Features and preliminary results of prostate cancer screening in Canton Aargau, Switzerland

Authors


Dr M. Kwiatkowski, Clinic of Urology, Kantonsspital Aarau, CH5001 Aarau, Switzerland. e-mail: maciej.kwiatkowski@ksa.ch

Abstract

OBJECTIVE

To report the results from Switzerland's participation in the ERSPC from 1998; importantly, epidemiological data showed that Switzerland has one of the highest rates of morbidity and mortality from prostate cancer in the world. The local study protocol was accepted by the ethical committee and after the successful pilot study phase, the centre joined the ERSPC.

SUBJECTS AND METHODS

From September 1998 to June 2003 10 300 men accepted an invitation for the study and were then randomized 1 : 1 into an active screening arm (assessed by testing prostate-specific antigen, PSA) or a control group (no intervention). The re-screening interval is 4 years and is ongoing (beginning in September 2002). The study protocol includes offering a prostate biopsy when the total PSA is > 3.0 ng/mL (the main study protocol in agreement with ERSPC requirements) or when the total PSA is 1–3 ng/mL and the free-to-total PSA ratio < 20% (side study protocol).

RESULTS

During the first 3 years of screening 3562 men aged 55–70 years were screened; 395 (11.1%) of all participants had a total PSA of > 3 ng/mL and 251 (7.4%) were eligible for the side-study. In all, 599 (17.2%) of 3562 accepted a prostate biopsy (93% of 646); 120 cases of prostate cancer were detected (3.4% detection rate). The incidence was 2.5% in main study group (positive predictive value, PPV, 24%) and 0.9% in side study group (PPV 13.6%). In radical prostatectomy specimens the cancers were mostly ‘significant’ (92% in main study group and 87% in side-study group).

CONCLUSIONS

A randomized screening study for prostate cancer is feasible in Switzerland. A longer follow-up is needed to address within the ERSPC the primary hypothesis (that there will be a reduction in mortality in the active screening arm) and to determine the level of over/under-diagnosis and over/under-treatment in the active screening and control arms, respectively.

INTRODUCTION

In 1998 Switzerland started participation in the ERSPC study and after a successful pilot study phase joined the ERSPC. The objective of this paper is to describe the progress of the Swiss study site. The general rationale for the ERSPC study is described elsewhere in this Supplement but some specific factors are important. Switzerland has one of the highest rates of morbidity and mortality from prostate cancer in the world. The reasons for this are unclear but it was obvious that Switzerland should participate in the ERSPC study. Also, the demographic development of Switzerland, similar to other western countries, shows that the number of people aged > 65 years will continuously increase from 15% in 2000 to 24% of the whole population by 2030 (data from the Swiss Federal Statistical Office), which will also result in a proportional increase in prostate cancer morbidity and possibly mortality. The preparations to begin the study took almost a year. The local study protocol was accepted by the ethical committee. The data protection commissioner of Canton Aargau accepted the study as conforming with the data protection laws in Switzerland, and, last but not least, the financial support was sought, as each centre of ERSPC study must secure financing of the study. We finally obtained grants from various organizations (see Acknowledgements).

The study started in September 1998; in Switzerland, because of the data protection laws, informed consent must be signed before randomization (post-consent randomization). Until 2003 we randomized 10 300 men in the core group (55–70 years old; 5150 into the active screening arm and 5150 into the control arm). After 4 years, in September 2002, the first re-screening began and is currently on schedule. As the screening is an ongoing process, preliminary results for the first 3562 men in an active screening arm will be reviewed.

SUBJECTS AND METHODS

The local study protocol comprises: (i) a mailed invitation to men 55–70-years old living in Canton Aargau; (ii) on signed informed consent, randomization 1 : 1 to the active screening or the control arm; (iii) measurement of the serum free and total PSA level in the active screening arm and follow-up with no intervention in the control arm; (iv) if the total PSA is > 3.0 ng/mL (main study protocol, in agreement with ERSPC requirements) or if it is 1–3 ng/mL and the free-to-total PSA ratio in this range is <20% (side-study protocol, the rationale being reported in [1]), a DRE and a TRUS-guided transrectal sextant biopsy (including DRE/TRUS lesion directed biopsy if applicable) is offered to the participant; (v) otherwise the participant is invited to return for re-screening after 4 and 8 years.

Blood was sampled with no prostatic manipulation in two institutions (Kantonsspital Aarau and Kantonsspital Baden). Serum was frozen within 2 h from blood sampling at −70 °C and samples thawed immediately before measurement, the PSA being assayed within 2 weeks from blood sampling. The immunoassays for total and free PSA were the AxSym (Abbott Laboratories, Abbott Park, Illinois) assay until June 2000 and the Access (Beckmann-Coulter Hybritech) assay beginning from July 2000 (as the Hybritech assay is used uniformly across all ERSPC study centres). However, the side-study protocol continued to use primarily on Abbott AxSym assay thresholds.

All men also completed the International Prostate Symptom Score (IPSS) questionnaire. The prostate biopsies were taken under TRUS guidance; sextant biopsies were taken laterally from the peripheral zone of the prostate, and each biopsy separately processed and evaluated. The Gleason score was used for tumour grading. All positive or suspicious histology findings were reviewed by the independent review pathologist. Upon diagnosis of prostate cancer, various therapy options for localized cancer, e.g. radical prostatectomy (RP), radiotherapy (RT) or ‘watchful waiting’ or (if applicable) for advanced cancer the immediate/deferred androgen deprivation were thoroughly discussed. The family physicians were strongly involved in this decision.

RESULTS

Figure 1 shows the screening process; within the first 3 years of screening, of 18 361 invited men, 7124 agreed to participate (38.8% acceptance rate). There was a total PSA of ≥ 3.0 ng/mL in 11.1% of all men (395); 94% of them accepted further evaluation and thus 372 (10.5% of all screened men) had a prostate biopsy (Fig. 1). In 89 cases prostate cancer was found (24% of biopsied men), and thus in relation to all screened participants the prostate cancer detection rate was 2.5%. Of the tumours, 93% were clinically localized and thus potentially curable and 7% were already advanced (Table 1). The distribution of PSA values of > 3 ng/mL and cancer cases is shown in Table 2. In all, at a PSA level of 3–3.9 ng/mL, 18.1% of biopsied men had prostate cancer and 89% of these cancers were pathologically organ-confined. With increasing PSA values the frequency of detected cancer increased and the percentage of organ-confined cancers decreased. In all, 59 patients had a RP; from the tumour volume measured after RP in 55 cases (92%) there was a clinically relevant (median tumour volume 2.5 mL) cancer. Four men (8%) had tumour volumes of < 0.5 mL (median 0.17), thus presenting with ‘clinically insignificant’ cancer [2–3]. Fifty-five of 59 patients who had RP were completely continent within 6 weeks of surgery (i.e. using no pads), four had with grade I stress incontinence (one pad per day as a precaution). Twenty-two men had external RT and three chose watchful waiting. Two of five men with advanced disease were treated with immediate androgen deprivation.

Figure 1.

Screening algorithm (the numbers given may not be definitive).

Table 1.  Results of the screening investigations
InvestigationN (%)
Prostate biopsy372 (10.5)
Prostate cancer diagnosis 89 (24)
Treatment in curative intent 84 (93)
Palliative treatment 5 (7)
Table 2.  Prostate cancer detection rates and percentage of pathologically organ-confined cancers (pT2) according to PSA distribution
PSA range, ng/mL% of all participants% of men with cancer, (89)% of menwith pT2 at RP (59)
 3–3.93.9 18.189
 4–9.95.4 20.670
10–19.90.9 5060
≥200.310014

The IPSS results according to PSA distribution and cancer diagnosis were not significantly different between the cancer and benign groups (Table 3).

Table 3.  Voiding and quality of life IPSS for BPH and cancer according to PSA level
ItemPSA range, ng/mL
3–3.94–9.910–19.9≥20
IPSS
BPH5.06.06.0
Cancer6.07.07.03.0
Obstructive
BPH3.03.02.0
Cancer3.03.05.01.0
Irritative
BPH2.03.04.0
Cancer3.03.03.02.0
QoL
BPH1.02.01.0
Cancer1.01.03.01.0

SIDE-STUDY PROTOCOL

Of the screened men, 38.3% had a total PSA of 1–3 ng/mL; when a threshold of ≤20% for the free-to-total PSA ratio was added, 251 men (7.4% of all men) fulfilled both criteria (Fig. 1). In all, 227 men (90.4% of those eligible) accepted a prostate biopsy; 31 cancers were detected in this group (13.7% cancer detection rate and 0.9% overall incidence rate, Fig. 2). All the cancers were clinically localized. Twenty-two patients chose RP and 91% of these tumours were pathologically organ-confined; one patient had positive lymph nodes and had no further surgery, six received RT and two ‘watchful waiting’. The tumour volume of the RP specimens showed relevant cancer in 78%, minimal disease in 9% and insignificant cancer in 13% of cases [2–3].

Figure 2.

Scatterplot demonstrating values of total PSA and free-to-total PSA ratio for each case (PSA range 1–4 ng/ml). PCa detection rates for each range are in brackets.

DISCUSSION

In this Swiss population using a threshold total PSA of 3 ng/mL resulted in a 2.5% incidence rate of prostate cancer. When the findings of the side-study were added, the overall incidence rate in the screened population was 3.4%. This is slightly above the life-time mortality rate of 3% but significantly below the life-time morbidity rate of 8%[4]. As > 90% of eligible men agreed to have a prostate biopsy these findings are representative. Most cancers found in the screening arm were clinically relevant, according to Stamey et al.[2] and Epstein et al.[3], and thus potentially harmful. However, there may be some selection bias for significant cancers as not all patients had surgery. The significant reduction in pathologically organ-confined cancers parallel to increasing PSA (Table 2) shows that the definition of the total PSA ‘grey zone’ of 4–10 ng/mL should be revised and at least extended. Only 70% of those cancers were pathologically organ-confined, meaning that ‘the window of opportunity’ for treating 30% of cases had been missed. These data support the decision of choosing 3 ng/mL as a threshold for prostate biopsy in the ERSPC study. The number of cancers found within the scope of the side-study was surprisingly high, almost reaching a 20% detection rate in the PSA range 2–3 ng/mL. If the data in Fig. 2. for the range of total PSA 3–4 ng/mL were extrapolated to lower ranges, it would mean that there are also many cancers when the free-to-total PSA ratio is > 20% in the range of 1–3 ng/mL, but the number of biopsies to find one cancer would be extremely high, and the clinical significance of those cancers may be questionable. The follow-up and re-screening rounds will be invaluable to address this problem.

In conclusion, these data show that a randomized screening study for prostate cancer is feasible in Switzerland. The participation in this study contributes importantly to answering the major hypothesis of the study (mortality reduction in the active screening arm) and will allow us to elaborate specific guidelines for Swiss health authorities in the future.

ACKNOWLEDGEMENTS

We acknowledge the assistance of our review pathologists Prof. Guido Sauter and Dr Bubendorf, University Hospital in Basel for their expertise in the field, our study nurse Mrs Denise Mathis for her engagement in participants information and care and, last but not least, all family physicians in Canton Aargau for the good co-operation. The Swiss site of ERSPC is supported by Swiss Cancer League (Grant Nr KFS 787-2-1999), Aargau Cancer League, Health Department of Canton Aargau and Horten Foundation.

Abbreviations
IPSS

International Prostate Symptom Score

RP

radical prostatectomy

RT

radiotherapy.

Ancillary