Articles

Platinum Priority – Prostate Cancer
Editorial by Christopher J. Keto and Stephen J. Freedland on pp. 506–508 of this issue

Prostate Cancer Incidence and Disease-Specific Survival of Men with Initial Prostate-Specific Antigen Less Than 3.0ng/ml Who Are Participating in ERSPC Rotterdam

By: Meelan Bullowast , Pim J. van Leeuwen, Xiaoye Zhu, Fritz H. Schröder and Monique J. Roobol

European Urology, Volume 59 Issue 1, April 2011, Pages 498-505

Published online: 01 April 2011

Keywords: Prostatic neoplasms, Early detection of cancer, Prostate-specific antigen, Incidence, Survival

Abstract Full Text Full Text PDF (363 KB)

Abstract

Background

The European Randomised Study of Screening for Prostate Cancer (ERSPC) applies a prostate-specific antigen (PSA) cut-off value ≥3.0ng/ml as an indication for lateralised sextant biopsy.

Objective

To analyse the incidence and disease-specific mortality for prostate cancer (PCa) in men with an initial PSA <3.0ng/ml.

Design, setting and participants

From November 1993 to December 1999, a total of 42 376 men identified from population registries in the Rotterdam region (55–74 yr of age) were randomised to an intervention or control arm. A total of 19 950 men were screened during the first screening round.

Intervention

A PSA <3.0ng/ml was below the biopsy threshold. PCa cases were identified at rescreens every 4 yr or as interval cancers.

Measurements

Distribution of incidence, aggressiveness, and disease-specific mortality of PCa per PSA range was measured. Causes of death were evaluated by an independent committee, and follow-up was complete until 31 December 2008.

Results and limitations

From 1993 to 2008, 915 PCa cases were diagnosed in 15 758 men (5.8%) with an initial PSA <3.0ng/ml and a median age of 62.3 yr. Median overall follow-up was 11 yr. PCa incidence increased significantly with higher initial PSA levels. Aggressive PCa (clinical stage ≥T2c, Gleason score ≥8, PSA >20ng/ml, positive lymph nodes, or metastases at diagnosis) was detected in 66 of 733 screen-detected PCa cases (9.0%) and 72 of 182 interval-detected PCa cases (39.6%). Twenty-three PCa deaths occurred in the total population (0.15%), with an increasing risk of PCa mortality in men with higher initial PSA values.

Conclusions

The risk of PCa, aggressive PCa and PCa mortality in a screening population with initial PSA <3.0ng/ml increases significantly with higher initial PSA levels. These results contribute to the risk stratification and individual management of men in PSA-based screening programmes.

Take Home Message

For men with an initial prostate-specific antigen (PSA) value <3.0ng/ml who are participating in a screening trial, the risk of developing aggressive prostate cancer (PCa) and PCa-specific death significantly increases with higher initial PSA values, although the overall risk of PCa death remains limited.

Keywords: Prostatic neoplasms, Early detection of cancer, Prostate-specific antigen, Incidence, Survival.

1. Introduction

After first being described in 1979 [1], prostate-specific antigen (PSA) became available as a biomarker [2] and potential screening tool for the early detection of prostate cancer (PCa) [3]. With PCa being the most frequent cancer diagnosed in men and playing an important role in cancer-related deaths worldwide [4] and [5], randomised studies set up to determine whether PSA-based screening can reduce the PCa-specific mortality [6] and [7] address an important health issue. In fact, results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) have shown that PSA-based screening can decrease PCa mortality by up to 30% [6] and [8].

However, despite the value of PSA in terms of lowering PCa mortality, its use in screening is limited as a result of its lack of specificity in lower PSA ranges [9]. Since 1997, the ERSPC has used a PSA value ≥3.0ng/ml as an indication for biopsy. To assess the risk of applying this cut-off value, we analysed the data of men with initial PSA levels <3.0ng/ml in the Rotterdam section of the ERSPC and evaluated PCa incidence and disease-specific mortality stratified by PSA group.

2. Methods

From November 1993 to December 1999, a total of 42 376 men 55–74 yr of age identified in the Rotterdam population registry were randomised to an intervention or a control arm. During the first screening round, 19 950 men were screened (excluding men previously diagnosed with PCa), with lateralised sextant biopsies being initially recommended for an abnormal digital rectal examination (DRE) or PSA level ≥4.0ng/ml. From May 1997 on, DRE was abandoned as a screening test, and a PSA level ≥3.0ng/ml was applied to recommend biopsies. Men diagnosed during the first screening round were excluded from this study to focus on the risk of being diagnosed with PCa during follow-up.

During the second screening round (November 1997 to December 2003), two side studies were carried out. The first side study (November 1997 to April 2001) provided a biopsy indication for men who doubled their PSA at the second screening in the PSA range of 1–3ng/ml. The second side study (April 2001 to August 2002) investigated the positive predictive value (PPV) and detection rate in men with PSA values of 2.0–3.9ng/ml. The third round started in November 2001 and concluded in December 2007; the fourth round started in November 2005 and is ongoing. Another side study was carried out (September 2007 to February 2009), providing a biopsy indication for men with a PCa antigen 3 score ≥10. The cancers found in the side studies are considered screen-detected in the context of this report. Total PSA was measured with the use of Hybritech assay systems (Beckman-Coulter, Fullerton, CA, USA), and a 4-yr screening interval was used. Follow-up of PCa cases and causes of death was carried out as previously described [10] and [11]. Data were complete for a total period of 15 yr (December 1993 to December 2008).

Aggressive cancer was defined as clinical stage ≥T2c, PSA at diagnosis >20ng/ml, or Gleason score ≥8, according to the D’Amico criteria [12], next to positive lymph nodes or distant metastases at diagnosis. Comorbidity at study entry was evaluated by assigning a Charlson score to each subject based on an independently completed questionnaire on medical history. For the purpose of this study, cases were scored as no (Charlson score=0), mild (Charlson score=1), or severe (Charlson score >2) comorbidity. Interval cancers were defined as all cancers detected clinically (either triggered by lower urinary tract symptoms, symptomatic disease, or opportunistic screening) during a screening interval or after reaching the 75-yr age limit.

The number of PCa cases, overall deaths, and disease-specific deaths classified by PSA group (<1.0ng/ml, 1.0–1.9ng/ml, or 2.0–2.9ng/ml) and number per 1000 life years (LY) were recorded as well as the tumour characteristics (Gleason score and TNM classification) at diagnosis. Cox regression analysis was used to determine PCa incidence, overall survival (OS), and disease-specific survival (DSS) adjusted for age and comorbidity and classified by PSA group. For incidence, the duration of follow-up from first screening to whatever came first of diagnosis, death, or censor date was calculated. For survival, time from first screening to either death or censor date was used. The proportional hazard assumption was tested and found to be applicable, using log–log survival curves. OS and DSS were assessed using the Kaplan-Meier method. Statistical analyses were performed using SPSS v.17.0 (SPSS, Chicago, IL, USA). All statistical tests were two-sided, and a p value <0.05 was considered statistically significant.

3. Results

A total of 21 210 men were randomised to the screening group, of which 19 950 men were actually screened. An initial PSA value <3.0ng/ml was measured in 15 837 men. The population used for this analysis consisted of 15 758 men (15 837–79 first-round PCa). The number of detected cancers per screening round and interval is indicated in Fig. 1. From 1993 to 2008, a total of 915 PCa cases were diagnosed in 15 758 men. Of these, 733 were screen-detected and 182 were interval-detected cases, of which 63 men (34.6%) were diagnosed when they were 75 yr or age or older. Median follow-up amounted to 11.1 and 11.5 yr overall and for PC cases, respectively. Median age of the study population at baseline PSA measurement was 62.3 yr of age. Study population characteristics are provided in Table 1.

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Fig. 1 Consort flow chart showing prostate cancer detection during screening rounds and intervals of men initially presenting with prostate-specific antigen levels <3.0ng/ml in the Rotterdam section of the European Randomised Study of Screening for Prostate Cancer.PSA=prostate-specific antigen; PCa=prostate cancer.

Table 1 Characteristics of the study population classified by prostate-specific antigen group

Characteristic PSA (ng/ml) Total study population
<1.0 1.0–1.9 2.0–2.9
Subjects, No. (%) 7126 (45.2) 6156 (39.1) 2476 (15.7) 15 758 (100)
Median age at initial PSA test, yr 61.2 62.8 64.3 62.3
Charlson score, No. (%)
0 5189 (72.8) 4579 (74.4) 1820 (73.5) 11 588 (73.5)
1 1638 (23.0) 1319 (21.4) 545 (22.0) 3502 (22.2)
2 266 (3.7) 208 (3.4) 93 (3.8) 567 (3.6)
Unknown 33 (0.5) 50 (0.8) 18 (0.7) 101 (0.6)
PCa, No. (per 1000 LY) 129 (1.7) 415 (6.4) 371 (14.5) 915 (5.5)
Aggressive PCa*, No. (per 1000 LY) 27 (0.36) 61 (0.94) 50 (1.95) 138 (0.83)
Median age at diagnosis, yr 69.5 68.9 68.2 68.8
Median time to diagnosis, yr 8.3 8.1 4.2 7.1
Overall deaths, No. (per 1000 LY) 1560 (20.8) 1365 (21.1) 610 (23.8) 3535 (21.4)
PCa deaths, No. (per 1000 LY) 3 (0.04) 11 (0.17) 9 (0.35) 23 (0.14)

* Defined as clinical stage ≥T2c, Gleason-score ≥8, PSA >20ng/ml, positive lymph nodes, or distant metastasis at diagnosis.

PSA=prostate-specific antigen; PCa=prostate cancer; LY=life years.

The median baseline PSA level was 1.8 (25–75p; 1.2–2.4) for men who developed PCa and 1.0 (25–75p; 0.6–1.6) for men who did not (p<0.001). At diagnosis, the median PSA level for screen-detected cases (3.5, 25–75p; 2.9–4.6) and interval-detected cases (8.1, 25–75p; 4.7–18.0) differed significantly (p<0.001).

In this study population, 5.8% (915 of 15 758) of all men were diagnosed with PCa at a median of 7.1 yr after initial PSA screening. The risk of PCa diagnosis increased from 1.7 per 1000 LY in men with PSA levels <1.0 ng/ml to 14.5 per 1000 LY in men with PSA levels of 2.0–2.9 ng/ml. The cumulative hazard of being diagnosed with PCa showed a 4.0- and 10.3-fold increased risk for PSA groups 1.0–1.9 and 2.0–2.9 ng/ml, respectively, compared to PSA group <1.0 ng/ml (p<0.001; Fig. 2). Aggressive cancer was present in 138 cases at diagnosis. Clinical stage and Gleason score were unknown in 5 and 41 cases, respectively. Tumour characteristics classified by PSA group are listed in Table 2. The cumulative hazard of being diagnosed with aggressive PCa was found to be statistically different (p<0.001), showing 2.7- and 6.2-fold increased risk for PSA groups 1.0–1.9 and 2.0–2.9 ng/ml, respectively, compared to PSA group <1.0 ng/ml (Fig. 3). To evaluate the influence of biopsied men per category, we corrected for the percentage of men per PSA group who were actually biopsied. This resulted in hazard ratios (HRs) of 2.1 and 3.3 for PCa incidence and 2.0 and 3.3 for aggressive PCa in the 1.0–1.9- and 2.0–2.9-ng/ml PSA groups, respectively, preserving their highly significant outcome.

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Fig. 2 Risk of prostate cancer diagnosis corrected for age and stratified by prostate-specific antigen group.PSA=prostate-specific antigen.

Table 2 Tumour characteristics classified by prostate-specific antigen group

PSA (ng/ml) Men, No. (%) PCa, No. (% of PSA group) Clinical stage ≤T1c, No. (% of PCa) Clinical stage ≥T2, No. (% of PCa) Gleason score ≤6, No. (% of PCa) Gleason score ≥7, No. (% of PCa) Aggressive PCa*, No. (% of PCa)
<1.0 7126 (45.2) 129 (1.8) 83 (64.3) 42 (32.6) 76 (58.9) 47 (36.4) 27 (20.9)
1.0–1.9 6156 (39.1) 415 (6.7) 276 (66.5) 132 (31.8) 310 (74.7) 89 (21.4) 61 (14.7)
2.0–2.9 2476 (15.7) 371 (15.0) 243 (65.5) 122 (32.9) 279 (75.2) 73 (19.7) 50 (13.5)
Total 15 758 (100) 915 (5.8) 602 (65.8) 296 (32.3) 665 (72.7) 209 (22.8) 138 (15.1)

* Defined as clinical stage ≥T2c, Gleason score ≥8, PSA >20ng/ml, positive lymph nodes, or distant metastasis at diagnosis.

PSA=prostate-specific antigen; PCa=prostate cancer.

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Fig. 3 Risk of aggressive prostate cancer corrected for age and stratified by prostate-specific antigen group.PSA=prostate-specific antigen.

Interval-detected PCa cases were aggressive more often (72 of 182; 39.6%) than screen-detected cases (66 of 733; 9.0%; p<0.001; Table 3). Of the interval-detected cases, 39 (21.4%) subjects were 75 yr of age or older.

Table 3 Hazard ratios for prostate cancer (PCa), aggressive PCa, and disease-specific mortality, adjusted for age and comorbidity score

PSA (ng/ml) PCa (95% CI) Aggressive PCa (95% CI) Overall mortality (95% CI) PCa mortality (95% CI)
<1.0 * * * *
1.0–1.9 4.0 (3.3–4.9)

(p<0.001)
2.7 (1.7–4.3)

(p<0.001)
0.9 (0.9–1.0)

(p=0.026)
4.0 (1.1–14.2)

(p=0.035)
2.0–2.9 10.3 (8.4–12.5)

(p<0.001)
6.2 (3.9–10.0)

(p<0.001)
0.9 (0.8–1.0)

(p=0.068)
7.6 (2.0–28.3)

(p=0.003)

* Reference group.

PSA=prostate-specific antigen; PCa=prostate cancer; CI=confidence interval.

The number of overall deaths and disease-specific deaths classified by PSA group is outlined in Table 1. After a 15-yr period, an overall mortality rate of 21.4 men per 1000 LY was observed (3535 of 15 758; 22.4%), while PCa-specific mortality reached 0.14 per 1000 LY (23 of 15 758; 0.15%). The risk of PCa-specific mortality increased with higher initial PSA levels from 0.04 per 1000 LY in the PSA range <1.0 ng/ml to an incidence of 0.35 per 1000 LY in the range 2.0–2.9 ng/ml. PCa-specific survival stratified by PSA group and corrected for age and comorbidity is shown in Fig. 4. There was a significant increase in risk of PCa death, which was 4.0 and 7.6 times higher for the PSA groups 1.0–1.9 and 2.0–2.9 ng/ml, respectively, than for the group PSA <1.0 ng/ml. Disease-specific mortality occurred in 5 of 733 (0.7%) screen-detected cases and in 18 of 182 (9.9%) interval-detected cases (p<0.001; Table 4). OS was higher in men with initial PSA levels of 1.0–1.9 ng/ml (HR: 0.9; p=0.026) compared to the lowest PSA range (Fig. 5). All HRs are provided in Table 3. For our cohort, the 5-yr, 10-yr, and 15-yr OS rates were 92.7%, 82.2%, and 67.9%, respectively; the PCa-specific survival rates were 100%, 99.9%, and 99.7%, respectively.

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Fig. 4 Cumulative disease-specific survival corrected for age and comorbidity and stratified by prostate-specific antigen group.PSA=prostate-specific antigen.

Table 4 Number of prostate cancer (PCa), aggressive PCa and disease-specific deaths in screen-detected and interval-detected cases classified by prostate-specific antigen group

PSA (ng/ml) Men, No. (%) PCa, No. (% of PSA group) Aggressive PCa*, No. (% of screening- or interval-detected PCa) PCa deaths, No. (% of screening- or interval-detected PCa)
Screening Interval Screening Interval Screening Interval
<1.0 7126 (45.2) 92 (1.3) 37 (0.5) 11 (12.0) 16 (43.2) 0 (0) 3 (8.1)
1.0–1.9 6156 (39.1) 345 (4.8) 53 (0.7) 29 (8.4) 32 (60.4) 4 (1.2) 7 (13.2)
2.0–2.9 2476 (15.7) 296 (4.2) 48 (0.7) 26 (8.8) 24 (50.0) 1 (0.3) 8 (16.7)
Total 15 758 (100) 733 (4.7) 182 (2.6) 66 (9.0) 72 (39.6) 5 (0.7) 18 (9.9)

* Defined as clinical stage ≥T2c, Gleason-score ≥8, PSA >20ng/ml, positive lymph nodes, or distant metastasis at diagnosis.

PSA=prostate-specific antigen; PCa=prostate cancer.

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Fig. 5 Cumulative overall survival corrected for age and comorbidity and stratified by prostate-specific antigen group.PSA=prostate-specific antigen.

4. Discussion

Results of the ERSPC have shown that early detection by PSA-based screening can decrease PCa mortality up to 30% after a median follow-up of 9 yr [6] and [8]. The Göteborg screening study, which is part of ERSPC, recently showed even more favourable results after 14-yr follow-up [13]. However, it is also known that PCa is prevalent in men with PSA levels below commonly used thresholds, with PSA lacking specificity, especially in these lower ranges [9]. This study was set up to quantify the predictive value of a negative result in PSA-based screening, to evaluate the risk of postponing PCa diagnosis in screening by applying a PSA cut-off ≥3.0ng/ml, and to contribute to the understanding of the natural history of PCa present in the low PSA ranges.

We identified a significant increase in PCa incidence in men with initial PSA values of 1.0–1.9 ng/ml and 2.0–2.9 ng/ml of 4.0- and 10.3-fold, respectively, compared to men with initial PSA levels <1.0 ng/ml. Similar results were observed for aggressive PCa, which showed a 2.7- and 6.2-fold increased risk in these groups, respectively. When we examined alternative definitions of aggressive PCa (ie, Gleason score ≥8 or PSA at diagnosis >20 ng/ml), the overall patterns held, with higher PSA levels being associated with higher risk. If we apply the PPV of 21.9%, as was reported from the control arm of the Prostate Cancer Prevention Trial [9] in 5587 biopsied men with initial PSA ≤3.0 ng/ml (>55 yr of age) receiving biopsies upon indication (PSA >4.0 ng/ml or abnormal DRE) or at the end of a 7-yr study, a total of 3468 PCa diagnoses would be expected in 15 837 men. This conclusion indicates that 2474 PCa cases were not (yet) diagnosed in our cohort. The absence of PSA and clinical progression after 11 yr of follow-up is reassuring, but longer observation periods are needed to judge the natural history of these biopsy-detectable cancers. Our data show that in particular, subjects with PSA values close to the PSA cut-off have a high probability of being diagnosed with PCa in subsequent rounds. Previous studies confirm the association of PSA ranges with PCa by showing a gradual increase in the odds of cancer during follow-up with higher baseline PSA measurements [14] and [15].

In total, 3535 subjects died, resulting in an overall mortality rate of 21.4 per 1000 LY. The slightly higher OS in the group with an initial PSA level of 1.0–1.9 ng/ml compared to the PSA <1.0 group remains unexplained. The overall risk of PCa death in our study cohort was limited, with a death rate equal to 0.14 per 1000 LY, compared to 1.55 per 1000 LY (p<0.001) for men with an initial PSA value ≥3.0 ng/ml (11-fold higher) and 0.49 per 1000 LY in the overall cohort. A significant increase in the risk of PCa-related death was observed with increasing initial PSA, leading to 4.0- and 7.6-fold higher risks in the 1.0–1.9 ng/ml and 2.0–2.9 ng/ml PSA groups, respectively. Interval-detected PCa had a substantial part in the incidence of aggressive PCa and disease-specific deaths. Further study on how to prevent these interval cases is warranted, because shortening the screening interval does not seem to solve the matter but is rather likely to increase overdiagnosis, as was previously shown [16].

Our results are consistent with previous studies showing PSA to be a predictor of death from PCa, even at moderate PSA levels [17] and [18]. Vickers et al. [19] reported comparable findings to ours from their cohort of unscreened men, showing that PCa deaths among men with initial PSA levels <1.0 ng/ml are rare. Results of the current study strengthen the justification of the use of PSA in risk stratification for screening purposes. The favourable outcome in men with PSA values <1.0 ng/ml supports the result of a previous study [20] to prolong the screening interval to 8 yr in this group. To contribute to decreasing PCa mortality by means of screening, a large number of PCa deaths would need to be prevented, which cannot be found in the low PSA ranges. More aggressive screening would lead to an unacceptable number needed to investigate (NNI) and number needed to treat (NNT). In line with this conclusion, a recent study [21] showed an NNI of 24 642 and an NNT of 724 for PSA values <2.0 ng/ml and in addition reveals excessive overdiagnosis and minor profit in PCa mortality of only 0.005 per 1000 LY between a screening cohort and a population-based cohort. Our results support the justification of a PSA threshold for screening based on current knowledge. Further effort should focus on the 2.0–2.9-ng/ml PSA range.

Obviously, mechanisms to selectively detect aggressive cancers are needed, because the increase in the PCa detection rate with higher baseline PSA values does not alter the fact that the greater part of cases does not harbour aggressive disease. Already now, risk-stratification instruments are available that avoid unnecessary biopsies and decrease overdiagnosis by incorporating clinically available risk modifiers and, once potentially indolent cancers are diagnosed, unnecessary treatments [22] and [23]. In addition, further study on molecular and genetic markers selectively identifying aggressive disease is warranted.

5. Conclusions

This study provides insight into the natural history of PCa cases that remain undetected and the fate of screening- and interval-detected PCa in men with initial PSA values <3.0 ng/ml. It was shown that the risk of developing PCa and aggressive PCa as well as PCa-specific death in men participating in a screening trial with an initial PSA value <3.0 ng/ml significantly increases in patients with higher initial PSA values. Interval-detected cancers more often have aggressive characteristics and a substantial influence in causing disease-specific death, although the overall risk of PCa death in this cohort is low compared to men with initial PSA values ≥3.0 ng/ml (11-fold higher) and compared to the risk of other causes of death (150-fold higher). These results contribute to the risk stratification and individual management of men in PSA-based screening programmes.

Author contributions: Meelan Bul had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Schröder, Roobol, Bul.

Acquisition of data: Bul, Zhu.

Analysis and interpretation of data: Bul, van Leeuwen, Zhu, Schröder, Roobol.

Drafting of the manuscript: Bul, van Leeuwen, Zhu.

Critical revision of the manuscript for important intellectual content: Bul, Schröder, Roobol, van Leeuwen, Zhu.

Statistical analysis: Bul, van Leeuwen.

Obtaining funding: None.

Administrative, technical, or material support: van Leeuwen, Zhu.

Supervision: Schröder, Roobol.

Other (specify): None.

Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: The ERSPC is supported by grants from the Dutch Cancer Society (KWF 94-869, 98-1657, 2002-277, 2006-3518); The Netherlands Organization for Health Research and Development (002822820, 22000106, 50-50110-98-311); the 6th Framework Program of the EU: P-Mark: LSHC-CT-2004-503011; Beckman-Coulter, Hybritech Inc.; and Europe against Cancer (SOC 95 35109, SOC 96 201869 05F02, SOC 97 201329, SOC 98 32241). The ERSPC received Erasmus MC and Ministry of Health institutional review board approval.

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Footnotes

Department of Urology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands

lowast Corresponding author. Erasmus MC, University Medical Centre Rotterdam, Department of Urology, Room NH-224, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel. +31 10 70332243; Fax: +31 10 7035315.

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