Metastatic Prostate Cancer Incidence and Prostate-specific Antigen Testing: New Insights from the European Randomized Study of Screening for Prostate Cancer

doi:10.1016/j.eururo.2015.02.042

European Urology

Volume 68, Issue 5, November 2015, Pages 885-890

https://doi.org/10.1016/j.eururo.2015.02.042 Get rights and content

Abstract

Background

The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer (PCa) mortality and a 1.6-fold increase in PCa incidence with prostate-specific antigen (PSA)-based screening (at 13 yr of follow-up). We evaluated PCa incidence by risk category at diagnosis across the study arms to assess the potential impact on PCa mortality.

Design, setting, and participants

Information on arm, centre, T and M stage, Gleason score, serum PSA at diagnosis, age at randomisation, follow-up time, and vital status were extracted from the ERSPC database. Four risk categories at diagnosis were defined: 1, low; 2, intermediate; 3, high; 4, metastatic disease. PSA (≤100 or >100 ng/ml) was used as the indicator of metastasis.

Outcome measurements and statistical analysis

Incidence rate ratios (IRRs) for screening versus control arm by risk category at diagnosis and follow-up time were calculated using Poisson regression analysis for seven centres. Follow-up was truncated at 13 yr. Missing data were imputed using chained equations. The analyses were carried out on an intention-to-treat basis.

Results and limitations

In the screening arm, 7408 PCa cases were diagnosed and 6107 in the control arm. The proportion of missing stage, Gleason score, or PSA value was comparable in the two arms (8% vs 10%), but differed among centres. The IRRs were elevated in the screening arm for the low-risk (IRR: 2.14; 95% CI, 2.03–2.25) and intermediate-risk (IRR: 1.24; 95% CI, 1.16–1.34) categories at diagnosis, equal to unity for the high-risk category at diagnosis (IRR: 1.00; 95% CI, 0.89–1.13), and reduced for metastatic disease at diagnosis (IRR: 0.60; 95% CI, 0.52–0.70). The IRR of metastatic disease had temporal pattern similar to mortality, shifted forwards an average of almost 3 yr, although the mortality reduction was smaller.

Conclusions

The results confirm a reduction in metastatic disease at diagnosis in the screening arm, preceding mortality reduction by almost 3 yr.

Patient summary

The findings of this study indicate that the decrease in metastatic disease at diagnosis is the major determinant of the prostate cancer mortality reduction in the European Randomized study of Screening for Prostate Cancer.

Introduction

An update to the European Randomized Study of Screening for Prostate Cancer (ERSPC) has recently confirmed the reduction in prostate cancer (PCa) mortality within the ERSPC screening arm invited to prostate-specific antigen (PSA) testing [1]. The validity of the result has been questioned [2], [3] based mainly on the differences in treatment between the arms, ignoring the difference in disease characteristics at presentation [4]. Previous evaluations of treatment and different methods of mortality analysis [5], [6], [7], [8], however, have shown that differences in treatment are unlikely to explain the impact of screening on mortality. Nevertheless, detailed analysis of key prognostic features of PCa across the study arms is worthwhile to better understand how the mortality difference has emerged.

In principle [9], assuming that the cancer staging system is consistent for the compared groups, the requirements for an effective screening programme are an ability to produce a stage migration (downstaging) in the screening arm, a stage migration accompanied by a decrease in the incidence of advanced cancers, and a decrease in advanced-stage incidence occurring before a mortality reduction in the screening arm.

Meeting these requirements would not mean that early diagnosis had been the cause (or the only cause) of any observed reduction in mortality; however, if these requirements were not met, it would be unlikely that screening could explain any observed mortality reduction.

A reduction in the risk of diagnosis of metastatic disease in the screening arm of four ERSPC centres was shown in a previous work [10]. That paper addressed the occurrence of metastatic disease both at diagnosis and in the post-treatment follow-up.

In the current study, we present updated results on the stage distribution by arm in seven ERSPC centres. We evaluated whether the aforementioned requirements were met and explored the association of the decrease of advanced-cancer incidence rates (if any) with the reduction in PCa mortality.

Section snippets

Materials and methods

The ERSPC is a multicentre, randomised screening trial comparing an intervention arm of men to whom regular PSA screening is offered with those in a control arm to whom such screening is not offered. The trial started in Belgium, The Netherlands, Finland, Sweden, Spain, Italy, Switzerland, and France during the period 1993–1998 [11]. The study methodology has been described in detail previously [12]. Data were obtained by linkage to local cancer registries for PCa incidence and national

Results

In the core age group, 162 338 men were randomised. The median age at randomisation was 60.2 yr.

With data truncated at 13.0 yr of follow-up, 7408 and 6107 PCa cases were diagnosed in the screening and control arms, respectively. The distribution of missing values was similar in the two arms (8% in the screening and 10% in the control arm); however, for some centres (Belgium, Italy, and Spain), data were missing for between 38% and 77% of cases, and there was an imbalance between the arms of at

Discussion

In the present study, we examined the incidence rates of PCa by risk category at diagnosis between the two arms of the ERSPC trial.

The net effect in the screening arm was a marked increase of the cumulative incidence of low-risk PCa, along with a significant reduction of cumulative incidence of metastatic disease at diagnosis. A slight increase in the intermediate-risk category and no difference in the high-risk category (with an early excess disappearing by year 10) were observed. When

Conclusions

The present results confirm a stage migration in the screening arm with a 40% reduction in metastatic disease at diagnosis, which preceded a mortality reduction by almost 3 yr. These results strongly suggest that a decrease of metastatic disease at diagnosis is a major determinant of the reduction of PCa mortality in the ERSPC trial, although we cannot exclude additional contributions from other factors.

References (19)

F.H. Schröder 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)
M. Zappa et al.
A different method of evaluation of the ERSPC trial confirms that prostate-specific antigen testing has a significant impact on prostate cancer mortality
Eur Urol
(2014)
F.H. Schröder et al.
Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC)
Eur Urol
(2012)
A.B. Miller
New data on prostate-cancer mortality after PSA screening
N Engl J Med
(2012)
I.E. Haines et al.
Prostate-specific antigen screening trials and prostate cancer deaths: the androgen deprivation connection
J Natl Cancer Inst
(2013)
S. Carlsson et al.
Re: Prostate-specific antigen screening trials and prostate cancer deaths: the androgen deprivation connection
J Natl Cancer Inst
(2014)
T. Wolters et al.
The effect of study arm on prostate cancer treatment in the large screening trial ERSPC
Int J Cancer
(2010)
P.J. Van Leeuwen et al.
Impacts of a population-based prostate cancer screening programme on excess all-mortality rates in men with prostate cancer: a randomized controlled trial
J Med Screen
(2013)
R. Kranse et al.
Excess all-cause mortality in the evaluation of a screening trial to account for selective participation
J Med Screen
(2013)

There are more references available in the full text version of this article.

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Prostate CancerMetastatic Prostate Cancer Incidence and Prostate-specific Antigen Testing: New Insights from the European Randomized Study of Screening for Prostate Cancer

Abstract

Background

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusions

Lancet

Eur Urol

Eur Urol

New data on prostate-cancer mortality after PSA screening

N Engl J Med

Prostate-specific antigen screening trials and prostate cancer deaths: the androgen deprivation connection

J Natl Cancer Inst

Re: Prostate-specific antigen screening trials and prostate cancer deaths: the androgen deprivation connection

J Natl Cancer Inst

The effect of study arm on prostate cancer treatment in the large screening trial ERSPC

Int J Cancer

Impacts of a population-based prostate cancer screening programme on excess all-mortality rates in men with prostate cancer: a randomized controlled trial

J Med Screen

Excess all-cause mortality in the evaluation of a screening trial to account for selective participation

J Med Screen

Prostate Cancer
Metastatic Prostate Cancer Incidence and Prostate-specific Antigen Testing: New Insights from the European Randomized Study of Screening for Prostate Cancer