was 5.39 (95% confidence interval 4.76 to 6.11) times that of Connecticut, and the prostate biopsy rate was 2.20 (1.81 to 2.68) times that of Connecticut during 1987-90. The 10 year cumulative incidences of radical prostatectomy and external beam radiotherapy up to 1996 were 2.7% and 3.9% for Seattle cohort members compared with 0.5% and 3.1% for Connecticut cohort members. The adjusted rate ratio of prostate cancer mortality up to 1997 was 1.03 (0.95 to 1.11) in Seattle compared with Connecticut.
Conclusion: More intensive screening for prostate cancer and treatment with radical prostatectomy and external beam radiotherapy among Medicare beneficiaries in the Seattle area than in the Connecticut area was not associated with lower prostate cancer specific mortality over 11 years of follow up.

What is already known on this topic Screening for prostate cancer with the prostate specific antigen test is widely practised in the United States and has resulted in a remarkable increase in incidence of diagnosed disease Randomised trials are under way to determine whether early detection and aggressive treatment reduce mortality from prostate cancer Recent reductions in prostate cancer mortality in the United States have been attributed to screening and treatment, raising questions about whether continuing the trials is ethical What this study adds Prostate cancer screening and treatment were much more intensive among men in the Seattle-Puget Sound area than in Connecticut early in the "prostate specific antigen era" Over 11 years of follow up, no difference in prostate cancer mortality was seen in the two cohorts The lack of association between more intensive screening and treatment and lower prostate cancer mortality suggests that trials should continue in order to settle this question

	Introduction

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During the early 1990s the incidence of prostate cancer in the United States rose dramatically after the introduction of testing for prostate specific antigen. The subsequent decline in incidence probably represents depletion of prevalent cases from the pool of men undergoing screening. ^{1 2} In the mid-1990s population based prostate cancer mortality peaked and then decreased by about 15%. ^{2 3} Although the decline in mortality may be attributable to screening, several studies have highlighted difficulties in making inferences about causation from cross sectional population based data.^4-6

This paper presents an 11 year longitudinal study of two cohorts of male Medicare beneficiaries from the Seattle-Puget Sound area and Connecticut exposed to different intensities of prostate cancer screening and treatment during the "early prostate specific antigen era," which we defined a priori as 1987-90. The age adjusted prostate cancer death rates in the two regions were almost identical before the introduction of prostate specific antigen testing.

	Methods

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Data sources and inclusion criteria We used four specific data sources for this study: Medicare denominator and vital status files, US National Cancer Institute's surveillance, epidemiology, and end results (SEER) program-Medicare linked database, and local SEER registry data (see bmj.com). We included men who were Medicare beneficiaries aged 65-79 without prostate cancer as of 1 January 1987 and resident within the Seattle-Puget Sound or Connecticut SEER region from 1 January 1987 to 31 December 1990. The primary end point for this study was prostate cancer mortality for the two cohorts from 1987 to 1997.

	Results

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The table shows the race and age distributions for the 215 521 eligible men in both cohorts. Cohort members in the Seattle-Puget Sound region were 5.39 (95% confidence interval 4.76 to 6.11) times more likely to undergo prostate specific antigen testing in 1988-90 and 2.20 (1.81 to 2.68) times more likely to undergo prostate biopsy in 1987-90 than their counterparts in Connecticut. Differences in prostate specific antigen testing and biopsy rates narrowed considerably in 1991-3; the Seattle to Connecticut adjusted rate ratio was 1.61 (1.48 to 1.75) for prostate specific antigen and 1.14 (0.93 to 1.40) for biopsy.

Prostate cancer incidence reflects screening rates (fig 1). The adjusted cumulative incidence of prostate cancer was 93% (81% to 107%) higher among men in Seattle-Puget Sound than in Connecticut in 1987-90. The difference in incidence diminished over time; during 1991-6 the cumulative prostate cancer incidence was only 11% (4% to 18%) higher in the Seattle area.

View larger version (21K): [in this window] [in a new window]   Fig 1.   Unadjusted 10 year cumulative incidence of prostate cancer for study cohort members in the Seattle-Puget Sound and Connecticut areas, 1987-96

Between 1987 and 1990 men in the Seattle area were more likely to have radical prostatectomy or external beam radiation than their counterparts in Connecticut. Men in the Seattle area had a 5.9-fold (5.0 to 6.9) higher rate of radical prostatectomy and 2.3-fold (2.2 to 2.5) higher rate of external beam radiation during 1987-90. The 10 year cumulative incidences of radical prostatectomy and external beam radiation from 1987 to 1996 were 2.7% and 3.9% for Seattle-Puget Sound cohort members and 0.5% and 3.1% for Connecticut cohort members (fig 2).

View larger version (27K): [in this window] [in a new window]   Fig 2.   Unadjusted 10 year cumulative incidence of radical prostatectomy (top) and external beam radiotherapy (bottom) for cohort members in the Seattle-Puget Sound and Connecticut areas, 1987-96

No significant difference in prostate cancer mortality existed between the Seattle and Connecticut cohorts over the entire 11 year follow up period. The adjusted rate ratio of prostate cancer mortality to 1997 was 1.03 (0.95 to 1.11) in Seattle compared with Connecticut. As any effect of more aggressive screening and treatment on mortality may have been delayed, we compared prostate cancer mortality separately for the earlier (1987-92) and later (1993-7) years of follow up. No significant differences occurred in either periodrate ratios 0.97 (0.81 to 1.16) versus 1.08 (0.98 to 1.20). Figure 3 shows cross sectional prostate cancer mortality for men aged 65-79 from 1987 to 1997, documenting similar decreases in both areas.

View larger version (15K): [in this window] [in a new window]   Fig 3.   Age adjusted prostate cancer mortality per 100 000 person years for men in Seattle-Puget Sound and Connecticut on the basis of cross sectional data, 1987-97

	Discussion

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A recent report has documented decreases in population based prostate cancer mortality in Tyrol compared with other states in Austria after the introduction of mass prostate specific antigen screening in Tyrol.⁹ Our results are in conflict with these for unclear reasons; although the intensity of screening in Tyrol seems similar to that in the Seattle area (about two thirds of men screened at least once over five years), the intensity of treatment in Tyrol and the intensities of both screening and treatment in the rest of Austria were not presented in that report.

Limitations of the study
Our study has several limitations. Firstly, the cohorts included only men aged 65 and over in 1987. Screening and treatment for prostate cancer may have a larger impact on younger men. However, as prostate cancer death is rare before age 70,³ if recent decreases in prostate cancer mortality in the United States are attributable to screening and treatment with surgery and radiation this impact would almost certainly be seen among Medicare age men.

Secondly, during 1987-90 Medicare did not routinely pay for prostate specific antigen screening tests. Claims may not have always been submitted, therefore, and numbers of prostate specific antigen tests may be underestimated. Nevertheless, the relative rates of testing between the two regions should not be biased, and the differences in biopsies and incidence confirm the higher intensity of screening in the Seattle area.

Thirdly, follow up over 11 years may not have been long enough to see a difference in prostate cancer mortality. However, if the decreases in population based prostate cancer mortality noted in both these areas are indeed attributable to screening and treatment with surgery or radiation, the time frame should have been sufficient to see an effect. Nevertheless, further follow up is planned.

Fourthly, we used SEER data to capture new diagnoses of prostate cancer, so records of diagnosis or cause of death for cohort members who moved out of their SEER areas after 1990 were unavailable. A differential rate of death from prostate cancer among men who moved after 1990 could introduce bias. However, Medicare enrolment files indicated that less than 1% of cohort members without prostate cancer moved out of their regions before dying. As only about 3% of these men would be expected to die of prostate cancer, the impact of any differential rate of death from prostate cancer should be minimal.

Fifthly, as the primary outcome measure was prostate cancer specific mortality a differential assignment of cause of death among prostate cancer patients in the two regions could bias comparisons. Earlier studies have shown a relatively high agreement (over 90%) between medical records and underlying causes of death as recorded on death certificates.^10-12

Sixthly, prostate specific antigen and biopsy data were incomplete for men enrolled in a Medicare health maintenance organisation in the two SEER areas during the early prostate specific antigen era. The men enrolled in health maintenance organisations were included in the primary analyses of treatment and mortality rates. Perhaps men enrolled in health maintenance organisations were not as intensively screened in the Seattle area, which would tend to dilute any mortality benefit attributable to screening. However, excluding men enrolled in health maintenance organisations from the mortality analysis did not affect the results.

Finally, men in the two cohorts may have differed on important risk factors for prostate cancer. Although only randomised trials can yield truly unbiased estimates of the efficacy of screening and treatment on prostate cancer mortality, their external validity might be limited.¹³ This longitudinal cohort study may provide complementary and important insights into what might be expected at the population level.

Conclusion
More intensive screening for prostate cancer and treatment with surgery or radiation among a cohort of Medicare beneficiaries in the Seattle-Puget Sound area compared with a cohort in Connecticut has not led to significantly lower mortality from prostate cancer over 11 years. Longer follow up will be necessary to fully assess the outcome of this natural experiment. Meanwhile, ongoing randomised trials assessing the effectiveness of screening and treatment for prostate cancer should be supported.

	Acknowledgments

The study used the linked SEER-Medicare database; the interpretation and reporting of these data are the sole responsibility of the authors. We acknowledge the efforts of the Applied Research Program, National Cancer Institute; the Office of Information Services and the Office of Strategic Planning, HCFA; Information Management Services (IMS); and the Surveillance, Epidemiology, and End Results (SEER) Program tumour registries in the creation of the SEER-Medicare database. Additionally, we thank E Robert Greenberg of the Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center for providing insightful comments, Maribel Franey and Edward Franey at HCFA/CMS for processing our data request and matching our cohort with the SEER-Medicare linked file, and the Seattle-Puget Sound and Connecticut SEER registries for updating and evaluating cancer incidence and mortality in the study cohorts.

Contributors: See bmj.com

	Footnotes

Editorial by Thornton

Funding: Agency for Health Care Research and Quality, grant Nos HS 08397 and HS 10278.

Competing interests: None declared.

This is an abridged version; the full version is on bmj.com

	References

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(Accepted 24 June 2002)