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Abstract

Although widely used, the value of prostate-specific antigen (PSA) in screening asymptomatic men for prostate cancer is controversial. Reasons for the controversy relate to PSA being less than an ideal marker in detecting early prostate cancer, the possibility that screening for prostate cancer may result in the overdetection and thus overtreatment of indolent disease and the lack of clarity as to the definitive or best treatment for men diagnosed with localized prostate cancer. Although the results from some randomized prospective trials suggest that screening with PSA reduces mortality from prostate cancer, the overall benefit was modest. It is thus currently unclear as to whether the modest benefit of reduced mortality outweighs the harms of overdetection and overtreatment. Thus, prior to undergoing screening for prostate cancer, men should be informed of the risks and benefits of early detection. Newly emerging markers that may complement PSA in the early detection of prostate cancer include specific isoforms of PSA and PCA3.

Introduction

Prostate-specific antigen (PSA) is the most widely used tumour marker, worldwide. As a tumour marker, PSA is unique in that its expression is almost exclusively organ specific, i.e. its production is predominantly confined to prostate cells, whether they are normal, benign or malignant. Although PSA expression does not appear to be increased in malignant vis-à-vis normal or benign prostate cells,^1,2 prostate cancer tissues release approximately 10 times more PSA into serum compared with normal or benign prostatic hyperplasia (BPH) tissue.³ This increased release of PSA is believed to result from disruption of the normal prostatic membrane structures. Consequently, PSA is widely used as a marker at all stages of prostate cancer detection and management. The aim of this article is to critically review the role of PSA in screening asymptomatic men for early prostate cancer. Firstly, however, we briefly review the structure and biological function of PSA.

Structure and biological function

PSA is a member of the kallikrein-related peptidase (KLK) family of molecules. KLKs, in turn, belong to the chymotrypisn (S1) family of serine proteases.⁴ In total, 15 KLK genes exist, all of which are located on the long arm of chromosome 19. Of the 15 members, the most widely studied is KLK3, which is better known as PSA. Although the biological function of most kallikreins is unknown, PSA is believed to mediate solubilization of the seminal coagulum, thereby decreasing its viscosity and increasing motility of spermatozoa.

PSA is initially synthesized as a preproprotein containing 261 amino acids.^5,6 Following removal of the 17-amino-acid proleader sequence, a 244-amino-acid precursor is formed. This proform is sometimes referred to as (−7)proPSA or (−7)pPSA, as it contains a 7-amino-acid propeptide leader. Following further cleavage, proPSA is converted to mature or active PSA. Originally, the (−7)pPSA form was believed to be the only precursor form of PSA. More recently, however, several other proforms have been described containing five, four or two amino acids instead of the native seven amino acids. These different forms of PSA are known as (−5)pPSA, (−4)pPSA and (−2)pPSA, respectively. Some of these precursor forms of PSA, especially the (−2) form, are currently undergoing evaluation as potential new markers for prostate cancer (please see section ‘Emerging markers for prostate cancer’).

Most of the PSA (70–90%) in blood exists as an 80–90 kDa complex with alpha-1-antichymotrypsin.⁵ Smaller amounts are bound to other protease inhibitors such as alpha-1-proteinase inhibitor, protein C inhibitor and alpha-2-macroglobulin. Approximately, 10–30% of the PSA in blood does not attach to protease inhibitors and is thus known as free PSA (fPSA). fPSA, however, is not homogenous but exists in three main molecular forms.^5,6 These are known as inactive PSA (iPSA) that is similar to native active PSA except that it is enzymatically inactive, precursor forms such as those mentioned above and BPSA. BPSA is so named as it was first found in patients with BPH. This form of PSA is clipped at amino acids 145–146 and 182–183, but remains intact because the molecule is held together by five disulphide bonds.^5,6

Use of PSA in screening for prostate cancer

In 1994, the Food and Drug Administration (FDA) in the USA approved PSA as an aid in the early detection of prostate cancer. PSA was to be used at a cut-off point of 4 µg/L and in combination with digital rectal examination. Since then, PSA has been increasingly used as a screening test for prostate cancer in asymptomatic men. Although widely practised, screening for prostate cancer is controversial. Reasons for the controversy relate to PSA being a non-ideal screening test for prostate cancer, the possibility that screening may result in the overdetection and thus overtreatment of indolent tumours, the lack of clarity as to the definitive or best treatment for men with localized prostate cancer and conflicting results from randomized trials as to whether screening reduces mortality from prostate cancer. These points are further discussed below.

PSA is a less than an ideal marker in screening for prostate cancer

PSA is a less than an ideal marker in screening for prostate cancer as substantial overlap exists between its serum levels in malignancy and non-malignancy (see Table 1 for a list of non-malignant conditions that may increase serum PSA levels). In particular, there is no cut-off point that clearly separates patients with cancer from men without cancer, i.e. there is no threshold below which a man can be reassured that he does not have prostate malignancy. Thus, in a phase III prostate cancer prevention trial comparing finasteride with placebo, almost 3000 men who never had a PSA >4 µg/L or an abnormal digital rectal examination, underwent prostate biopsy after seven years of follow-up.⁹ Overall, prostate cancer was detected in 15.2%, of which, 15% had high-grade disease (Gleason score of 7 or higher). The prevalence of prostate cancer was 6.6% in men with a PSA 0–0.5 µg/L, 10.1% in those with values of 0.6–1.0 µg/L, 17% in those with values of 1.1–2.0 µg/L, 23.9% in those with values of 2.1–3.0 µg/L and 26.9% in those with values of 3.1–4.0 µg/L. The prevalence of high-grade cancers increased from 12.5% of men with a PSA level of 0–0.5 µg/L to 25.0% of those with a PSA level of 3.1–4.0 µg/L. Clearly, based on this report, prostate cancer, including high-grade disease, is not uncommon among men with PSA levels <4.0 µg/L, the most frequently used cut-off value for this marker.

Table 1

Factors other than prostate cancer that may alter PSA levels

Benign diseases	Drugs	Preanalytical factors
BPH	Finasteride	Needle biopsy
Prostatitis	Dutasteroid	Transurethral resection
Urinary obstruction		DRE
		Ejaculation
		Rigid cystoscopy
		Ultrasound
		Vigorous bicycle riding
		Haemodialysis*
		Peritoneal dialysis*

BPH, benign prostatic hypertrophy; DRE, digital rectal examination

For review of above factors, see refs.^5,7,8

*Found to affect fPSA but not total PSA

While approximately 15% of asymptomatic men with a PSA <4 µg/L have prostate cancer detected by biopsy, most asymptomatic men with a PSA >4 µg/L do not have prostate cancer. This applies especially to men with PSA levels in the diagnostic grey zone of 4–10 µg/L. It was traditionally believed that in men with a PSA value of 4–10 µg/L, only about one in four had cancer confirmed by biopsy. However, more recent studies with extensive and repeat biopsies has shown that 35–40% of men with PSA levels in this grey zone have prostate cancer.^10–12 Thus, 60–70% of men with a PSA between 4 and 10 µg/L may undergo unnecessary biopsy or biopsies.

Rather than using a single cut-off point for PSA, Holmstrom et al. ¹³ investigated the sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of the marker at multiple cut-off points in predicting a subsequent diagnosis of prostate cancer. Although multiple cut-off points ranging from 0.5 to 20 µg/L were evaluated in this longitudinal study, none provided the necessary likelihood ratio formally required for a screening test. Thus, at the commonly used cut-off point of 4 µg/L, sensitivity was 44%, specificity was 92%, the positive likelihood ratio was 5.5 and the negative likelihood ratio was 0.61. These likelihood ratios are considerably lower than those usually considered to rule in disease, i.e. 10 or to rule out disease, i.e. 0.1.¹³

Because of the above limitation of PSA, several strategies have been investigated to improve its diagnostic accuracy for the early detection of prostate cancer (please see section ‘Attempts to improve the accuracy of PSA in detecting prostate cancer’).

PSA screening may result in overdetection of prostate cancer

A further reason as to why PSA screening is controversial is that it can lead to overdiagnosis and thus overtreatment. Overdiagnosis is the detection of latent malignancies that would not have been detected in the patient's lifetime in the absence of screening. Although overdiagnosis is also likely to occur with other screenings tests, it is a particular problem for prostate cancer. This is because of the large discrepancy between the prevalence of histological evidence of prostate cancer and its incidence in the absence of screening. Thus, autopsy studies show that 40% of 40-year-old men and 80% of 80-year-old men have histological evidence of prostate cancer.¹⁴ However, the lifetime risk of a prostate cancer diagnosis for a Caucasian man is only about 16% and the lifetime risk of dying from the disease is only about 3%.¹⁵ Thus, the majority of cancers found at autopsy would never become symptomatic during a man's lifetime.

A substantial number of these latent cancers, however, may be diagnosed as a result of PSA screening. Since in many situations it is not possible to identify the screen-detected cancers that have been overdiagnosed, many patients undergo unnecessary therapy which is associated with significant morbidity (please see section ‘Optimum therapy for men with localized prostate cancer is unknown’). Thus, the key consequence of overdiagnosis is overtreatment, which in turn, can cause side-effects such as impotence and incontinence and might even increase all-cause mortality.¹⁶

The proportion of overdiagnosed cancers depends on several factors including patient age, frequency of screening and definition of overdiagnosis. Using modelling studies, based on results from a PSA screening study, Draisma et al. ¹⁷ calculated that a single screen at 55 years of age resulted in an overdetection rate of 27%, while at age 75, it was 56%. With annual screening from age 55 to 67, the estimated overdetection rate was 50% and the lifetime risk of prostate cancer was increased by 80%. In the USA, it has been estimated that since the introduction of screening, an additional 1.3 million men have been diagnosed with prostate cancer that would not have been detected in the absence of screening.¹⁸

Optimum therapy for men with localized prostate cancer is unknown

The definitive or best therapy for patients with localized prostate cancer remains to be established. Possible options at present include radical prostatectomy, external beam radiotherapy, brachytherapy or active surveillance. Radical prostatectomy, external beam radiotherapy and brachytherapy are associated with severe and longstanding side-effects (for review, see refs^19,20). Active surveillance involves close monitoring of the patient with intervention only when signs of progression become evident.

In an attempt to compare the benefits of radical prostatectomy with surveillance, Bill-Axelson et al. ²¹ carried out a randomized study on 695 men with early prostate cancer. Routine follow-up of all patients occurred twice a year for the first two years and then annually. Transurethral resection was recommended in the control group as a treatment for local progression. After a median follow-up of 10.8 years, radical prostatectomy was found to reduce the formation of metastasis by 6.7% and to reduce death rates by 5.4%. However, the reduction in metastasis and death were confined to men <65 years of age. Overall mortality was not significantly different in the two arms.

As regards side-effects, erectile dysfunction (80% versus 45%) and urinary leakage (49% versus 21%) were more common after radical prostatectomy, whereas urinary obstruction (28 versus 44%) was less common. Bowel function, frequency of anxiety, depression and the subjective quality of life were similar in the two groups.²² As most of the prostate cancers in the above study were not detected following PSA screening, the relevance of the findings to screen-detected cancers is unclear.

Currently, a prospective trial (ProtecT) evaluating the comparative effectiveness of radical prostatectomy, radiotherapy and active monitoring in men with localized prostate cancer is ongoing in the UK.²³ The primary outcome of this trial is prostate-specific mortality at 10 years of follow-up. Secondary outcomes include overall mortality, quality of life and cost. Results are expected in 2016. Hopefully, this trial will finally resolve the debate surrounding the optimum treatment for men diagnosed with localized prostate cancer.

Preliminary results from screening trials are unequivocal

The gold-standard procedure for evaluating disease screening tests is a large randomized trial comparing disease-specific mortality in screened and non-screened control groups. Recently, Djulbegovic et al. ²⁴ carried out a systematic review of the literature and meta-analysis of such trials evaluating PSA as a screening test for prostate cancer. Six trials, containing a total of 387,286 participants that met inclusion criteria, were identified. These trials varied widely with respect to design, length of follow-up and number of men included. All had one or more substantial methodological limitation.

Meta-analysis showed that screening was associated with an increased probability (46%) of being diagnosed with prostate cancer. This increase was mainly due to a greater number of men being diagnosed with early (stage I) disease. Screening had no significant impact on the diagnosis of stages II, III and IV prostate cancer. Although some of the individual trials reported that screening reduced mortality from prostate cancer, the combined data showed that screening had no significant impact on deaths from either prostate cancer or from any cause.

Two of the trials included in the meta-analysis contained relative large number of subjects and are briefly discussed below. One of these large trials, i.e. the Prostate, Lung, Colorectal and Ovarian study was carried out in the USA.²⁵ In this trial, 76,693 men were randomized to either annual screening or standard care. PSA was measured at one centre using only the Hybritech/Beckman Coulter assay. The cut-off point used for PSA was 4 µg/L. After 7–10 years of follow-up, similar rates of death were found in the two groups. A limitation of this study was that approximately 50% of men in the control group underwent screening during the study. This trial might thus be regarded as a comparison between a heavily screened group and a less heavily screened group rather than a true randomized trial. A further limitation was that approximately 40% of the men participating had a PSA test prior to the start of the trial. These men were thus less likely to be diagnosed with prostate cancer during the trial proper.

In the European study (European Randomised Study for Screening of Prostate Cancer or ERSPC), 162,243 men were randomly assigned to PSA screening at an average of once every four years or to a control group not subjected to screening.²⁶ As with the American study, Hybritech/Beckman Coulter assays were used to measure PSA. In contrast to the American trial, in this study, 5/7 centres used a cut-off point of 3 µg/L for PSA, with the remaining two centres using a cut-off value of 4 µg/L. In the two centres, using 4 µg/L as a cut-off point, ancillary tests such as digital rectal examination and/or %fPSA were performed if PSA levels were 2.5/3.0–3.9 µg/L.

After a median follow-up of nine years, death rates from prostate cancer were found to be 20% lower in the screened compared with the control group. This difference in mortality barely reached statistical significance (rate ratio, 0.80; 95% confidence interval, 0.65–0.98; P= 0.04) and was restricted to men aged 55–69 years. This possible benefit, however, was associated with overdetection and overtreatment, i.e. the authors calculated that 1410 men would have to be screened and 48 additional cases of prostate cancer would have to undergo treatment to prevent one death from prostate cancer.²⁶ In a follow-up study that adjusted for non-attendance and contamination (i.e. PSA screening in the control group), the risk of dying from prostate cancer was reduced by 31% in the men actually screened.²⁷ A limitation of the European study was that variations in screening schedules, age of entry, ancillary tests and PSA cut-off points existed as the different sites. Thus, there was not a uniform approach to screening.

Attempts to improve the accuracy of PSA in detecting prostate cancer

Because of the limitations of PSA as a screening test for prostate cancer, a number of strategies have been attempted in order to improve its diagnostic accuracy (Table 2). Of the various strategies listed in Table 2, the most widely evaluated include measurement of %fPSA and PSA velocity (PSAV). The use of %fPSA and PSAV in the early detection of prostate cancer is now briefly discussed.

Table 2

Potential strategies for improving sensitivity and specificity of PSA

Strategy	Advantages/potential advantages	Disadvantages
%PSA	Can decrease number of biopsies, especially in men with PSA levels 2.5/4–10 µg/L. Reasonably well validated	Only useful at extreme values. fPSA is labile in serum
cPSA	More stable in vitro than fPSA	Less widely studied compared with %fPSA. Not in widespread clinical use
PSAV	Potentially useful in prognosis as well as early detection	Does not add independent predictive information. Standardized method not available for its measurement. Optimum cut-off point unknown. As several PSA measurements are required, information may be too late for early diagnosis
PSAD	Attempts to correct for the effect of prostate volume on PSA levels. Can potentially reduce number of negative biopsies in men with PSA levels 4–10 µg/L	Requires ultrasound that is costly and operator dependent. Optimum cut-off value unclear
Age-related reference ranges	Increases sensitivity for young men and increases specificity for older men	May result in missing cancer in older men. May overdetect ‘insignificant’ cancers in some younger men
Measurement of new markers*	Potentially decrease number of biopsies, especially in men with PSA levels 2.5/4–10 µg/L	No marker apart from PSA is adequately clinically validated for clinical use

PSAV, PSA velocity; PSAD, PSA density (obtained by dividing serum PSA by prostate volume)

Data summarized from refs^7,28–30

*See Table 3

Percent fPSA

As mentioned above, approximately 10–30% of PSA in blood exists in a free form, i.e. does not form complexes with protease inhibitors. Although measurement of the absolute level of fPSA does not appear to have diagnostic utility, the ratio of free to total or %fPSA can be helpful, especially in men with borderline total PSA (tPSA) levels. For men with PSA levels 4–10 µg/L, %fPSA can increase specificity, whereas for men with PSA levels 2.5 to 4 µg/L, %fPSA can increase sensitivity.³¹

Most of the studies involving %fPSA contained small numbers of patients and were retrospective in design. Roddam et al. ³² carried out a systematic review of the literature on these studies published between January 1986 and December 2004. In total, 66 eligible reports were identified. Meta-analysis showed that %fPSA improved diagnostic performance in men with a tPSA of 2–4 µg/L or 4–10 µg/L compared with tPSA alone. As might be expected, the diagnostic performance of %fPSA was significantly better for men with tPSA between 4 and 10 µg/L than for men with tPSA between 2 and 4 µg/L. Overall, use of %fPSA can potentially reduce the number of unnecessary prostate biopsies by 25–40% for men with tPSA levels 4–10 µg/L.^32,33 A small number of cancers (approximately 10%), however, may be missed. %fPSA is most useful at low and high values. Thus, men with a %fPSA value <10% have a greater than 50% probability of being diagnosed with prostate cancer, whereas those with a value >25% have a less than 10% chance of being diagnosed with prostate cancer.^32,33

The potential value of %fPSA in population-based screening for prostate cancer was evaluated prospectively in almost 18,000 men with a tPSA level <3 µg/L.³⁴ During a median follow-up of 5.8 years, men with a %fPSA in the lowest quartile (<14.2%) had a seven-fold risk of being diagnosed with prostate cancer compared with men in the highest quartile group (>23.7%). Importantly, 27% of the tumours detected could be regarded as high risk based on tumour grade and stage.

According to the National Academy of Clinical Biochemistry guidelines ‘the use of %fPSA is recommended as an aid in distinguishing prostate cancer from BPH, when the total PSA levels in serum are in the range of 4–10 µg/L and DRE is negative.’³⁵ A similar recommendation has been published by the European Group on Tumor Markers (EGTM).³⁶ It is important to state that the fPSA and tPSA should be measured using kits obtained from the same supplier.

One of the problems in using %fPSA in the detection of prostate cancer is selecting the optimum cut-off point. Indeed, there is no universally accepted cut-off point for %fPSA. Rather, there is a continuum of risk, the lower the %fPSA, the greater the probability of prostate cancer. A second problem is analyte instability at room temperature.³⁷ According to the National Academy of Clinical Biochemistry guidelines,³⁵ serum for fPSA can be stored at refrigerated temperatures for up to 24 h. Samples not analysed within 24 h of collection should be stored frozen at −20°C or lower. For long-term storage, freezing at −70°C was recommended.

PSA velocity

A further attempt to increase the accuracy of PSA for the detection of early prostate cancer involves the measurement of PSAV. PSAV measures the rate of change in PSA levels over time. It is normally expressed as µg/L/y. Several studies have shown that men with rapidly increasing PSAVs are at a higher risk of developing prostate cancer than those with low PSAV.^38–42 As pointed out by O'Brien et al.,⁴¹ most of these reports had deficiencies. Firstly, in many of the studies, it was assumed that men who were not biopsied had no cancer. Secondly, some assumed that there was a linear relationship between PSAV and cancer risk. Thirdly, many reports did not establish if PSAV added independent information to existing predictors.

In an attempt to address this latter point, O'Brien et al. ⁴¹ carried out a systematic review of the literature on studies relating PSAV to prostate cancer risk. Based on a review of 64 studies identified, the authors concluded that there was little evidence that measurement of PSAV in untreated men provided predictive information beyond that available from PSA alone. Similarly, in a larger population-based screening trial, it was found that PSAV only marginally enhanced the predictive accuracy of a baseline models including absolute PSA levels and patient age or PSA levels, %fPSA and patient age (area under the curve of 0.569 versus 0.531 and 0.626 versus 0.609, respectively).⁴²

A major problem with PSAV is lack of a standardized method for its determination. For example, it is unclear as to how many PSA levels should be used in its calculation or the time interval between successive measurements. It should also be borne in mind that PSA exhibits a relatively wide intra-individual biological variation. For men >50 years of age with a PSA level between 0.1 and 20, the estimated biological variation is 20%.⁴³ Combining this biological variation with an analytical variation of approximately 5%, suggests that baseline PSA levels have to change by >50% to be significant at P < 0.05.⁴⁴ Finally, it is also unclear as to the optimum PSAV value for separating men at low and high risk.

Despite the limitations associated with PSAV, a number of expert panels including the National Cancer Center Comprehensive Network⁴⁴ and the National Academy of Clinical Biochemistry³⁵ recommend its use in the early detection of prostate cancer.

Emerging markers for prostate cancer

In recent years, several new markers have been proposed for prostate cancer (Table 3).

Table 3

Emerging/potential markers for prostate cancer..

Marker	Type of molecule	Measurement fluid	Ref.
PCA3	RNA	Urine	45,46
−2proPSA	Protein	Serum	47,48
KLK-2	Protein	Serum	49,50
TMPRSS2-Ets fusion mRNA	DNA/RNA	Tumour tissue/urine	51,52
EPCA-2*	Protein	Serum	53,54
Methylated GSTP1 gene	DNA	Tumour tissue/serum/urine	55

PCA, prostate cancer antigen; KLK, kallikrein; EPCA, early prostate cancer antigen; GSTP, glutathione-S-transferase P

*Findings with EPCA-2 have not been confirmed

Of these, PCA3 and −2proPSA are the most widely investigated.^45–48 The main potential use of these new markers is likely to be in enhancing the diagnostic accuracy in men with tPSA values between 2.0 or 2.5 and 10 µg/L. It is still, however, unclear as to which of the markers listed in Table 3 best complements PSA in this grey zone. None of these emerging markers have yet undergone evaluation in large-scale population-based screening trials.

Conclusion

Based on available evidence, it is unclear as to whether PSA screening of asymptomatic men for prostate cancer does more harm than good. It is therefore not surprising that guidelines published by different expert panels vary in their recommendations regarding PSA screening.^{35,36,44,56–59} Although differences exist, many expert panels currently recommend a shared approach to decision-making between patient and doctor. Thus, in the UK, the Prostate Cancer Risk Management Programme state ‘that men who are concerned about the risk of prostate cancer receive clear and balanced information about the advantages and disadvantages of the PSA test and treatment for prostate cancer’.⁵⁸ To aid this, information leaflets were sent to general practitioners to assist them in the counselling of men who ask about PSA testing.

A somewhat similar approach exists in the USA, where the American Cancer Society (ACS) recommends that ‘asymptomatic men who have at least a 10-year life expectancy have an opportunity to make an informed decision with their health-care provider about screening for prostate cancer after they receive information about the uncertainties, risks, and potential benefits associated with prostate cancer screening’.⁵⁹ According to the ACS, men at average risk should receive this information beginning at age 50 years. Men in higher risk groups should receive this information before age 50 years. Men should either receive this information directly from their health-care providers or be referred to reliable and culturally appropriate sources.

Uncertainty regarding the value of PSA screening is likely to continue for a number of years. Indeed, it is clear from Table 4 that the use of PSA in screening for prostate cancer still lacks some of the World Health Organization criteria for disease screening. Hopefully, updated results for the ongoing randomized controlled trials mentioned above will provide clearer information regarding benefit–risk ratio of the process. For the present therefore, an informed and shared decision-making approach is a reasonable way forward.

Table 4

How PSA testing for prostate cancer meets World Health Organization criteria for disease screening

Criteria	Criteria met	Comment
The condition sought should be an important health problem for the individual and community	Yes	Prostate cancer is one of the most common male cancers and a major cause of death
There should be an accepted treatment or useful intervention for patients with the disease	No	Best treatment for men with localized prostate cancer is unclear
The natural history of the disease should be adequately understood	No	The prognosis of men with newly diagnosed prostate cancer is highly variable. Factors responsible for this variability are poorly understood
There should be a latent or early symptomatic stage	No	A specific high-risk premalignant lesion for prostate cancer has not been identified
There should be a suitable and acceptable screening test or examination	Partially	PSA is less than an ideal screening test for prostate cancer. It is, however, well accepted
Facilities for diagnosis and treatment should be available	Partially	Implementation of a population-based screening strategy would require a substantial increase in resources
There should be an agreed policy on whom to treat as patients	No	Difficult to differentiate indolent from life-threatening cancers
Treatment started at an early stage should be of more benefit than treatment started later	Unknown	The benefit of early treatment over late treatment has not yet been investigated in a large randomized trial or at least results have not been published
The cost should be economically balanced in relation to possible expenditure on medical care as a whole	Unknown	Little data available on the cost of a population-based screening programme and follow-up care

DECLARATIONS

Competing interests: None.

Funding: None.

Ethical approval: Not relevant.

Guarantor: MJD.

Contributorship: MJD researched the literature, conceived and wrote the manuscript.

Acknowledgements: None.

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Prostate-specific antigen: does the current evidence support its use in prostate cancer screening?

Abstract

Introduction

Structure and biological function

Use of PSA in screening for prostate cancer

PSA is a less than an ideal marker in screening for prostate cancer

PSA screening may result in overdetection of prostate cancer

Optimum therapy for men with localized prostate cancer is unknown

Preliminary results from screening trials are unequivocal

Attempts to improve the accuracy of PSA in detecting prostate cancer

Percent fPSA

PSA velocity

Emerging markers for prostate cancer

Conclusion

DECLARATIONS

References