Update on screening for prostate cancer with prostate-specific antigen

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1 Critical Reviews in Oncology/Hematology 50 (2004) Update on screening for prostate cancer with prostate-specific antigen Hans-Peter Schmid a,, Walter Riesen b, Ladislav Prikler a a Department of Urology, Kantonsspital, CH-9007 St. Gallen, Switzerland b Institute of Clinical Chemistry and Hematology, Kantonsspital, CH-9007 St. Gallen, Switzerland Accepted 4 November 2003 Contents 1. Introduction PSA as an organ specific marker Concepts for improving the specificity of PSA Static concepts Dynamic concepts Clinical guidelines Ongoing screening trials Federal State of Tyrol, Austria Quebec City area, Canada Prostate, Lung, Colorectal and Ovarian (PLCO), USA European Randomized Study (ERSPC), Europe Summary Reviewers Acknowledgements References Biography Abstract Serum prostate-specific antigen (PSA) determination in conjunction with digital rectal examination (DRE) is recommended by the majority of clinical guidelines for early detection(opportunistic screening) of prostate cancer provided the patient is well informed and has a life-expectancy of at least 10 years. The major disadvantage of PSA is its lack of specificity. Various static and dynamic concepts have been developed to improve the diagnostic performance of PSA of which free/total PSA ratio and PSA doubling time seem to be the most promising. Apart from early detection, population screening(mass screening) is a distinct topic. The effect of the latter one with regard to reduction of prostate cancer specific mortality and quality of life issues is not yet clear. Several national and international prospective trials are currently being conducted to answer these important questions but results will only be available in a few years Elsevier Ireland Ltd. All rights reserved. Keywords: Prostatic carcinoma; Prostate-specific antigen; Screening; Diagnosis; Guidelines 1. Introduction Corresponding author. Tel.: ; fax: address: hans-peter.schmid@kssg.ch (H.-P. Schmid). Prostate cancer is unique among malignant tumors due to its high prevalence and relatively slow natural history [1]. Prevention is not yet possible because none of the firmly /$ see front matter 2003 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 72 H.-P. Schmid et al. / Critical Reviews in Oncology/Hematology 50 (2004) established risk factors advancing age, race and familial aggregation can be influenced. Thus, nowadays, early detection strategies are in the focus of attention. Population or mass screening is defined as examination of asymptomatic men (at risk). Usually, this procedure takes place within the framework of a trial or study and is initiated by a screener. In addition, and contrary to that, early detection or opportunistic screening represents individual case finding. It is initiated by the screenee (patient) and/or his physician. Both, screening for and early detection of prostate cancer with prostate-specific antigen (PSA), have been a matter of discussion and controversy since the late 1980s [2]. The main rationale for screening for prostate cancer include: early stage disease is asymptomatic. Only organ-confined cancer (T1-2 N0 M0) can be cured, while radical prostatectomy, external beam radiotherapy and interstitial brachytherapy all achieve comparable disease-free survival rates [3]. The criteria of the World Health Organization for screening of disease are met to a great extent in case of prostatic carcinoma [4]. Arguments against screening are: the effectiveness of treatment modalities with regard to reduction of cancer specific mortality is not yet proven. The risk benefit balance is unclear (side effects and costs of diagnostic and therapeutic procedures). There is a considerable risk for overdiagnosis of prostate cancer given the fact that the incidence mortality ratio for the year 2000 in the United States was 6.3 [5]. Thus, it is understandable that watchful waiting can be a viable option for carefully selected patients [6]. The primary endpoint of screening is two-fold: first, the reduction of prostate cancer specific mortality. The goal is not to detect more and more carcinomas nor is survival the endpoint because survival is heavily influenced by lead-time. Secondly, quality of life is important as expressed by quality of life adjusted gain in life years (QUALYs). In a recent short-term evaluation of quality of life in radical prostatectomy and radiation treated patients, there were no relevant differences between screen-detected and clinically diagnosed cases [7]. The primary tool in screening for prostate cancer is PSA which is widely acknowledged to be the most important tumor marker not only in Urology but possibly in the entire field of medicine ever since the landmark publication by Stamey et al. [8]. The widespread use of PSA testing has led to an enormous increase of the reported incidence of prostate cancer and to a dramatic shift towards detection of early stage disease. The major disadvantage of PSA is its lack of specificity. To improve the diagnostic performance, several concepts have been introduced over the past 10 years to try to reduce the number of unnecessary prostate biopsies. In the present report, these strategies are discussed and a structured analysis of current clinical guidelines for the use of PSA is undertaken. Such activity should contribute towards the development of improved recommendations for the use Table 1 Probability of prostate cancer in relation to prostate-specific antigen level a Prostate-specific antigen (ng/ml) Probability of cancer (%) <2.5 Unknown > a In men with normal digital rectal examination, adapted from [50]. of PSA which are based on the highest possible levels of evidence. 2. PSA as an organ specific marker PSA is a glycoprotein that is almost exclusively produced by epithelial cells of the prostate, and is perhaps better considered a specific organ marker rather than a tumor marker. There are only very rare circumstances when PSA can be measured in non-prostatic diseases and these findings are usually limited to polyclonal rather than monoclonal assays [9]. A variety of pre-analytical and clinical factors should be considered when interpreting a given PSA value. Every laboratory report should contain the name of the assay used (more than 80 methods are currently available in Europe) and a valid reference range, specifically generated for the assay used [10]. Factors other than prostate volume that may influence PSA serum concentrations include: biopsy and transurethral resection of the prostate, acute urinary retention, acute prostatitis, prostatic infarction and ejaculation [11]. Where prostatitis is suspected to be the cause of serum PSA elevation, effective antibiotic therapy prior to a repeat PSA measurement may be advisable. Some drugs may lower serum PSA, among them finasteride and herbal extracts (e.g. PC-SPES). Digital rectal examination (DRE) does not influence the concentration of total PSA to a clinically significant extent but the proportion of free PSA may be more susceptible to such manipulations. In addition, physical exercise does also not seem to change serum values [12]. Most important from a clinical point of view is the ability to discriminate cancer from benign disease. There is unfortunately considerable overlap in PSA concentrations between patients with organ-confined carcinoma and patients with benign prostatic hyperplasia (BPH). Conversely, approximately 25% of patients with prostate cancer show no elevation of serum PSA. The sensitivity and specificity of the PSA test and the threshold at which a biopsy is indicated are not clear. The true sensitivity and specificity of PSA cannot be calculated unless all prostates are surgically removed for pathological investigation. Table 1 shows the probability for prostate cancer diagnosis as a function of PSA in men with a normal DRE. Among men with slightly elevated PSA levels (4 10 ng/ml), four men have to undergo biopsy to detect one man with prostatic cancer. The finding of abnormal values may cause significant anxiety in healthy men without the disease, a circumstance which has been termed

3 H.-P. Schmid et al. / Critical Reviews in Oncology/Hematology 50 (2004) Table 2 Concepts for improving the specificity of prostate-specific antigen (PSA) Concept Original publication/source Static PSA density (PSAD) Babaian et al., 1990 [17]; Veneziano et al., 1990 [18] PSA density of transition Kalish et al., 1994 [20] zone (PSAT) Age specific reference Oesterling et al., 1993 [22] ranges Ratio of free/total PSA Lilja et al., 1991 [23]; Stenman et al., 1991 [24] Complexed PSA (cpsa) Allard et al., 1998 [28] Isoenzymes of free PSA Huber et al., 1995 [35] Dynamic PSA velocity (PSAV) Carter et al., 1992 [36] PSA doubling time (PSADT) Schmid et al., 1993 [37] PSAdynia [13]. In a recent interesting report, the ability of PSA for early detection of organ-confined cancer has been questioned. Serum PSA levels between 2 and 9 ng/ml showed a weak and unreliable correlation to carcinoma but a strong relationship with BPH (as reflected by prostate weight) [14]. There is growing concern that widespread PSA testing will diagnose clinically insignificant prostate cancer. Although we do not really know what constitutes an insignificant cancer, it may be a cancer volume of less than 0.5 cc for the largest focus in the prostate [1]. In a highly selected group of patients undergoing radical prostatectomy at Johns Hopkins, the largest cancer focus found was less than 0.5 cc in nearly 30% of prostate specimens [15]. An epidemiological study from the Surveillance, Epidemiology, and End Results (SEER) Cancer Registry of the National Cancer Institute reported that 18 39% of white men and 20 44% of black men were overdiagnosed by PSA screening [16]. In the light of the low positive predictive value of PSA for the detection of clinically relevant but curable prostate cancer, it is highly desirable to enhance the specificity of this marker without losing its sensitivity. Another additional approach would be to evaluate alternative tumor markers, for example human Kallikrein 2 (hk2). Like PSA (hk3), hk2 is a serine protease which has a 79% homology to PSA and a serum concentration of about 2%. Data on this new marker are still scanty and do not yet allow a statement on its future role as a screening tool. 3. Concepts for improving the specificity of PSA Since 1989, several concepts to further improve the diagnostic accuracy of PSA have been developed with the aim of avoiding unnecessary biopsies. These can be divided into static and dynamic concepts (Table 2). Those in the static group apply at a single timepoint whereas the dynamic approaches depend on follow up of the patient with serial PSA determinations (i.e. more than one timepoint) Static concepts The oldest concept is PSA density (PSAD) which is determined by dividing the serum PSA level by the volume of the entire prostatic gland as measured by transrectal ultrasonography (TRUS) [17 19]. Since cancerous tissue may secrete up to 12 times more PSA per volume of tissue into the serum than benign hyperplastic tissue, PSAD should be higher in cancer patients and its use should achieve higher specificity than PSA alone. However, the use of PSAD in daily practice is hampered by several factors. Determination of prostate volume by TRUS is largely operator dependent and may vary considerably. Additionally, TRUS is not always available, and is time-consuming and relatively expensive. PSAD can also give false positive results due to subclinical prostatitis and infarction. Finally, where there is concomittant BPH, there may be a dilution effect leading to falsely low values (Fig. 1). A further development of the density idea is PSA density of the transition zone (PSAT) [20]. In men with lower urinary tract symptoms and serum PSA values below 10 ng/ml, PSAT is superior to PSAD with respect to diagnostic accuracy [21]. Problems with PSAT occur most often in small prostates because identification of the transition zone with TRUS is sometimes difficult in these cases. Furthermore, a small gland contains less BPH (low volume of transition zone) and consequently the value for PSAT tends to be higher and the difference between benign and malignant prostatic tissue less clear. In a community-based study of healthy men it was found that serum PSA levels were directly correlated to patient age and volume of the prostate, the latter also being directly related to age [22]. The authors therefore established age specific reference ranges for PSA with the expectation that use of these should increase test sensitivity in younger men and improve its specificity in older men. This concept is easily applicable in routine practice, but has been criticised because it is likely to lead to a certain number of unnecessary biopsies in younger men and a few cancers will be missed in older men. Until now, there is no study proving the effectiveness of prostatic biopsies using age specific reference ranges below 4 ng/ml. The concept most extensively investigated in the past few years is the free/total PSA ratio to discriminate BPH from cancer. In serum, PSA is found either in the free form or, more commonly, as a complex bound to the serine protease inhibitor alpha 1-antichymotrypsin [23]. It has been shown that the proportion of circulating complexed PSA is higher in patients with carcinoma than in those with BPH [24]. Determination of the free/total ratio can stratify the risk of cancer for men with total PSA levels between 4 and 10 ng/ml and with a negative digital rectal examination. In a prospective multicenter trial, prostate cancer was found on biopsy in 56% of men with a ratio less than 0.10 but only in 8% of men with a ratio of more than 0.25 [25]. In another prospective trial from a defined geographic area, a

4 74 H.-P. Schmid et al. / Critical Reviews in Oncology/Hematology 50 (2004) Fig. 1. Dilution effect of benign prostatic hyperplasia (BPH) on prostate-specific antigen density (PSAD). Prostate cancer in patient B is masked by concomittant BPH thus resulting in an unsuspicious low PSAD. significant number of prostate cancer were detected in the total PSA range of 1 3 ng/ml when the free/total ratio was 0.2 or less and the majority of these tumors were clinically relevant [26]. Nevertheless, the concept must be interpreted with caution. Several pre-analytical and clinical factors may influence the free/total PSA ratio, e.g. instability of free PSA both at 4 C and at room temperature, assay characteristics (equimolar versus skewed response), and a dilution effect in large prostates due to concomittant BPH, a problem similar to that for PSAD (Fig. 1) [27]. The free/total ratio is clinically useless in total serum PSA values above 10 ng/ml and in follow up of patients with known prostate cancer. The determination of various complexed forms of PSA (cpsa) using a blocking antibody to prevent binding of free PSA has been introduced recently [28]. Studies comparing the diagnostic efficacy of cpsa with total PSA and the free/total PSA ratio report diverging results. Superior performance for cpsa over total PSA or the free/total ratio [29], superiority of cpsa over total PSA but not over the free/total ratio [30], equivalency of cpsa with total PSA and the free/total ratio [31], as well as equivalency of cpsa with total PSA but superiority of the free/total ratio over cpsa [32] have all been reported. Analogous to the early experience with the free/total PSA ratio, the performance of cpsa may well depend on the total PSA concentration range investigated and recent studies focus on very narrow and low total PSA ranges, e.g. 2 or ng/ml [33]. The role of cpsa in the diagnosis of prostate cancer still remains to be defined [34]. The observation of an irregular intracellular glycosylation process of proteins in dysplastic cells of the prostate prompted Huber et al. [35] to study the microheterogeneity of serum PSA. Isoenzymes of free PSA in the sera of patients with BPH were mainly located in the pi (isoelectric point) range of , whereas isoenzymes in the sera of prostate cancer patients were mainly in the pi range of These results suggest that PSA isoenzymes released from BPH tissue contain more sialic acid residues than PSA released from cancerous tissue but these experimental observations still require clinical validation Dynamic concepts An increase of PSA over time can either be expressed as PSA velocity (PSAV) orpsa doubling time (PSADT). Carter and co-workers [36] recommended PSAV as a means of enhancing the specificity of PSA for prostate cancer detection [36]. PSAV has been defined as an absolute annual increase in serum PSA (ng/ml per year). PSADT was established in untreated patients with known prostate cancer who were followed expectantly by urologists from Stanford University [37]. PSADT takes into account the exponential increase of serum PSA over time reflecting a relative change, and thus, is completely different from PSAV (Table 3). The original formula for calculation is: PSADT = log2 t log(final PSA) log(initial PSA) where t is the time between the two PSA determinations [37]. PSADT has two major advantages when compared to PSAV. First, it is independent of the baseline PSA value. In the example in Table 3, patient A is more likely to harbor prostate cancer than patient B based on his shorter PSADT. Note that PSAV is identical in both patients. Secondly, PSADT is also independent of the assay, provided the same assay Table 3 Example for the difference between the two dynamic concepts a Patient A Patient B PSA increase within 1 year (ng/ml) PSA velocity (ng/ml per year) PSA doubling time (years) a Reproduced from [51].

5 H.-P. Schmid et al. / Critical Reviews in Oncology/Hematology 50 (2004) is used in a given patient [10]. Comparison of serial PSA measurements in men from different study populations using different assays should therefore be made using PSADT and not PSAV. Given the fact that in the general population the distribution of PSA levels is less than 4 ng/ml in about 90% of cases, many men do not require immediate biopsy but instead are being followed with serial PSA determinations. Thus, the majority of men will be judged by their PSA kinetics. Since the current data for PSAV and PSADT are not yet conclusive, the clinical usefulness of both dynamic concepts should be further evaluated in ongoing prospective trials such as the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Project (PLCO). bination with DRE as an aid to diagnosis (Table 4). However, until this date no governmental body in the world has made official recommendations concerning prostate cancer screening. It must be emphasised that for the majority of these guidelines the target population are men 50 years of age or older with a life expectancy of at least 10 years. Early detection may start at the age of 45 years in men with a positive family history. In any case, patients should be well informed about the potential consequences prior to PSA testing. Although the methods of improving the diagnostic accuracy of PSA described above are often mentioned in text accompanying published guidelines, they usually do not reach a sufficiently high level of evidence level to permit their inclusion in recommendations (Table 4). 4. Clinical guidelines Increasing interest in implementing the practice of evidence-based medicine in oncology has encouraged the development of clinical guidelines with the ultimate aim of improving the standard of patient care [38]. In a recent review, guidelines from national and international expert groups and relating to the use of tumor markers for specific cancers were analysed considering the recommendations made for their use in screening and diagnosis [39]. Ideally, such guidelines are distilled conclusions from quantitative systematic reviews on the Cochrane Library database. However, for logistic reasons, the majority of guidelines are based on conventional literature searches, followed by critical appraisal by an appropriate group of experts and finally validation by specialists in cancer care delivery as exemplified by the European Association of Urology guidelines [40]. The benefits of PSA as a screening tool (in conjunction with DRE) is a much debated issue (Table 4). Results from prospective randomised trials like ERSPC and PLCO are eagerly awaited. Currently, of nine major American organisations concerned with health, only three advocate routine testing for prostate cancer [41]. Less controversial, and recommended in most guidelines, is the use of PSA in com- 5. Ongoing screening trials Several national and international prospective studies are being conducted to address mass screening for prostate cancer (Table 5) Federal State of Tyrol, Austria In 1993, a prospective natural experiment was initiated to compare prostate cancer mortality in Tyrol, where PSA testing was introduced at no charge, with the rest of Austria, where it was not introduced. In the first year, of 65,123 men aged years, 32.3% underwent determination of PSA [42]. At least two-thirds of all men in this age range have been tested at least once during the first 5 years of the trial. DRE was not part of the screening procedure. In the beginning, the indication for prostatic biopsy was based on age referenced PSA levels and a free/total PSA ratio of less than 22%. Later on, in order to increase the specificity of the test and to reduce the number of unnecessary biopsies, bisected PSA levels and a free/total PSA ratio of less than 18% were introduced. From 1993 to 1995, the standard sextant biopsy was performed, and from 1995, 10 systematic biopsies were taken. Patients underwent treatment with curative intent and there was no policy of watchful waiting. Table 4 Summary of key guideline recommendations a ACS [52] AUA [41] DGU [53] EAU [40] EGTM [54] NACB [55] PSA for Screening (with DRE) Y Y N Y Early diagnosis (with DRE) Y Y Y Y Y Y Free/total PSA as an aid to diagnosis Y Y Age specific reference ranges N Y ACS: American Cancer Society; AUA: American Urological Association; DGU: Deutsche Gesellschaft für Urologie (German Urological Society); EAU: European Association of Urology; EGTM: European Group on Tumour Markers; NACB: National Academy of Clinical Biochemistry. Y: recommended; N: not recommended; blank space indicates no consideration and/or no recommendation; DRE: digital rectal examination. a Modified from [39].

6 76 H.-P. Schmid et al. / Critical Reviews in Oncology/Hematology 50 (2004) Table 5 Ongoing screening trials Trial Geographic area Type of trial Total number of participants Age group (years) Tyrol Federal state of Tyrol, Austria Prospective, not randomized Quebec Quebec City area, Canada Prospective, randomized PLCO USA Prospective, randomized ERSPC Finland, Sweden, The Netherlands, Belgium, Italy, Spain, Switzerland Prospective, randomized a PLCO: Prostate, Lung, Colorectal and Ovarian Cancer Screening Project; ERSPC: European Randomized Study of Screening for Prostate Cancer. a core age group. A significant stage migration toward lower stages has been observed since the introduction of the program in Tyrol. The trends in prostate cancer mortality rates since 1993 differ significantly between Tyrol and the rest of Austria [43]. Based on age-specific death rates, the difference between the number of expected and observed deaths from prostate cancer in Tyrol was 10 in 1996, 17 in 1997, 22 in 1998 and 18 the following year [42]. Trials that run over a longer period of time are susceptible to changes in the protocol. In the present series, indications for and techniques of biopsies are rather heterogenous which will certainly influence the detection rate of cancer. Important issues like rate of unnecessary biopsies, costs, quality of life and potential hazard of overdiagnosis are not addressed. Most striking, however, is the fact that mortality rates decreased very shortly after widespread PSA testing became available. Considering a certain lead time, this phenomenon is more likely due to opportunistic screening (early detection with PSA and DRE) in the time period between 1988 and Finally, it must be emphasised that the effects were calculated from expected death rates and these rates were extrapolated from historic data Quebec City area, Canada A prospective randomized study from Quebec showed an improvement of 67% in the relative risk of dying from prostate cancer in a screened population [44]. However, this trial was methodologically flawed and, thus, heavily criticised. The compliance for screening was only 23% and the study did not fullfill all the criteria of a strictly randomized comparison Prostate, Lung, Colorectal and Ovarian (PLCO), USA The PLCO cancer screening project was initiated in the United States by the National Cancer Institute. 74,000 men aged years were randomly assigned to either yearly prostate cancer screening for 3 years or to a control group [45]. The trial is expected to be completed in 2009 at which time disease specific mortality and morbidity can be compared after 12 years of follow-up. It might well be that the age group is not appropriate and that follow up is too short to detect differences in mortality. Furthermore, there is a considerable contamination of the control group by opportunistic screening: in 1988 contamination was only 0.9%, but in 1998 it was already 38% [46] European Randomized Study (ERSPC), Europe The European Randomized Study of Screening for Prostate Cancer began in 1994 and plans to enroll a total of 196,500 men in seven countries (Finland, Sweden, The Netherlands, Belgium, Italy, Spain, Switzerland). In the intervention group, prostatic biopsies were performed if the PSA was more than 4 ng/ml or DRE was positive. From 1997, DRE was abandoned and PSA was lowered to 3 ng/ml [47]. In the control group, men were managed according to current clinical practice. The study aims to detect a 20% difference in cancer specific mortality by the year 2008 with a statistical power of 90%. Several problems may arise in such a large-scale, long-lasting trial. First, there is a considerable problem with compliance in the intervention group. Not every man who is randomized to screening will actually participate. Not every man with an elevated PSA will undergo biopsy and, finally, not every man with prostate cancer will be treated with curative intent. As a result, the statistical power of the test is diminished. Secondly, there is a considerable contamination rate in the control group. The original assumption in 1994 was 12% but meanwhile it is up to 30% (Mickisch G, personal communication) (see also Section 5.3). This will further decrease the statistical power and it is questionable if the trial will detect a 20% difference in mortality if there was any at all. Thirdly, the Norwegian Urological Cancer Group decided against participating in ERSPC for above mentioned reasons but also because of ethical concerns [48]. Assuming a positive predictive value of an elevated PSA of only 6%, healthy men require biopsies to detect 1 case of cancer. If, indeed, screening could prove a reduction in prostate cancer-related mortality then several problems may arise on a political rather than a medical level. Public Health Systems in Western countries face increasing economic burden through ageing of the general population and technical developments. In the near future, it will be interesting to learn if large-scale screening programs could be implemented under these difficult circumstances.

7 H.-P. Schmid et al. / Critical Reviews in Oncology/Hematology 50 (2004) Summary The currently available data suggest a decrease in prostate cancer specific mortality through the introduction of population screening (mass screening). However, scientific proof is pending and results from important prospective randomized trials are expected only in a few years [49]. Data on quality of life and economic issues are also lacking. In the meantime, individual case finding (opportunistic screening) could be offered to men with a life-expectancy of at least 10 years according to the guidelines of the European Association of Urology [40]. Serum PSA measurement in conjunction with DRE is recommended by the majority of clinical guidelines provided the patient is well informed about the potential benefits and harms prior to PSA testing. Of the various concepts to improve the specificity of PSA, free/total PSA ratio and PSA doubling time seem to be the most promising. In conclusion, the optimal strategy for early detection of prostate cancer with PSA still remains unknown and will be a matter of debate for many years. Reviewers Jan Adolfsson, M.D., Ph.D., Editor-in-Chief, Scandinavian Journal of Urology and Nephrology, c/o WHO Center for Urologic Tumors, Karolinska Hospital, SE Stockholm, Sweden. Tel.: ; fax: Hans-Jürg Leisinger, M.D., Professor and Chairman, Department of Urology, University Hospital, CH-1011 Lausanne, Switzerland. Tel.: ; fax: Karl Pummer, M.D., Associate Professor, Department of Urology, Karl-Franzens-University, Auenbruggerplatz 7, A-8036 Graz, Austria. Tel.: ; fax: Franz Recker, M.D., Professor and Head, Division of Urology, Kantonsspital, CH-5001 Aarau, Switzerland. Tel.: ; fax: Acknowledgements The authors are grateful to Mrs. Gaby Schmalz for careful editing of the manuscript. References [1] Stamey TA, Freiha FS, McNeal JE, Redwine EA, Whittemore AS, Schmid H-P. Localized prostate cancer. 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No randomised trial of prostate-cancer screening in Norway. Lancet Oncol 2001;2: [49] Schröder FH. Screening for prostate cancer. Urol Clin N Am 2003;30: [50] Barry MJ. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med 2001;344: [51] Semjonow A, Schmid H-P. The rise and fall of PSA: clinical implications of prostate-specific antigen kinetics. Urol Res 2002;30:85 8. [52] Smith RA, Cokkinides V, von Eschenbach AC, Levin B, Cohen C, Runowicz CD, et al. American Cancer Society guidelines for the early detection of cancer. CA Cancer J Clin 2002;52:8 22. [53] Leitlinien der Deutschen Gesellschaft für Urologie. Leitlinie zur PSA-Bestimmung in der Prostatakarzinomdiagnostik (Früherkennung des Prostatakarzinoms) (Kurzfassung). Urologe [A] 2002;41: [54] Semjonow A, Albrecht W, Bialk P, Gerl A, Lamerz R, Schmid H-P, van Poppel H. Tumour markers in prostate cancer: EGTM recommendations. Anticancer Res 1999;19: [55] Fleisher M, Dnistrian AM, Sturgeon CM, Lamerz R, Wittliff JL. Practice guidelines and recommendations for use of tumor markers in the clinic. In: Diamandis EP, Fritsche H, Schwartz MK, Chan DW, editors. Tumor markers: physiology, pathobiology, technology and clinical applications. Chicago: AACC Press; p Biography Hans-Peter Schmid, M.D. Professor and Chairman of the Department of Urology at the Kantonsspital, St. Gallen, Switzerland since September Medical School at the University of Zürich ( ), training in surgery and urology at the University of Basel ( ). Research Fellow at Stanford University, California (1990/1991), postgraduate training at the CHU Bichat in Paris (1995) and the University of Münster, Germany ( ). Special interest in uro-oncology.