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The Value of Free PSA in Addition to Total PSA in the Early Detection of Prostate Cancer
European Oncology Review, 2005:60-2
The incidence of prostate cancer has increased substantially in many countries over the last few decades. Fifteen to 20 years ago, the probability that a man would be diagnosed with prostate cancer was 4% to 6% in most industrialised countries but, currently, 17% of men in the US and 5% to 10% in Europe are expected to be diagnosed with this disease during their lifetime. At the same time, mortality has remained fairly constant ranging from 2% to 3.5% in various countries.1,2 Thus, prostate cancer is a serious health problem. To reduce morbidity and mortality, opportunistic screening based on determination of prostatespecific antigen (PSA) in serum is increasingly used.
Long-term studies utilising serum bank samples have shown that serum PSA starts to increase over the commonly used cut-off of 4μg/l already five to 10 years before prostate cancer surfaces clinically.3,4 At this stage most prostate cancers are clinically localised and potentially curable by radical therapy.5
However, 25% to 30% of the patients with clinically localised disease will experience a clinical or a biochemical relapse, i.e. increasing PSA levels in serum.6 Therefore, some centres have lowered the cut-off to 2.5 to 3μg/l in order to catch cancer at an even earlier stage.5,7–9 While this will increase the likelihood of cure it will also increase overdiagnosis, which, with screening every fourth year, is estimated to be around 50%,10 but it may actually be higher.
The high rate of over-diagnosis is explained by the slow development of most prostate cancers and the high prevalence of subclinical disease. Because of this slow development it takes on average 17 years from an increase in serum PSA over 4μg/l before a conservatively treated prostate cancer becomes lethal.4
The prevalence of occult tumours has been studied by examination of prostates removed at autopsy and this reveals a cancer in about half of all men aged 60 years old, and in three-quarters of those aged 70 to 80 years old.11 The vast majority of the occult tumours will never surface clinically, but many of them are now detected as a result of opportunistic screening. The probability that an occult tumour will develop into clinical disease is strongly related to the level of PSA in serum. Thus, the time it takes for a tumour to develop into clinical disease is longer the lower the PSA level.
Therefore, early detection and treatment of small prostate cancers in elderly men is not likely to provide a survival benefit. On the basis of a serum bank study it was calculated that screening of men over 65 years of age would not reduce disease-specific mortality4 and this was actually verified in a randomised study on radical prostatectomy versus watchful waiting. However, in younger men, therapy caused a significant reduction in disease-specific mortality.12
There is no generally accepted strategy for prostate cancer detection; various expert groups have issued recommendations both for and against screening. Irrespective of the recommendations, PSA testing is increasingly used, and in some countries this has caused a dramatic increase in prostate cancer incidence, e.g. in Finland the increase has been three-fold over the last 15 years.13
It is too early to evaluate the outcome of the present prostate cancer detection strategies but there are reasons to suspect that they are not optimal; it is obvious that harmless tumours are over-diagnosed while many aggressive cancers are not being cured.
The results from the on-going European Randomized Screening for Prostate Cancer (ERSPC) will help to improve strategies but it will take at least five more years before the results are available. Meanwhile, attempts to improve strategies should be made on the basis of currently available data.
- Wilson S S, Crawford E D, “Screening for prostate cancer”, Clin. Prostate Cancer (2004);3: pp. 21–25.
- Jemal A, Tiwari R C, Murray T, Ghafoor A, Samuels A, Ward E, et al., “Cancer statistics, 2004”, CA Cancer J. Clin. (2004);54: pp. 8–29.
- Carter H B, Pearson J D, Metter E J, Brant L J, Chan D W, Andres R, et al., “Longitudinal evaluation of prostatespecific antigen levels in men with and without prostate disease”, JAMA (1992);267: pp. 2,215–2,220.
- Stenman U-H, Hakama M, Knekt P, Aromaa A, Teppo L, Leinonen J, “Serum concentrations of prostate specific antigen and its complex with a1-antichymotrypsin before diagnosis of prostate cancer”, Lancet (1994);344: pp. 1,594–1,598.
- Catalona W J, Ramos C G, Carvalhal G F, Yan Y, “Lowering PSA cutoffs to enhance detection of curable prostate cancer”, Urology (2000);55: pp. 791–795.
- D’Amico A V, Chen M H, Roehl K A, Catalona W J, “Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy”, N. Engl. J. Med. (2004);351: pp. 125–135.
- Hugosson J, Aus G, Lilja H, Lodding P, Pihl C G, “Results of a randomized, population-based study of biennial screening using serum prostate-specific antigen measurement to detect prostate carcinoma”, Cancer (2004);100: pp. 1,397–1,405.
- Schroder F H, Roobol-Bouts M, Vis A N, van der Kwast T, Kranse R, “Prostate-specific antigen-based early detection of prostate cancer—validation of screening without rectal examination”, Urology (2001);57: pp. 83–90.
- Auvinen A, Maattanen L, Finne P, Stenman U H, Aro J, Juusela H, et al., “Test sensitivity of prostate-specific antigen in the Finnish randomised prostate cancer screening trial”, Int. J. Cancer (2004);111: pp. 940–943.
- Draisma G, Boer R, Otto S J, van der Cruijsen I W, Damhuis R A, Schroder F H, et al., “Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer”, J. Natl. Cancer Inst. (2003);95: pp. 868–878.
- Sakr W, Grignon D, Haas G, Heilbrun J, Crissman J, Pones J, “Pathology of prostate cancer and premalignant lesions in African-American and caucasian men: an epidemiologic and morphologic study”, In: Cockett A, Aso Y, Chatelain C, Denis L, Griffiths K, Khoury S, Murphy G (eds), Proceedings of the Third International Consultation on Benign Prostatic Hyperplasia: Scientific Communication Int. (1996); pp. 389–400.
- Bill-Axelson A, Holmberg L, Ruutu M, Haggman M, Andersson S O, Bratell S, et al., “Radical prostatectomy versus watchful waiting in early prostate cancer”, N. Engl. J. Med. (2005);352: pp. 1,977–1,984.
- Stenman U, Abrahamsson P, Aus G, Lilja H, Bangma C, Hamdy F, et al., “Prognostic value of serum markers for prostate cancer”, Scand. J. Urol. Nephrol. (Suppl ) (2005).
- Stenman U H, Leinonen J, Alfthan H, Rannikko S, Tuhkanen K, Alfthan O, “A complex between prostate-specific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer”, Cancer Res. (1991);51: pp. 222–226.
- Lilja H, Christensson A, Dahlen U, Matikainen M T, Nilsson O, Pettersson K, et al., “Prostate-specific antigen in serum occurs predominantly in complex with alpha 1-antichymotrypsin”, Clin. Chem. (1991);37: pp. 1,618–1,625.
- Zhu L, Leinonen J, Zhang W M, Finne P, Stenman U H, “Dual-Label Immunoassay for Simultaneous Measurement of Prostate-specific Antigen (PSA)-alpha(1) Antichymotrypsin Complex Together with Free or Total PSA”, Clin. Chem. (2003);49: pp. 97–103.
- Catalona W J, Smith D S, Wolfert R L, Wang T J, Rittenhouse H G, Ratliff T L, et al., “Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening”, JAMA (1995);274: pp. 1,214–1,220.
- Finne P, Auvinen A, Aro J, Juusela H, Määttänen L, Rannikko S, et al., “Estimation of prostate cancer risk on the basis of total and free prostate-specific antigen, prostate volume and digital rectal examination”, Eur. Urol. (2002);41: pp. 619–627.
- Aus G, Becker C, Lilja H, Khatami A, Pihl C G, Hugosson J, “Free-to-total prostate-specific antigen ratio as a predictor of non-organ-confined prostate cancer (stage pT3)”, Scand. J. Urol. Nephrol. (2003);37: pp. 466–470.
- Southwick P C, Catalona W J, Partin A W, Slawin K M, Brawer M K, Flanigan R C, et al., “Prediction of post-radical prostatectomy pathological outcome for stage T1c prostate cancer with percent free prostate specific antigen: a prospective multicenter clinical trial”, J. Urol. (1999);162: pp. 1,346–1,351.
- Raaijmakers R, Blijenberg B G, Finlay J A, Rittenhouse H G, Wildhagen M F, Roobol M J, et al., “Prostate cancer detection in the prostate specific antigen range of 2.0 to 3.9 ng/ml: value of percent free prostate specific antigen on tumor detection and tumor aggressiveness”, J. Urol. (2004);171: pp. 2,245–2,249.
- Finne P, Finne R, Bangma C, Hugosson J, Hakama M, Auvinen A, et al., “Algorithms based on prostate-specific antigen (PSA), free PSA, digital rectal examination and prostate volume reduce false-positive PSA results in prostate cancer screening”, Int. J. Cancer (2004);111: pp. 310–315.