PSA testing has made prostate cancer screening a reality for men in many parts of the world, but its benefit for men's health continues to be debated. In men exposed to PSA testing, there has been a well-documented change in the presentation of prostate cancer with a shift towards earlier pathological stage, not without justifiable concern about over-diagnosis by prostate biopsy. Increasingly, men now diagnosed with early stage cancer have previous PSA exposure and are selected for biopsy based on PSA change in relation to cutoff values. Some recent observations suggest that PSA may no longer be an effective marker for early stage tumours, with PSA elevation failing to discriminate tumour-specific characteristics from benign gland enlargement. Traditionally, variation in pathological stage of clinically localised prostate cancer at diagnosis has related to clinical stage, PSA and biopsy Gleason grade, but with distinctions based upon these three assessments declining and an increasing proportion of organ-confined tumours at presentation, new methods of cancer detection and prognostic assessment are now required. Molecular technologies hold great promise in this respect, and in the future biomarker signatures are likely to overshadow total PSA for guiding early diagnosis and prognostic assessment. While arguments about prostate screening will continue, owing not least to its feasibility, future debate is likely to focus increasingly on technological advances and molecular profiling of these notoriously heterogeneous tumours.
Following the discovery of prostate-specific antigen (PSA) and recognition of its clinical utility as a serum marker for prostate cancer, the availability of PSA testing made prostate cancer screening a reality for men in many parts of the world. The overall benefit of screening to men's health has been debated fiercely, owing not least to the importance of the opportunity but also the need for robust evidence to support it. Nearly 20 years on, with PSA testing now routine in clinical practice, the place of PSA in the assessment of early stage prostate cancer is radically changing, but the debate on screening continues.
Prostate cancer is a major health factor, it is the most frequently diagnosed male cancer, killing over 10 000 men in the UK every year. In 2000, the number of new cases of prostate cancer was estimated at 513 000 worldwide.1 The incidence of prostate cancer is increasing steadily in almost all countries.2 In the UK, the lifetime risk of being diagnosed with prostate cancer is one in 14 and the strongest risk factor is age.3 Aside from the human cost the economic considerations are considerable. The cost of treating prostate cancer in England and Wales this year will approach £100 million.
The management of prostate cancer in its early stages remains controversial owing to the absence of a prospective randomised trial relating an overall benefit to clinical intent. The views of oncologists, urologists and epidemiologists are divided. Some continue to believe that no asymptomatic man should ever be screened and others advocate that every man over a certain age with a life expectancy of at least 10 years should be screened. The views of individual patients are therefore often significant in decision-making and outcomes. Here, the current place of PSA testing in relation to prostate cancer screening will be reviewed.
PSA is a protein that is produced in the glandular epithelium of the prostate. It is secreted into the lumen of the prostatic acini and has an important physiological role in prostatic fluid. Its principal function is to break down a protein called seminogelin, which is responsible for the rapid clotting of ejaculate, resulting in a viscous fluid for emission. Seminal PSA liquefies this coagulum, contributing to successful sperm migration.4 The concentration of PSA is a million times higher in the prostatic fluid than in the blood, and normally only a small amount is absorbed into the blood stream.
Abnormal leakage of PSA into the circulation is influenced by the level of PSA expression in malignant epithelium and by distortion of prostatic glandular architecture. Increased serum levels relate nonspecifically to prostatic pathology or prostatic manipulation, and the risk of clinically significant malignancy increases with the serum PSA concentration.
PSA testing has been clinically available since the 1980s to monitor the progression of prostate cancer in men where the cancer had already been diagnosed. In 1994 the US Food and Drug Administration approved the use of the PSA test for detecting prostate cancer. That decision essentially endorsed prostate cancer screening in the US, and challenged prostate health care policies and practices worldwide.
PSA testing is now routinely used for the diagnosis and monitoring of prostate cancer, as well as its response to treatment. The use of PSA as a screening tool is widely advocated in the United States, especially by the American Urological Association, the American College of Radiology and the American Cancer Society. It is estimated that over 25 million PSA tests are done in the USA per year. But, for the growing millions of men with elevated PSA and biopsies negative for cancer, the oncological significance of the elevated PSA is uncertain, and concerns of both physicians and patients relate to subsequent clinical management.
When PSA testing is examined critically against established requirements and principles of screening, evidence to support a significant overall health benefit is lacking. It is for this reason and concern about the impact of treatment-related morbidity that population screening has not been recommended by technology assessment agencies in the United Kingdom and other countries that include Canada, Australia and Sweden. Clinical practice has shown that screening may detect tumours at various stages in its natural history from those that resemble the indolent, nonaggressive phenotype (for which treatment has traditionally been considered unnecessary) to those that are too advanced for cure.
The purpose of screening tests is to identify disease in asymptomatic persons at a stage when treatment will favourably alter the natural history of the condition. Before a screening test can be recommended as a public health policy certain well established criteria must be fulfilled, these are outlined in Figure 1.5
At this time, prostate cancer screening does not fulfil all of these requirements. The main problem is that although prostate cancer is a common malignancy, it is not responsible for death in the majority of patients having histological evidence of the disease.
Does the natural history of early stage prostate cancer justify detection and treatment?
The natural history and clinical significance of prostate cancer relates to its pathological stage and grade at diagnosis, but is nevertheless highly variable and therefore unpredictable in individual patients, in spite of other available prognostic indicators. A high prevalence of microscopic foci of well differentiated adenocarcinoma is found at autopsy among men over the age of 50 years with prostate glands clinically considered normal.6 Small lesions (<0.5 cm3) are equally prevalent in countries having significantly different patterns of clinical disease, indicating poor correlation between the presence of such lesions and their pathological behaviour.7 Most early cancers therefore have a slow rate of growth and do not become clinically apparent within a man's lifetime. Men are much more likely to die with such foci of prostate cancer rather than from the clinical disease. Put another way, the risk of a 50-year-old man having microscopic prostate cancer is 42%, whereas the lifetime risk of prostate cancer death is about 3%.8
It is currently not possible to differentiate reliably those tumours that become aggressive from those that are indolent at a stage where they are curable. Opponents of screening believe PSA screening predominantly leads to the detection of indolent cancers, with the detrimental consequences of overdiagnosis and overtreatment outweighing any minority benefit. Proponents argue that the balance of benefit and risk relates to length of follow-up and that in men with at least a 10-year life-expectancy, this may be acceptable to individual patients and physicians.
The goal of screening for prostate cancer is to detect lesions that are or will be ‘clinically important’, when treatment of these lesions will reduce morbidity, improve survival and maintain quality of life for longer. The advocates of PSA screening would argue that a large proportion of cancers detected through PSA are clinically significant, allowing for 10 years progression, and that the proportion of tumours treated with radical prostatectomy that are pathologically insignificant is small. However, there is currently no accepted definition for what (on diagnostic criteria) is clinically significant prostate cancer or (on prognostic and therapeutic criteria) how to distinguish patients who will benefit from treatment from those who will not.
Pathological stage is the best single indicator of prognosis, and the detection of organ-confined prostate cancer has become a surrogate marker of outcome in evaluating screening, treatment and prevention.9 Clinical stage, Gleason grade and serum PSA individually and independently correlate with pathological stage and prognosis. By incorporating clinical stage and histologic grade with PSA in a multivariate model, prediction of pathological stage can be refined. In 1993, Partin et al.10 examined medical records of 703 patients with clinically localised disease who underwent a radical prostatectomy. The authors related three preoperative findings, the serum PSA, the Gleason score and clinical stage to the presence of pathologically organ-confined disease, capsular penetration, seminal vesicle invasion and lymph node involvement. The original Partin tables were revised in May 1997 based on data from three major prostate cancer research institutions: Johns Hopkins in Baltimore, Baylor School of Medicine in Houston, and the Michigan Prostate Institute in Ann Arbor. Data accumulated from 4133 patients treated by radical prostatectomy were used, confirming the utility of this concept in a multi-institutional experience.11 The tables were further updated in 2001 to reflect the trends in presentation and pathologic stage for men newly diagnosed with clinically localised prostate cancer.12 Clinicians can use these and similar nomograms to counsel individual patients and help them make important decisions regarding their disease.13
During the past 10 years, the stage at presentation has shifted, with more men presenting with Stage T1c, Gleason score 5–7, and serum PSA levels <10.0 ng/ml. Cancers are, however, increasingly diagnosed in men already exposed to PSA testing. The majority of tumours that are diagnosed early are now clinical stage T1c, with low PSA levels (less than 10 ng/ml) and Gleason Grade 3 or 4 disease on needle biopsy, consequently pathologically and prognostically favourable. With mens’ growing exposure to PSA testing, the impact of the ‘Tables’ on clinical decision-making has and will continue to decline. The PSA era has brought about a need for new tests to provide prognostic distinctions and guide individual therapeutic recommendations.
Is serum PSA an effective test for detection of early stage prostate cancer?
Serum PSA testing has two big advantages: firstly, it is an easy test to perform; secondly, the assay is relatively cheap, and reproducible. However, just like any test it has its drawbacks. A raised PSA is not a sure indicator of prostate cancer, since it can be raised in benign disease of the prostate and men with low levels can have prostate cancer.
Two studies investigated the validity of PSA as a prospective test for prostate cancer. The first was a nested case–control with stored serum samples collected from 49 261 men. They found that 265 previously asymptomatic men developed prostate cancer; these were matched with 1055 controls. The results revealed that PSA levels were higher in the group of 265 men who developed prostate cancer compared to the control group. In the first 3 years the proportion of men who developed prostate cancer and had raised levels of PSA (⩾12 times the median) was 81% (sensitivity) (95%CI 54–96%). The proportion of men who did not develop prostate cancer but had levels this high was 0.5% (false positive rate). Men aged 60–74 years with a raised PSA (⩾12 times the normal median level) had a 50% chance of developing prostate cancer within the next 3 years. The authors concluded that PSA is a highly discriminatory screening test for prostate cancer in healthy men.14
The second study came from Finland and was conducted in a similar fashion. They estimated the sensitivity of the test to be 44% with a specificity of 94% at a cutoff of 4.0 ng/ml. The sensitivity improved to 86% in patients diagnosed 5 years after the blood test. The test was found to have a better sensitivity and specificity in men less than 65 years of age, 93 and 96%, respectively.15
The positive predictive value of the PSA test for cancer on prostate biopsy is dependent on the cutoff level of the serum PSA as well as epidemiological characteristics of the screened population. In general, a man with a PSA level of above 4.0 ng/ml has a 20–30% chance of having prostate cancer; for levels above 10 ng/ml, the likelihood increases to between 42 and 64%.16, 17
A number of ways have been used to refine the accuracy of PSA in prostate cancer detection. PSA density (=PSA/gland volume) corrects for higher PSA levels associated with larger prostates. Limitations of PSA density include the need to perform transrectal ultrasound (TRUS) in all patients and an inherent inaccuracy in estimation of prostate volume. Another means to adjust for age-related benign prostatic enlargement is use of age-adjusted reference ranges; serum PSA tends to increase with age and therefore the acceptance of higher ‘normal’ levels in older men will result in fewer biopsies (Table 1).18
Circulating PSA consists of various fractions and isoforms. Some is bound to proteins as complexed PSA, and some exists as free PSA. Total PSA is the sum of these. The ratio of free to total PSA in men with PSA levels between 4 and 10 ng/ml relates to the probability of underlying cancer and restricting biopsy to those with lower free-total ratios improves specificity with minimal impact on sensitivity.19 Various molecular forms of free PSA have now been identified that appear to be specific to benign or malignant prostate tissues and may further improve cancer detection. Benign PSA (BPSA) is a form of free PSA that is associated with benign prostatic hyperplasia. Pro-PSA is another form of free PSA, consisting of truncated fractions that relate to the presence of prostate cancer.20 In men with total PSA values from 2 to 10 ng/ml, pro-PSA has been shown to distinguish between cancer and benign conditions better than total PSA, free PSA, or complexed PSA. Moreover, pro-PSA may selectively identify more aggressive forms of prostate cancer, as indicated by Gleason score 7 or greater and/or extracapsular tumour extension.21
Stamey et al.22 have emphasised that in men with early stage prostate cancer and PSA levels under 10 ng/ml, PSA levels are now more strongly associated with prostate volume than any cancer-related factor including the size and grade of the tumour. It would thereby be expected that PSA cut-offs lower than 4.0 ng/ml would increase detection of cancer in smaller prostates, as well as increase the number of men having negative biopsies. Unfortunately, even PSA levels lower than 4.0 ng/ml can be associated with prostate cancer, and these tumours may be pathologically significant in terms of grade and volume.23 If treatment of early stage cancer can be safely deferred in highly selected cases, particularly in older men, it is not known how early in relation to PSA elevation the organ-confined tumours should be diagnosed and treated in younger men.24
Growing concerns relate to overdiagnosis and overtreatment of cancers detected by PSA driven prostate biopsy. In various multivariate models, the prognostic significance of the initial serum PSA level has been emphasised; PSA velocity and doubling time may also be valuable prognostic indicators for both untreated and treated patients with early stage disease.25, 26 Although not the focus of this article, PSA is a valuable tumour marker in men with prostate cancer. However, as initial diagnosis is made at increasingly earlier stages of the natural history and in association with ever lower PSA levels, the discriminatory value of PSA will decline and prognostic evaluation will become more complex.
Prostate cancer is now detected predominantly by PSA testing, and increasingly in men previously tested. Consequently PSA levels at diagnosis are decreasing towards ever lower clinical cutoffs. It is therefore not surprising that differences in PSA between patients with early stage cancer no longer reflect tumour-specific indices, as Stamey et al.22 have observed. Indeed, observations of prostate gland volume in men treated by radical prostatectomy for organ confined prostate cancer have suggested that PSA may bias prostate cancer detection towards men with larger prostates.27 Prostate cancer can be detected early in its natural history, but new markers of biological potential are now urgently required.
Is there an effective treatment for early stage prostate cancer?
In the United States, radical prostatectomy has been the most common treatment for localised prostate cancer. It is performed with curative intent in men with a life expectancy of over 10 years. There is observational evidence that radical prostatectomy is an effective treatment for organ-confined prostate cancer, with 10 year disease-free survival between 68 and 95% reported, and improving outcomes observed within the last decade suggest results at the upper end of this range should now be expected.26, 28, 29 Other treatments, particularly radiation therapy, may also be curative, but long-term outcomes cannot be related to the pathological stage of the primary tumour when the prostate is not removed. In a nonrandomised, prospective study of 60 000 patients treated for prostate cancer, men referred for radical prostatectomy had a better 10-year survival rate than those for whom the initial treatment decision was radiotherapy or watchful waiting.30
A prospective randomised trial conducted in Scandinavia comparing radical prostatectomy with watchful waiting in early prostate cancer was reported by Holmberg et al.31 695 men were randomised to each arm and were followed up for a median of 6.2 years. Compared with watchful waiting, radical prostatectomy was associated with significant decreases in metastatic disease and disease-specific mortality over eight years of follow-up but with no significant difference in overall mortality. The reduction in disease-specific mortality for an individual man was about 6%. Therefore, around 17 prostatectomies would be carried out to prevent one death from prostate cancer in the next 8 years. With longer follow-up, a more substantial benefit from radical prostatectomy may be expected from the ongoing reduction in metastatic rate.
Does disease-specific outcome with early intervention justify screening?
Prostate cancer mortality rates in the UK and USA have declined since the early 1990s.32 The similar mortality trends are surprising and coincide with substantially different attitudes to screening and PSA testing. A number of factors may be responsible for these observations other than the impact of truly curative treatment. PSA testing results in a dramatic ‘stage shift’ in cancers being diagnosed by virtue of detecting the tumour earlier. Early and better treatment, whether or not curative, and increased awareness of prostate cancer may contribute to the epidemiological observations.
Two important epidemiological biases contribute to apparently improved outcomes following an increase in early diagnosis of a disease. Firstly, lead-time bias occurs when screening detects disease earlier in its course: the individual apparently lives longer from diagnosis to death, even if the natural history has not been altered. Secondly, there is length bias: among tumours diagnosed by screening, there will be a greater proportion of less aggressive cancers, and these men then survive longer after diagnosis, irrespective of the therapy used. These biases are real, difficult to quantify and their impact will vary between patients: their effects cannot be eliminated without a randomised clinical trial of screening.33 While breast cancer screening and colon cancer screening have been proven to be efficacious through randomised clinical trials, such a study has yet to be completed for prostate cancer screening. Thus, one can only speculate that early detection of asymptomatic prostate cancer may lead to increased life expectancy.
Two randomised trials are currently examining the role of prostate cancer screening. The Prostate, Lung and Colorectal and Ovarian Cancer Screening Trial (PLCO) is enrolling 148 000 men and women ages 55–74 at 10 screening centres in the United States with balanced randomisation to intervention and control arms. For prostate cancer, men receive a digital rectal examination and a blood test for PSA.34 Provisional results have revealed that the majority of low-risk prostate cancer patients could undergo less frequent screening.35 Data that were analysed from more than 27 000 men, aged 55 through 74 years, who participated in the PLCO trial found 99% of men with very low PSA levels could be safely tested less often. A statistical model applied to the men's data predicted more than 98% of men with serum PSA <1 ng/ml at baseline would remain in normal range for the next 4 years, suggesting these men could safely be tested every 5 years. The model also showed more than 98% of those with levels between 1 and 2 ng/ml would remain in normal range during the next year, so for these biannual testing could safely be recommended.
In the European Randomised study of Screening for Prostate Cancer (ERSPC), screening tests include PSA, digital rectal examination and TRUS.36, 37 There are eight participating centres: the Netherlands, Sweden, Finland, Belgium, Italy, Portugal, Spain and Switzerland. At the present time, nearly 206 000 men aged 50–74 years have been randomised to either the screening or control arm, and over 5500 cancer cases have been detected. The first results from the study are expected before 2010. Importantly, in the Rotterdam section, the median lead-time has recently been estimated to be 11–12 years, raising justifiable concern about overdiagnosis in half of screen-detected cancers.38
Another prospective randomised study, now completed, was conducted in Quebec.39 It began in 1988 and involved 46 200 men, but only 8200 men could be screened resulting in an acceptance rate of 23%. Only 15 deaths per 100 000 man-years in the screened population were observed compared to 49 per 100 000 man-years in unscreened men. This study has been criticised for selection bias. Owing to its design limitations, this study does not give convincing evidence that PSA screening reduces mortality from prostate cancer.
In 1993, PSA screening was introduced in the Austrian state of Tyrol. Within 5 years, the incidence of metastatic disease and disease-specific mortality was significantly less than in the rest of Austria.40 This was not a randomised trial, and downstaging may contribute substantially to this effect, with true survival advantage requiring longer-term follow-up. Nevertheless, the epidemiological impact of this screening policy has been dramatic.
An important study in the UK (ProtecT) that opened for recruitment in 2001 is recruiting from nine centres outside London (Birmingham, Bristol, Cambridge, Cardiff, Edinburgh, Leeds, Leicester, Newcastle and Sheffield). These centres will invite 230 000 men aged 50–69 for a PSA test. The study aims to evaluate treatments for localised prostate cancer, randomising men to surgery, radiotherapy and active monitoring. The primary end point will be survival to 10 years, with many secondary end points including disease progression, morbidity, quality of life impact, performance of diagnostic tests and tumour molecular biology.41 This study will provide valuable insights into PSA detection of early stage prostate cancer and its natural history.
Non-Oncological sequelae of PSA testing, investigation and treatment
PSA testing and confirmatory tests for prostate cancer may be associated with various physical and psychological problems in otherwise healthy men. The diagnosis of prostate cancer requires histological examination of biopsy specimens. The discomfort of prostate biopsy may be reduced by local infiltration with local anaesthesia. Infection, septicaemia and bleeding are uncommon. Anxiety relates to waiting for a test result and the consequences of a positive result. Quality of life may be threatened by treatment for localised disease, owing to the fact that PSA screening identifies cancers that would not otherwise have been discovered, and must be weighed against the future impact of disease without early treatment. Adverse effects and complications that follow treatment for localised prostate cancer are relatively common.
After radical prostatectomy, overall impotence rates are high (10–90%)42, 43 and 2–5% of men will have severe incontinence.44 A recent large study evaluated quality of life in men prospectively randomised to radical prostatectomy or watchful waiting.45 Following surgery 80% of men had erectile dysfunction, compared to 45% in the watchful waiting group, and 49% had urinary leakage, compared to 21% in the watchful waiting group. Subjective quality of life was similar in the two groups. Life threatening complications from radical prostatectomy are relatively rare: a Medicare analysis of 10 1604 prostatectomies from 1991 to 1994 showed a 30-day operative mortality rate of 0.54%.46 The best outcomes reported following radical prostatectomy are from single institution, large volume academic centres.
External beam radiotherapy can also have significant side effects that may include severe bladder irritation in 5% of patients, rectal irritation resulting in diarrhoea, urgency, bleeding and tenesmus in up to 10% of patients and impotence in 40–50%.47 Brachytherapy techniques allow higher radiation doses to be delivered to the prostate. Various techniques are now routinely utilised to minimise the risk of side effects that relate particularly to the effects of radiation on normal structures adjacent to the prostate.
Interest in minimally invasive interventions for prostate cancer is growing, particularly cryotherapy, hyperthermia and high-intensity focused ultrasound. These modalities are currently considered experimental interventions for primary therapy, and long-term randomised trials will be required to compare outcomes with current standards, including active monitoring.
Is screening cost-effective?
Although an individual PSA test is inexpensive, costs escalate when abnormal test results are further evaluated. Cost-effectiveness of prostate cancer screening has been estimated in a few studies, but these have tended to focus on the cost per cancer detected and not the cost associated with the false positive results, repeated tests and secondary treatments. Nor is consideration generally given to the socio-economic implications and costs of not screening, including treatment and palliation of advanced disease and premature death.48 Important issues to be addressed include the additional costs of treating other potentially fatal diseases subsequently acquired in the screened population, particularly in the elderly who represent the largest age group to experience the benefit of reduced prostate cancer mortality but may nevertheless experience little overall improvement in survival.
Does PSA testing fulfil the criteria of a screening test?
The criteria that need to be met for an overall benefit from screening were published nearly 40 years ago. In the current age of PSA testing for prostate cancer, many but not all of those criteria support prostate cancer screening. Considerable diagnostic and therapeutic progress has been made within the past 20 years. Prostate cancer is clearly an important health problem, and it has a long, detectable, preclinical phase. Current treatment options are acceptable and the diagnostic tests are cheap, convenient and sufficiently reliable. Treatment of early stage disease represents the best opportunity for long-term progression-free survival.
Unfortunately, tests do not predict reliably the future disease-specific morbidity and mortality in individuals initially treated conservatively. Also, there are no satisfactory recommendations for the growing number of men with elevated PSA and negative biopsies. Refinements in the analysis PSA and its molecular profile however promise improved accuracy for cancer detection, and with new molecular-based diagnostic approaches a significant reduction of the negative biopsy rate may be feasible. There are no detailed contemporary studies of the cost of prostate cancer and the long-term cost-effectiveness of treatment or screening, in relation to distinct perspectives of health care provision, public health policy and the health of individuals. Further evidence is required to assure the safety, effectiveness and need for treatment in the setting of population screening.
With men's increasing exposure to widespread availability of PSA testing and the utilisation of lower cutoffs, the value and performance of PSA as a screening test has changed substantially. In ongoing randomised trials of screening, there are analytical concerns about ‘contamination’ of the control arms by exposure to PSA testing. Biopsies may be significantly overdetecting cancers that will not give rise to clinical disease. In men with biopsies positive for cancer, clinical stage T1c disease and PSA levels under 10 ng/ml, variation in PSA level may no longer relate to tumour-specific factors, and tumour grade is no longer a major discriminator of early stage tumours. For men continuing in an early detection program or opportunistic PSA monitoring, and eventually requiring biopsy, prognostic indicators other than PSA and Gleason grade are urgently required to guide future surveillance or need for therapeutic intervention. PSA surveillance is likely to be improved by new diagnostic technologies and tests more appropriate for screening.
A vision for the future
Ongoing development of new tests for prostate cancer will contribute diagnostic, staging and prognostic information. PSA testing will then become one component of an integrated and refined molecular assessment of prostate pathology. PSA profiles incorporating analysis of its multiple isoforms are likely to detect prostate cancer more reliably than assays of total PSA or any individual component. Urine-based tests are also becoming available, such as uPM3, identifying clinically significant cancer.49 Clinical practice may be further improved through imaging, refining localisation and staging. One particular technique that can assess the degree of angiogenesis supporting the growth of the prostate cancer is contrast-enhanced colour Doppler ultrasonography (CDUS).50 Among a growing number of targeted imaging techniques, anatomical definition and molecular characterisation can be superimposed.
Proteomics is a promising field for current laboratory research, but is yet to be introduced to routine urological clinical practice. Proteins, peptides, and other small molecules present at low concentrations are characterised using mass spectrometry techniques. Although still in the early phases of development and requiring further validation, this new technology holds great promise for characterising new biomarkers.
Technologies such as microdissection, microarray, and comparative genomic hybridisation provide the means to identify, clone, and characterise new tissue biomarkers. Marker profiles may soon be used to define the malignant potential of prostate cancer in individual patients. Prostate-specific membrane antigen (PMSA) and prostate stem-cell antigen (PSCA) are two among many more recently studied prostate-associated proteins. Both show increased expression in prostatic epithelium, but are not entirely specific for prostate tissue or cancer.51, 52 Many others are justifiably the subjects of intensive research.
This ongoing research is providing new perspectives and insights that will overshadow an increasingly historical focus on the benefits and shortfalls of PSA testing. It will provide the opportunity to find new tests that either determine or reflect the clinical behaviour of this common and sometimes fatal malignancy.
Early detection of prostate cancer is the focus of probably the single most important ongoing debate concerning men's healthcare. When PSA testing first became available, it provided a valuable new test for prostate cancer and interest in prostate cancer screening was renewed. Today, after men's increasing exposure to opportunistic testing, the oncological significance of total PSA in men having biopsy is decreasing. Recent advances in diagnostic technology suggest that PSA testing will be replaced by molecular profiling and prostate cancer testing will incorporate these advances.
For the individual, PSA testing may avoid future prostate cancer related death and morbidity, but this may be at a personal cost including side effects of treatment. Early treatment may not be justified for all patients who are curable owing to the variability and uncertainty of the clinical behaviour of the pathological disease in its very early stages. Better understanding of prostate cancer biology, its progression and its metastatic phenotype is needed to develop the means to successfully diagnose and treat, or better still prevent, this disease.
Proof of the benefits of screening for prostate cancer can only be obtained from randomised controlled clinical trials that are currently underway in the United States, Europe and the United Kingdom. PSA screening may indeed facilitate early detection of prostate cancer; however there is as yet no study that has proved this would improve men's health and life expectancy in the context of population screening. Total PSA may become of historical interest in the evolution of prostate cancer screening, as new generations of diagnostic and prognostic tests emerge.
Parkin DM, Whelan SL, Ferlay J, Teppo L . Cancer Incidence in Five Continents. Vol. VII. IARC Scientific Publication: Lyon, 1997.
Gronberg H . Prostate cancer epidemiology. Lancet 2003; 36: 859–864.
Cancer research UK. Prostate Cancer Stats 2002. Cancer Research UK: London.
Amelar RD, Dubin L . Semen Analysis, In Male Infertility. W.B. Saunders, 1997.
Wilson JMG, Jungner G . Principles and Practice of Screening. WHO: Geneva, 1968.
Chamberlin J, Melia J, Shearer RJ, Eeles R, Muir G, Stratton M et al. Prostate cancer. Lancet 1993; 342: 901–905.
Breslow N, Chan CW, Dhom G, Drury RA, Franks LM, Gellei B et al. Latent carcinoma of prostate at autopsy in seven areas. Int J Cancer 1977; 20: 680–688.
Whitmore Jr WF . Localised prostatic cancer: management and detection issues. Lancet 1994; 343: 1263–1267.
Krumholtz JS, Carvalhal GF, Ramos CG, Smith DS, Thorson P, Yan Y et al. Prostate-specific antigen cutoff of 2.6 ng/mL for prostate cancer screening is associated with favourable pathologic tumor features. Urology 2002; 60: 469–473.
Partin AW, Yoo J, Carter HB, Pearson JD, Chan DW, Epstein JI et al. The use of prostate specific antigen, clinical stage, and Gleason Score to predict pathological stage in men with localized prostate cancer. J Urol 1993; 150: 110–114.
Partin AW, Kattan MW, Subong EN, Walsh PC, Wojno KJ, Oesterling JE et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997; 277: 1445–1451.
Partin AW, Mangold LA, Lamm DM, Walsh PC, Epstein JI, Pearson JD . Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology 2001; 58: 843–848.
Kattan MW, Shariat SF, Andrews B, Zhu K, Canto E, Matsumoto K et al. The addition of interleukin-6 soluble receptor and transforming growth factor beta1 improves a preoperative nomogram for predicting biochemical progression in patients with clinically localized prostate cancer. J Clin Oncol 2003; 21: 3573–3579.
Parkes C, Wald NJ, Murphy P, George L, Watt HC, Kirby R et al. Prospective observational study to assess value of prostate specific antigen as screening test for prostate cancer. BMJ 1995; 311: 1340–1343.
Hakama M, Stenman UH, Aromaa A, Leinonen J, Hakulinen T, Knekt P . Validity of the prostate specific antigen test for prostate cancer screening: followup study with a bank of 21 000 sera in Finland. J Urol 2001; 166: 2189–2191.
Coley CM, Barry MJ, Fleming C, Mulley AG . Early detection of prostate cancer. Part I: Prior probability and effectiveness of tests. The American College of Physicians. Ann Intern Med 1997; 126: 394–406.
Woolf SH . Screening for prostate cancer with prostate-specific antigen. An examination of the evidence. N Engl J Med 1995; 333: 1401–1405.
Richardson TD, Oesterling JE . Age-specific reference ranges for serum prostate-specific antigen. Urol Clin North Am 1997; 24: 339–351.
Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA 1998; 279: 1542–1547.
Mikolajczyk SD, Rittenhouse HG . Tumor-associated forms of prostate specific antigen improve the discrimination of prostate cancer from benign disease. Rinsho Byori 2004; 52: 223–230.
Catalona WJ, Bartsch G, Rittenhouse HG, Evans CL, Linton HJ, Horninger W et al. Serum pro prostate specific antigen preferentially detects aggressive prostate cancers in men with 2–4 ng/ml prostate specific antigen. J Urol 2004; 171 (Part 1): 2239–2244.
Stamey TA, Caldwell M, McNeal JE, Nolley R, Hemenez M, Downs J . The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J Urol 2004; 172: 1297–1301.
Thompson IM, Goodman PJ, Tangen CM, Lucia MS, Miller GJ, Ford LG et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003; 349: 215–224.
Khan MA, Carter HB, Epstein JI, Miller MC, Landis P, Walsh PW et al. Can prostate specific antigen derivatives and pathological parameters predict significant change in expectant management criteria for prostate cancer? J Urol 2003; 170: 2274–2278.
D’Amico AV, Chen MH, Roehl KA, Catalona WJ . Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 2004; 351: 125–135.
Pound CR, Partin AW, Epstein JI, Walsh PC . Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am 1997; 24: 395–406.
Feneley MR, Landis P, Simon I, Metter EJ, Morrell CH, Carter HB et al. Today men with prostate cancer have larger prostates. Urology 2000; 56: 839–842.
Catalona WJ, Smith DS . Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer: intermediate-term results. J Urol 1998; 160 (Part 2): 2428–2434.
Zincke H, Oesterling JE, Blute ML, Bergstralh EJ, Myers RP, Barrett DM et al. Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer. J Urol 1994; 152 (Part 2): 1850–1857.
Lu-Yao GL, Yao SL . Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 1997; 349: 906–910.
Holmberg L, Bill-Axelson A, Helgesen F, Salo JO, Folmerz P, Haggman M et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002; 347: 781–789.
Oliver SE, May MT, Gunnell D . International trends in prostate-cancer mortality in the ‘PSA ERA’. Int J Cancer 2001; 92: 893–898.
George N In: Mundy AR, Fitzpatrick JM, Neal DE, George NJR (eds). Screening in Urology. In: The Scientific Basis of Urology. Isis Medical Media: Oxford, 1999.
Gohagan JK, Prorok PC, Kramer BS, Hayes RB, Cornett JE . The prostate,lung,colorectal, and ovarian cancer screening trial of the National Cancer Institute. Cancer 1995; 75: 1869–1873.
Crawford ED . PSA testing interval: data from PLCO screening trial. American Society of Clinical Oncology Abstracts (4); May 18-21, 2002.
Schröder FH . The European screening study for prostate cancer. Can J Oncol 1994; 4 (Suppl): 102–109.
Draisma G, de Koning HJ . MISCAN: estimating lead-time and over-detection by simulation. BJU Int 2003; 92 (Suppl 2): 106–111.
Labrie F, Candas B, Dupont A, Cusan L, Gomez JL, Suburu RE et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999; 38: 83–91.
Bartsch G, Horninger W, Klocker H, Reissigl A, Oberaigner W, Schonitzer D et al. Prostate cancer mortality after introduction of prostate-specific antigen mass screening in the Federal State of Tyrol, Austria. Urology 2001; 58: 417–424.
Stanford JL, Feng Z, Hamilton AS, Gilliland FD, Stephenson RA, Eley JW et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000; 283: 354–360.
Siegel T, Moul JW, Spevak M, Alvord WG, Costabile RA . The development of erectile dysfunction in men treated for prostate cancer. J Urol 2001; 165: 430–435.
Weldon VE, Tavel FR, Neuwirth H . Continence, potency and morbidity after radical perineal prostatectomy. J Urol 1997; 158: 1470–1475.
Steineck G, Helgesen F, Adolfsson J, Dickman PW, Johansson JE, Norlen BJ et al. Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 2002; 347: 790–796.
Yao SL, Lu-Yao G . Population-based study of relationships between hospital volume of prostatectomies, patient outcomes, and length of hospital stay. J Natl Cancer Inst 1999; 91: 1950–1956.
Shipley WU, Zietman AL, Hanks GE, Coen JJ, Caplan RJ, Won M et al. Treatment related sequelae following external beam radiation for prostate cancer: a review with an update in patients with stages T1 and T2 tumor. J Urol 1994; 152 (Part 2): 1799–1805.
Labrie F, Dupont A, Suburu R, Cusan L, Gomez JL, Koutsilieris M et al. Optimized strategy for detection of early stage, curable prostate cancer: role of prescreening with prostate-specific antigen. Clin Invest Med 1993; 16: 425–439.
Fradet Y, Saad F, Aprikian A, Dessureault J, Elhilali M, Trudel C et al. uPM3, a new molecular urine test for the detection of prostate cancer. Urology 2004; 64: 311–315.
Shigeno K, Igawa M, Shiina H, Kishi H, Urakami S . Transrectal colour Doppler ultrasonography for quantifying angiogenesis in prostate cancer. BJU Int 2003; 91: 223–226.
Chang SS, Reuter VE, Heston WD, Bander NH, Grauer LS, Gaudin PB . Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res 1999; 59: 3192–3198.
Reiter RE, Gu Z, Watabe T, Thomas G, Szigeti K, Davis E et al. Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc Natl Acad Sci USA 1998; 95: 1735–1740.
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Constantinou, J., Feneley, M. PSA testing: an evolving relationship with prostate cancer screening. Prostate Cancer Prostatic Dis 9, 6–13 (2006). https://doi.org/10.1038/sj.pcan.4500838
- prostate-specific antigen
- prostate cancer
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