Prostate cancer risk management programme (PCRMP): benefits and risks of PSA testing

Published 29 March 2016

1. Background

The purpose of this guidance is to help primary care teams give asymptomatic men information about the potential benefits, limitations and implications of having a prostate specific antigen (PSA) test for prostate cancer. It provides background information about the diagnosis and treatment of prostate cancer and outlines the issues surrounding the use of the PSA test.

In 2002, more than 100 GPs and primary care cancer leads and an expert multidisciplinary group set up by the Department of Health were consulted before the publication of the first edition of this guidance. The second edition was subsequently published in 2010 1.

The Prostate Cancer Risk Management Programme (PCRMP) commissioned this third edition in 2015 based on the recent UK National Screening Committee (UK NSC) evidence review for prostate cancer screening2 which incorporates information from research developments and the recommendations of the National Institute for Health and Care Excellence (NICE) in the Prostate cancer: diagnosis and treatment guidelines3. It was reviewed by GPs and members of the PCRMP scientific reference group prior to publication.

Accompanying summary information sheets for men and GPs can also be downloaded and printed out.

The overall benefits of prostate cancer screening remain uncertain but there have been considerable advances in our understanding while reviewing the emerging evidence.

2. Introduction

Prostate cancer is the most common cancer in men in the UK4. The PSA test is the most commonly used test that can lead to the diagnosis of localised prostate cancer for which potentially curative treatment can be offered. Increased PSA levels may be associated with a raised probability of prostate cancer.

Not all men with increased PSA levels have cancer. Some will have low-risk disease (a relatively indolent tumour) that is unlikely to progress or require treatment. The low specificity of the PSA test has led to harms of overdiagnosis and overtreatment in up to 50% of men5. There have been considerable advances in our understanding of prostate cancer but currently there is no evidence that the overall benefits of a PSA-based screening programme would outweigh the harms2.

3. Informed choice

The PCRMP aims to help primary care give clear and balanced information to asymptomatic men who ask about testing for prostate cancer. The PSA test is available free to any man aged 50 or over who requests it, after careful consideration of the implications. GPs should not proactively raise the issue of PSA testing with asymptomatic men.

Before men who are concerned about their risk of prostate cancer make a decision about whether or not to have a PSA test, they should be given information about the advantages and disadvantages of the PSA test, biopsy and treatments for prostate cancer. This means men can make informed decisions about whether or not to have a PSA test.

Potential advantages of having a PSA test for an individual include knowing his PSA level and finding cancer at an early stage. There are also potential disadvantages to being tested. The man’s personal preferences are an important factor in the decision.

Decisions about whether or not to have a PSA test will vary between individuals, based on:

  • being at higher than average risk of prostate cancer (having a family history of prostate cancer or being of black ethnicity)

  • fear of cancer

  • consequences, such as anxiety of being diagnosed with a disease that is unlikely to become symptomatic

  • potential impact of treatment complications on quality of life

  • understanding of the scientific evidence

Despite the uncertainties, many men still want the PSA test because it is seen as “just another blood test” or as responsible health behaviour to prevent prostate cancer6. Some men may accept PSA testing without clearly understanding the potential harms6 7.

A study of GPs showed variation in the amount of information given to the patient. A full and balanced view of potential harms and benefits may not always be conveyed8. Men who need further investigation after a PSA test may often experience increased anxiety, regret and uncertainty, even if they receive a “normal” result7.

In a randomised controlled trial, approximately 1,000 men aged 40 to 75 in selected practices in England and Wales were randomised to receive either a patient decision aid that provided balanced information about the potential benefits and limitations of the PSA test (intervention) or no patient decision aid (controls). The men who received the decision aid had improved knowledge of the PSA test and less positive attitudes towards the test9.

4. Incidence and mortality

Prostate cancer is the most common cancer in men, representing about a quarter of all new male cancer diagnoses in the UK4. It is the second most common cause of cancer-related deaths in men in the UK. In 2013, 47,300 men were diagnosed with prostate cancer4 and, in 2012, 10,837 men died from the disease 10. The age-standardised incidence rate is 182 new prostate cancer diagnoses per 100,000 men in the UK population4. The mortality rate is substantially lower at about 23 deaths per 100,000 men10.

Incidence and mortality are significantly higher in:

  • black men11

  • men with a family history of prostate cancer12 13

  • men who are overweight or obese (specifically for advanced prostate cancer)14

Prostate cancer is strongly associated with increasing age15.

Figure 1. Average number of new cases of prostate cancer per year and age-specific incidence rates for men in the UK, 2011-2013
Figure 1. Average number of new cases of prostate cancer per year and age-specific incidence rates for men in the UK, 2011-2013

Diagnosis is less common below the age of 50 (Figure 1 4). The most common age to be diagnosed is 65 to 69 years and the highest mortality rate is seen in the 85 and older age group.

The number of deaths by age in 2012 is shown in Figure 2 10.

Figure 2. Average number of deaths per year and age-specific mortality rates per 100,000 population in the UK, 2010-2012 [^10]
Figure 2. Average number of deaths per year and age-specific mortality rates per 100,000 population in the UK, 2010-2012

The number of prostate cancer cases has risen steadily since 19754 16.

Reasons include:

  • ageing population

  • improved ascertainment by cancer registries leading to increased diagnostic accuracy

  • additional methods of detecting prostate cancer, including an increase in the use of the PSA test

  • increase in ultrasound guided biopsies in men with raised PSA levels

Early detection and treatment may reduce mortality from prostate cancer. The European Randomized Study of Screening for Prostate Cancer (ERSPC), the largest randomised trial of PSA testing for prostate cancer, found a significant reduction in risk of death from prostate cancer by 21% after 13 years of follow-up17.

Reasons include:

  • ageing population

  • improved ascertainment by cancer registries leading to increased diagnostic accuracy

  • additional methods of detecting prostate cancer, including an increase in the use of the PSA test

  • increase in ultrasound guided biopsies in men with raised PSA levels

5. Natural history of prostate cancer

The natural history of prostate cancer is not fully understood. The underlying mechanisms that influence cancer development are under investigation. Prostate cancer develops in the following stages:

  • initiation

  • diagnosis by screening

  • diagnosis by clinical symptoms

  • clinically detectable metastatic disease

  • death

Treatment and management of prostate cancer is difficult due to the broad spectrum of the disease, which is defined by the rate of tumour growth observed. For instance, slow-growing ‘clinically insignificant’ tumours in asymptomatic men are unlikely to progress or require treatment. Rapidly growing ‘clinically significant’ tumours have the potential to progress and metastasize. It is not known why some tumours are more aggressive.

6. Risk factors for prostate cancer

There is often increased anxiety amongst men with factors that put them at higher than average risk of prostate cancer. If these men present in primary care, it is important they receive the best available information and support to help them decide whether or not to have a PSA test.

In the UK, about 1 in 8 men will get prostate cancer at some point in their lives11. Factors that increase a man’s risk include:

  • increasing age

  • black ethnicity

  • family history of prostate cancer

  • being overweight or obese (specifically advanced prostate cancer)

These risk factors suggest potentially different clinical management strategies.

6.1 Age

Prostate cancer mainly affects men over the age of 50 and risk increases with age. Autopsy studies have shown that prostate cancer can have a long latent period and men show evidence of cancer cells in their prostate as early as in their 20s and 30s 18 19. By the age of 80, about 80% of men will have evidence of cancer cells in their prostate. However, only 2 in 50 of all men will die from prostate cancer, which supports the evidence that men are more likely to die from other causes rather than from prostate cancer10 18.

6.2 Ethnicity

Men of black ethnicity are at greater risk of prostate cancer than men of white ethnicity, while Asian men have a lower risk. The lifetime risk of being diagnosed with prostate cancer is 1 in 4 for black men compared to 1 in 8 for white men11. The UK PROCESS (Prostate Cancer in Ethnic Subgroups) Study showed black men present about 5 years younger and are more likely to have higher PSA on presentation, compared to white men20 21 22. A number of biological 23 24 25 or genetic factors 26 27 28 may explain the higher frequency of disease in black men. However, the evidence is inconclusive and further investigation is needed before understanding its usefulness in genetic screening.

To date, there is no evidence screening black men at high risk for the disease will reduce their risk of prostate cancer-related death2.

6.3 Family history and genetics

Studies dating back to the 1950s show family history is a risk factor for prostate cancer29. Overall lifetime risk of prostate cancer according to family history is summarised in Table 1 30 . A man without a family history has an absolute lifetime risk of prostate cancer of 8%. This risk increases to 12% if the father was affected at age 60 or above. The risk increases as the number of relatives affected by prostate cancer increases and if the relative was affected before age 60.

Table 1. Effect of family history of prostate cancer on lifetime risk of prostate cancer30

Family history Lifetime risk
No history 8%
Father with prostate cancer at ≥ 60 years 12%
One brother affected at ≥ 60 years 15%
Father affected before 60 years 20%
One brother affected before 60 years 25%
Two male relatives with prostate cancer* 30%
Three or more affected male relatives 35 to 45%

*Father and brother, or two brothers, or a brother and a maternal grandfather or uncle, or a father and a paternal grandfather or uncle

About 5-10% of all prostate cancers diagnosed are associated with hereditary genetic mutations31 32. There is some evidence that some men with these genetic mutations are particularly susceptible to early onset of disease (age ≤50)33 34. It is unclear to what extent these genetic mutations cause disease. Data shows men with early onset of disease are more likely to die from prostate cancer than older men with similar clinical diagnoses35, particularly those with high grade or locally advanced disease.

6.4 Obesity and diet

A 2014 review from the World Cancer Research Fund and the American Institute for Cancer Research summarises the level of evidence available linking diet, nutrition and physical activity risk factors with prostate cancer. See Table 2 14.

There is increasing evidence linking overweight and obesity with advanced prostate cancer14. With a quarter of men in the UK considered obese (24%)36 and prostate cancer being the most common cancer in men, the association raises an important public health concern. The biological mechanisms are thought to be related to lower levels of testosterone in obese men, which lower their risk of localised non-aggressive tumours but increase their risk for more aggressive tumours. As well as being at higher risk for more aggressive tumours, obese men are more prone to treatment failure and complications, and prostate cancer-related deaths37 38 39. Men have a 15 to 20% increased risk of dying from prostate cancer with every 5 kg/m2 increase in BMI39. Although obesity is a modifiable risk factor, little data exists on the effectiveness of weight loss or exercise interventions to reduce prostate cancer risk40 41 42.

There is strong evidence to show that there is no association between consumption of beta-carotene in food or supplements and prostate cancer14.

There is limited evidence that consumption of dairy products and diets high in calcium are associated with an increased risk of prostate cancer. In a meta-analysis of 45 observational studies, there was no association between dairy or milk intake and risk of prostate cancer43. However, in a meta-analysis of 13 cohort studies, the relative risk of prostate cancer increased by 13% when comparing the highest with the lowest quintile of milk consumption44.

There is limited evidence that consumption of high plasma alpha-tocopherol concentrations reduces the risk of prostate cancer. In a review of 17 studies, the relative risk of prostate cancer fell by 1% for any prostate cancer and 2% for aggressive prostate cancer per 1mg/ml of serum alpha-tocopherol14.

The selenium and vitamin E cancer prevent trial (SELECT) study did not identify an association between selenium and prostate cancer risk45 46. However, the US Nutritional Prevention of Cancer Trial, a randomised controlled trial of selenium (intervention) vs. yeast (placebo), found after 7.5 years of follow-up that the relative risk of prostate cancer decreased by 49%47. The summarised evidence suggests that the link between selenium and prostate cancer risk is limited.

Table 2. WCRF/AICR evaluation of endogenous prostate cancer risk factors (reproduced from the World Cancer Research Fund International and the American Institute for Cancer Research Continuous Update Project Report: Diet, Nutrition, Physical Activity, and Prostate Cancer. 2014) 14

Factors that increase prostate cancer risk

Level of evidence  
STRONG EVIDENCE: probable Body fatness (BMI, waist circumference and waist-hip ratio) for advanced prostate cancer only, adult attained height (likely due to genetic, environmental, hormonal and nutritional factors)
LIMITED EVIDENCE – suggestive Dairy products, diets high in calcium, low plasma alpha-tocopherol concentrations, low plasma selenium concentrations

Factors that decrease prostate cancer risk

Level of evidence  
LIMITED EVIDENCE – no conclusion Cereals (grains) and their products, dietary fibre, potatoes, non-starchy vegetables, fruits, pulses (legumes), processed meat, red meat, poultry, fish, eggs, total fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, plant oils, sugar (sucrose), sugary foods and drinks, coffee, tea, alcoholic drinks, carbohydrate, protein, vitamin A, retinol, alpha carotene, lycopene, folate, thiamine, riboflavin, niacin, vitamin C, vitamin D, vitamin E supplements, gamma-tocopherol, multivitamins, selenium supplements, iron, phosphorous, calcium supplements, zinc, physical activity, energy expenditure, vegetarian diets, Seventh-day Adventist diets, individual dietary patterns, body fatness (non-advanced prostate cancer), birth weight, energy intake
STRONG EVIDENCE – substantial effect on risk unlikely Beta-carotene

7. Clinical features

7.1 Localised prostate cancer

Localised prostate cancer (confined within the capsule) is usually asymptomatic. Prostate cancers, unlike benign prostatic enlargement (BPE), tend to develop in the outer part of the prostate gland. It is unusual for these early cancers to cause any symptoms, but they may be palpable by digital rectal examination (DRE). Localised cancers range from just a few cells to more extensive disease that is considered ‘clinically important’.

7.2 Locally advanced prostate cancer

These cancers have extended outside the prostatic capsule and are also frequently asymptomatic.

7.3 Metastatic prostate cancer

Metastases may be the first sign of prostate cancer, which frequently metastasises to the bones, causing pain. Appearance on x-ray is usually a sclerotic lesion. Although the majority of men with metastatic prostate cancer die from the disease, it does respond well to hormonal therapy, which often keeps it controlled for several years. About 1 in 3 men (30%) with metastatic disease will live for at least 5 years after diagnosis48.

7.4 Lower urinary tract symptoms and prostate cancer

Lower urinary tract symptoms (LUTS) are common in older men. It is important to realise that early prostate cancer itself will not usually produce symptoms and that LUTS (frequency, urgency, hesitancy, terminal dribbling and/or overactive bladder) are usually related to the presence of BPE rather than prostate cancer49. Between 70% and 80% of prostate tumours originate in the peripheral zone of the gland distant from the urethra50 51. As a result, by the time prostate cancer itself causes LUTS, it may have reached an advanced and incurable stage. Due to the high coincidence of BPE and prostate cancer in the older age group, some men will have a benign pathology and a co-existing early prostate cancer 52 53. When a man seeks advice about LUTS this can lead to investigations which diagnose what is a coincidental prostate cancer.

7.5 Referral guidance for prostate cancer

According to the NICE Suspected Cancer: recognition and referral guideline (NG12)54:

  • refer men using a suspected cancer pathway referral (for an appointment within 2 weeks) for prostate cancer if their prostate feels malignant on DRE.

  • consider a PSA test and DRE to assess for prostate cancer in men with any of the following:

    • any LUTS, such as nocturia, urinary frequency, hesitancy, urgency or retention

    • erectile dysfunction

    • visible haematuria

  • refer men using a suspected cancer pathway referral (for an appointment within 2 weeks) for prostate cancer if their PSA levels are ≥3 ng/mL2. More details on the new recommended value for referring asymptomatic men can be found in section 9.4 below.

8. Prostate cancer diagnosis

The NICE clinical guideline 175 3 outlines the recommended guidelines for diagnosis and treatment of prostate cancer.

The following procedures are commonly used as diagnostic tests for prostate cancer:

  • prostate-specific antigen (PSA) test

  • digital rectal examination (DRE)

  • transrectal ultrasound (TRUS)

  • TRUS-guided prostate biopsy and histology

  • magnetic resonance imaging (MRI) scan

9. The PSA test

The PSA test should not be added to a list of investigations without a careful explanation of why it is being performed and its implications.

PSA is a glycoprotein responsible for liquefying semen and allowing sperm to swim freely. It is expressed in both benign and malignant processes involving epithelial cells of the prostate. Due to an alteration in the architecture of the prostate in conditions such as prostatitis and BPE, as well as prostate cancer, PSA leaks out, leading to increased levels in the bloodstream.

Men who have a PSA test increase their chance of a prostate cancer diagnosis. The PSA test provides the opportunity for clinically relevant prostate cancer to be diagnosed at a stage when treatment options and outcome may be improved. However, the PSA test may lead to investigations which can diagnose clinically insignificant cancers which would not have become evident in a man’s lifetime.

The most commonly used PSA test measures the total amount of prostate-specific antigen. The PSA test is currently the best method of identifying an increased risk of localised prostate cancer. However, PSA is an enzyme also found in men without prostate cancer.

9.1 Test benefits

Potential benefits of having a PSA test include:

  • it may lead to the detection of cancer before symptoms develop

  • it may lead to the detection of cancer at an early stage when the cancer could be cured or treatment could extend life

  • repeat PSA tests may provide valuable information, aiding a prostate cancer diagnosis

9.2 Test limitations or risks

Potential limitations or risks of having a PSA test include:

  • the PSA test is not diagnostic: those with an elevated PSA level may require further investigation, possibly a TRUS-guided prostate biopsy (see section 9.7) and histology to confirm the presence of prostate cancer

  • PSA is not tumour specific in the prostate 55. PSA levels can increase due to a number of other factors:

    • BPE

    • older age – PSA levels normally increase with age

    • prostatitis – infection or inflammation of the prostate gland

    • ejaculation – may increase PSA levels for a short time

  • lower PSA levels can be influenced by factors such as drugs containing 5-alpha-reductase inhibitors (such as finasteride or dutasteride)56, aspirin, statin, thiazide diuretics57. Obese men also have lower levels of PSA58

  • the PSA test may give false-positive results. A man may have an elevated PSA level but have no cancer. About 75 out of every 100 men who have an elevated PSA level have a false-positive result 59

  • the PSA test result may not be elevated and provide false reassurance. One study has shown that approximately 15% (1 in 7) of all men with a ‘normal’ PSA level may have prostate cancer, and 2% (1 in 50) will have high-grade cancer, although it is not known how many of these would have become clinically evident in a man’s lifetime 60. This is due to the poor sensitivity and specificity of the PSA test 61. A one-off test is therefore not reliable enough to provide reassurance

  • the PSA test may lead to the identification of prostate cancers which might not have become clinically significant in the man’s lifetime

  • a single PSA test will not distinguish between aggressive tumours which are at an early stage but will develop quickly and those which are not, but further tests may provide valuable information

9.3 Test practicalities

Before having a PSA test, men should not have:

  • an active urinary infection (PSA may remain raised for many months)

  • ejaculated in the previous 48 hours

  • exercised vigorously in the previous 48 hours

  • had a prostate biopsy in the previous 6 weeks

Before performing a PSA test, the conditions above should be met in order to ensure that, where possible, a raised PSA result is the result of prostate cancer, not a confounding physical condition62.

Evidence indicates PSA is stable in whole blood for up to 16 hours at room temperature. When taking blood you should ensure that the specimen will reach the laboratory and be separated within this time frame. The quality of PSA testing can vary between laboratories, depending on the type of PSA test employed.

9.4 Referral guidance

In 2008, the PCRMP recommended age-related referral values1. An updated review of the literature shows that age-specific PSA cut-offs for detecting prostate cancer are highly variable and may reflect differences in demographics and clinical characteristics in a population2.

In addition to the wide-ranging PSA reference levels that exist in the literature, there is a wide range of referral practice throughout the UK1. Before a consensus can be found, the previously recommended age-related referral values by the programme have been reconsidered1. This is due to the concern of missing a high proportion of clinically significant cancers in older men (low sensitivity) and the potential increased rate of unnecessary biopsies in younger men (low specificity).

The two largest randomised PSA-based screening trials – ERSPC17 and Prostate, Lung, Colorectal and Ovarian Cancer (PLCO)63 – have evaluated PSA testing among men aged 55-69 years with biopsy indication among those with PSA ≥3.0 ng/mL. Recommended prostate biopsy referral values are being realigned to the evidence emerging from these two trials.

The new recommended referral value for men aged 50-69 is 3ng/mL2. Further diagnostic evaluation should consider the man’s history of comorbidities, ethnicity, family history and abnormal DRE findings prior to biopsy.

The serum PSA level alone should not automatically lead to a prostate biopsy. Other factors that should be considered in conjunction with the PSA level are:

  • prostate size

  • DRE findings

  • age

  • ethnicity

  • family history of prostate cancer

  • body weight/BMI

  • co-morbidities

  • history of any previous negative biopsy

  • any previous PSA history

The patient should be involved in any decision about referral to another healthcare provider.

9.5 Digital rectal examination (DRE) of the prostate

The DRE is a useful diagnostic test for men with lower urinary tract symptoms or symptoms suggestive of advanced disease. Symptoms for both conditions are the same (not very specific). The DRE cannot be used solely to diagnose prostate cancer. DRE should be used in combination with PSA testing.

The DRE allows assessment of the prostate for signs of prostate cancer (a hard gland, sometimes with palpable nodules) or benign enlargement (smooth, firm, enlarged gland). However, a gland that feels normal does not exclude a tumour. Most prostate cancers are located in the peripheral zone of the prostate and may be detected by DRE when the volume is about 0.2 ml or larger.

Men should be referred (for an appointment within 2 weeks) for suspected prostate cancer if their prostate feels malignant on DRE54.

9.6 Transrectal ultrasound (TRUS)

TRUS can be used to examine the prostate and determine its size accurately but its main value is in enabling precise needle placement in the prostate during systematic prostate biopsy. It is not reliable enough to exclude prostate cancer and should not be used to screen asymptomatic men.

9.7 TRUS-guided prostate biopsy and Gleason score

Prostate cancer diagnosis is confirmed using a needle biopsy in the UK. A TRUS biopsy involves taking 10 to 12 cores of prostatic tissue through the rectum under ultrasound guidance64. A series of biopsies is taken in a systematic manner and additional biopsies may be taken if a lesion is seen. If a tumour is detected, histological examination reveals how well the tumour is differentiated. Tumour differentiation is graded by a Gleason score, by analysing the most common and second most common tumour patterns. Each tumour pattern is assigned a grade (1 to 5) and these grades are combined to produce the Gleason score (2 to 10). The lower the score, the better differentiated the tumour, the less likely it is to progress and the better the prognosis. Tumours can be classified into three categories on the basis of their Gleason score: low (≤6), intermediate (=7) and high grade (8 to 10). The sensitivity of detecting clinically significant prostate cancer (Gleason>6) using 12-core biopsy is 80%65. This suggests that about one in five prostate cancers (Gleason >6) are missed on TRUS biopsy and may require additional diagnostic evaluation if symptoms persist and PSA levels continue to increase.

As with other medical procedures, the biopsy procedure can cause significant anxiety. Most men describe the biopsy as an embarrassing, uncomfortable experience and some describe it as painful (although this should be alleviated by use of local anaesthetic).

Benefits of having a biopsy include:

  • it can find cancer before symptoms develop

  • it can identify cancerous tissue and identify the grade of tumour

  • a negative biopsy result can relieve anxiety about prostate cancer, although a second biopsy may be necessary if recommended by the multidisciplinary team, particularly if the PSA level remains elevated

  • the diagnosing capability of the biopsy procedure increases with the number of cores taken

Limitations of having a biopsy include:

  • post-biopsy complications include bleeding and infection66

  • up to 45% of tumours are missed at biopsy (false negatives)67 68 69, although the number of tumours missed at biopsy decreases as the number of cores taken increases

  • diagnosis of prostate cancer that is not clinically significant may have a significant impact on the patient. The patient may experience increased anxiety

  • management of men with a negative biopsy but a persistently elevated PSA level is very difficult. Prolonged periods of follow-up, with the possibility of re-biopsy, may cause considerable anxiety

9.8 Magnetic resonance imaging (MRI)

False negative rates associated with TRUS-guided biopsy can be as high as 45%67 68 69. Up to half of men who are initially diagnosed with low-risk disease are under-staged and actually have a higher burden of high-risk disease68 70 71 72 73 74 75. However, diagnosis and staging of disease has the potential to improve with MRI before prostate biopsy3. MRI is a non-invasive test that uses a powerful magnetic field, radio frequency pulses and a computer to provide a detailed image of the prostate. Lesions seen on a pre-biopsy MRI can be used to select appropriate targets for TRUS-biopsy and may add additional information that can assess what treatment should be used to manage patients with low and intermediate risk.

Triage of men with clinical suspicion of prostate cancer (elevated PSA and abnormal DRE) to MRI prior to prostate biopsy could be more specific in selecting those with clinically significant cancer that requires treatment. This strategy could reduce the number of men with clinically insignificant disease who undergo unnecessary biopsy and treatment. This would also reduce the rate of complications that could interfere with accurate disease staging and improve disease risk stratification to manage appropriate treatment with active surveillance or radical therapies.

NICE guidelines3 recommend that men who are negative on TRUS 10 to 12 cores biopsy should be further evaluated with multiparametric MRI (mpMRI) to consider whether a repeat biopsy with targeted biopsy is needed. mpMRI provides better visualisation of the prostate to detect clinically significant prostate cancer76. However, it has lower accuracy in detecting smaller tumours with low grade disease77. If the man is negative on mpMRI, then another biopsy should not be offered unless they are positive for other risk factors. Evidence suggests this strategy will reduce the number of repeat biopsies required compared to routine systematic TRUS re-biopsy.

10. The future of prostate cancer detection

The PSA test is the best test currently available for prostate cancer, but there are concerns about its accuracy. There has been much debate about how it can be improved to provide a more reliable detection procedure, as well as a method of differentiating between indolent and aggressive cancers. A number of additional PSA tests, risk prediction models, and screening and triage biomarkers are under investigation to improve prostate cancer detection.

10.1 Reflex testing with PSA isoforms

A total PSA test has poor specificity. Studies have suggested that reflex testing with PSA isoforms, such as ratio of free to total PSA (f/tPSA) or complex PSA (cPSA), for men with PSA values <10 ng/mL (known as the diagnostic “grey zone”) could improve specificity and reduce the number of unnecessary biopsies. Studies suggest that triage of men in the “grey zone” with tPSA 2 to 10 ng/ml using PSA isoforms could potentially reduce overdiagnosis and maintain a high cancer detection rate78.

10.2 Risk prediction models

Risk prediction models have developed in recent years to help clinicians and patients predict prostate cancer diagnosis, stage and prognosis. These models aim to improve the accuracy of screening to detect prostate cancer. Besides PSA testing, models consider age, ethnicity, DRE result and other risk factors to predict a man’s risk of having detectable prostate cancer. A number of these risk assessment tools are readily available online as a decision aid for an individual man to evaluate his own risk for prostate cancer. These include the Prostate Cancer Prevention Trial (PCPT) Risk Calculator79 and the European Randomized Study of Screening for Prostate Cancer (ERSPC) Risk Calculator80. A recent review81 identified more than 120 unique risk prediction models. However, only six models to detect any prostate cancer and only one model, PCPT, to detect clinically significant prostate cancer have been evaluated in ≥5 study populations. This suggests that many poorly validated models exist. The review found that, in general, compared to PSA testing, prediction models have a higher predictive accuracy to detect any prostate cancer compared to PSA testing only. Although risk prediction models have the potential to improve the accuracy of PSA screening, further investigation is needed to evaluate the effect of these predictive risk models to detect clinically significant prostate cancers.

It is not clear whether or not these publicly available online risk models help men make informed decisions about the need for a prostate biopsy or a repeat biopsy after PSA screening. It is also unclear whether they help men understand their risk of clinically significant prostate cancer compared to their overall risk of prostate cancer.

The effect of these predictive risk models on reducing mortality and side effects related to overdiagnosis and overtreatment is unknown. Additional evaluations of the clinical effectiveness of these risk prediction models in clinical practice are needed before they are recommended for use.

10.3 New screening and triage markers

Recent research advances have focussed on identifying biomarkers to stratify men with low-risk and high-risk aggressive disease so that men can be managed appropriately, minimising potential harms of overdiagnosis and overtreatment82.

Two promising urinary RNA biomarkers are prostate cancer antigen, PCA3 and fusion gene TMPRSS2:ERG, to identify men with low-risk (indolent) and aggressive (clinically significant) cancers83.

PCA3 is highly overexpressed in over 95% of prostate cancer tumours, or up to 100 times greater in men with cancer than in those with a normal prostate84 85. A review found that the sensitivity of PCA3 test (54-82%) was found to be less than PSA testing (81-98%) but the specificity for PCA3 was much better than PSA (66-89% vs. 5-28%)86. Therefore, the higher specificity would reduce overdiagnosis and overtreatment cases. A weakness of these studies was that none of them used PCA3 scores as a screening test to indicate prostate biopsy, making it difficult to understand its clinical value. However, PCA3 has also been considered as a reflex test for diagnosing prostate cancer. A recent NICE review87 which investigated the clinical effectiveness of the test found no additional clinical benefit in adding PCA3 as a reflex test in diagnosing prostate cancer.

Prostate gene fusion between TMPRSS2 and ERG, an ETS (e-twenty-six) transcription factor is also overexpressed in about 50% of prostate cancers from PSA-screened cohorts88 89. However, population-based cohorts have shown a much lower prevalence of 15%89. The reasons for these differences in prevalence are not well understood but the prevalence of TMPRSS2:ERG was found to be lowest in men with early stages tumours (T1), suggesting this marker may be useful in identifying men at risk of more aggressive disease. Further research is still needed to fully understand its clinical utility in screening and its potential use in prostate cancer management (prognosis).

Results from the prospective population-based Stockholm 3 (STHLM3) screening study suggest a combination of plasma protein biomarkers (PSA, free PSA, intact PSA, hk2, MSMB, M1C1), genetic polymorphisms (232 SNPS), clinical variables (age, family, history, previous prostate biopsy, prostate exam) and PSA concentration would increase the specificity of screening without decreasing the sensitivity of PSA testing using a cut-off of at least 3 ng/ml to diagnose high-risk prostate cancers90. The model performed significantly better than PSA alone for detection of clinically significant cancers (Gleason score ≥7). The clinical usefulness of these data suggests that the STHLM3 model could reduce the number of biopsies by 32% and avoid 44% of benign biopsies. Despite these promising results, the study was only carried out in Stockholm, Sweden, where the population is relatively homogenous and men were mainly of northern European descent. Further investigations are needed to validate the STHLM3 model in other populations and in ethnic groups.

11. Management of prostate cancer

The management of localised prostate cancer is central to the controversy surrounding screening. Men considering a PSA test should understand that:

  • early detection and treatment of prostate cancer may be beneficial

  • there is uncertainty about how to distinguish between aggressive and non-aggressive cancers

  • there is no strong evidence to indicate which treatment option is most suitable for which man

  • active treatments have significant side-effects, although improvements to treatment regimens and their side-effects are being made

12. Management options of localised prostate cancer

To date, there is no data from randomised controlled trials giving clear evidence about the optimum treatment for localised prostate cancer.

In the UK, the Prostate Testing for Cancer and Treatment (ProtecT) trial91 92 screened more than 82,000 population-based men aged 50-69 years and randomised more than 1,600 men with PSA-detected localised prostate cancer to receive one of three frequently used treatments – active monitoring, radical prostatectomy, or radical radiotherapy – in order to evaluate its impact on 10-year survival . The recruitment phase of the trial has been completed but data is not yet available as follow-up has not been completed. The first outcome results will be reported in 2016.

Results will provide key information needed to manage localised prostate cancer as well as quantifying the potential harms of over-detection and overtreatment compared with the survival gains in PSA-detected prostate cancer.

Full NICE guidance on treatment options is available 3.

Evidence suggests that any benefit to a man from undergoing radical treatment for prostate cancer may be best for those whose comorbidities and age suggests a life expectancy of >10 years. Men with advanced prostate cancers are less likely to benefit from radical treatment alone.

The main treatment options for localised prostate cancer are:

  • active surveillance

  • radical prostatectomy (open, laparoscopic or robotically assisted laparoscopic)

  • external beam radiotherapy (EBRT)

  • brachytherapy (low and high dose rate)

  • watchful waiting

  • high intensity focused ultrasound (HIFU)

  • cryotherapy

Men with low-risk localised prostate cancer will normally be offered active surveillance (monitoring of PSA kinetics, DRE, and prostate rebiopsy) or treatment with radical prostatectomy or radical radiotherapy. If a man is under active surveillance, a decision to proceed with radical treatment should be made based on his preferences, comorbidities and life expectancy. Radical treatment may also be offered if there is evidence of disease progression.

Men with intermediate-risk localised prostate cancer can consider active surveillance (if the man does not wish to undergo radical treatment immediately) or be offered radical treatment. They may also be offered a combination of radical radiotherapy and androgen deprivation therapy, rather than radical radiotherapy or androgen deprivation therapy alone. High-dose rate brachytherapy in combination with external beam radiotherapy may also be considered.

Men with high-risk localised prostate cancer are offered radical treatment if there is a realistic probability of long-term disease control. They should not be offered active surveillance. Men will also be offered 6 months of androgen deprivation therapy before, during or after radical treatment. High-dose rate brachytherapy in combination with external beam radiotherapy may also be considered. High-intensity focussed ultrasound and cryotherapy would not be offered to men with localised prostate cancer outside the context of a controlled clinical trial.

Watchful waiting may be elected by asymptomatic men with localised prostate cancer, since prostate cancers are often slow growing and treatment can cause side effects, including sexual dysfunction and urinary incontinence, and impact on a man’s daily life. A man under watchful waiting will be monitored for disease progression by a member of the urological MDT (multidisciplinary team) over the long term in order to avoid treatment unless symptoms appear.

Before choosing a treatment regimen, men should be appropriately counselled about the important quality of life differences between the options. For example, radical treatment for prostate cancer can result in loss of sexual potency, ejaculation, fertility and urinary continence.

12.1 Active surveillance and active monitoring

During active surveillance or monitoring the patient is followed up regularly by an oncologist or urologist. This option is offered to men who are generally younger and fitter and who wish to avoid the possibility of unnecessary treatment of indolent cancers. The downside is that disease may spread locally and advanced disease may develop, which may be more difficult to treat. The aim is to monitor those with stable disease and identify where radical treatment may be appropriate for those whose cancer progresses. Men on active monitoring will be monitored by serial PSA tests. Men on active surveillance will be monitored by serial PSA tests and repeat prostate biopsies. Radical treatment with curative intent is offered if there are signs of disease progression.

12.2 Radical prostatectomy (open, laparoscopic and robotic)

The aim of radical prostatectomy is to remove the entire prostate gland and to cure the disease. Complete tumour clearance is not always achieved and approximately 20% of men go on to develop biochemical or clinical recurrence of the disease1. Recurrence does not necessarily equate with death from prostate cancer. Complications of surgery include operative mortality, sexual dysfunction and urinary problems. This treatment is uncommon in men over 70.

12.3 Radiotherapy (external beam and brachytherapy)

Radiotherapy such as external beam radiotherapy (EBRT) and brachytherapy aims to cure the disease. EBRT involves an external source of radiation targeted at the tumour. Short-term side-effects relate mainly to bowel and bladder problems from the radiation. Longer-term complications include sexual dysfunction and urinary problems. This treatment is not usually recommended for men with less than 10 years’ life expectancy.

Brachytherapy may be given by two very different techniques. Low dose rate (LDR) brachytherapy involves the permanent implantation of tiny radioactive seeds into the prostate to deliver a high radiation dose into the gland. High dose rate (HDR) brachytherapy requires fine catheters to be inserted into the prostate, through which a radioactive source is temporarily passed. Although the isotope used has a higher dose rate, the overall dose is lower than that given by LDR brachytherapy so it is usually given in conjunction with EBRT. This latter technique is much more recent, with limited clinical data, and is usually reserved for patients with high-risk disease. Possible side-effects include urinary symptoms and sexual dysfunction.

12.4 Watchful waiting

During watchful waiting the patient is followed up regularly in primary care. The approach is non-invasive and avoids unpleasant side-effects. Watchful waiting is offered to men who, on the grounds of their age or co-morbidity or on the basis of having slowly progressing tumours, are likely to die from other causes and will not suffer significant morbidity from their prostate cancer. These men will be offered palliative treatment only if and when symptoms of prostate cancer develop. Such treatment will not be curative, but will aim to slow the cancer growth sufficiently to prevent the man dying from it.

12.5 High-intensity focussed ultrasound and cryotherapy

High-intensity focused ultrasound (HIFU) and cryotherapy are newer radical therapies for the treatment of localised prostate cancer and are not currently recommended other than in the context of controlled clinical trials. HIFU aims to cure the disease by heating the prostate gland using ultrasound waves to cause tissue damage by mechanical and thermal effects as well as by cavitation. Cryotherapy aims to cure the disease by freezing the prostate gland.

12.6 Hormone therapy

Adjuvant hormone therapy is being used following surgery and in conjunction with radiotherapy for localised disease with the aim of improving survival3. Hormone therapies (luteinising hormone-releasing hormone [LHRH] analogues or anti-androgens) attempt to suppress growth of the cancer by reducing circulating androgen levels. They can be used as adjuvant treatments to those outlined above and are also widely used in the control of metastatic disease. Side-effects include sexual dysfunction, loss of libido, breast swelling, hot flushes and osteoporosis. Men on the watchful waiting regimen who develop symptoms of progressive disease are usually managed with hormone therapy.

13. Locally advanced and metastatic prostate cancer

Surgery alone cannot normally eradicate clinically advanced localised cancer. The rate of progression of the disease varies considerably. Patients with locally advanced disease mainly receive radiotherapy or hormone therapy. Some men live for many years with few symptoms, while others develop extensive disease quite rapidly.

14. Monitoring effectiveness of treatment with PSA

PSA levels are used to monitor disease activity in those with established prostate cancer, giving an indication of response to treatments. They may also give an early indication of the progression of a cancer either after treatment or as part of an active surveillance or monitoring protocol.

15. Population screening for prostate cancer

To date there is no UK data from randomised controlled trials to show the benefits outweigh the harms of using the PSA test for prostate cancer screening. Evidence from the ERSPC shows that the PSA test can reduce the risk of death from prostate cancer17. However, the benefits of PSA screening remain unresolved on issues of overdiagnosis and overtreatment of clinically insignificant prostate cancers as well as identifying the optimum treatment for localised prostate cancer.

The UK Cluster randomised trial of PSA testing for Prostate Cancer (CAP) Study93 aims to address these unanswered questions by evaluating whether PSA testing of men aged 50-69 years will reduce prostate cancer mortality and be cost-effective. The study design is a cluster randomisation controlled trial of primary care centres to either PSA screening (intervention arm) or to standard clinical care (comparison arm). More than 400,000 men in England and Wales have been randomised. The ProtecT trial is the randomised controlled trial (intervention arm of CAP) that is evaluating active surveillance, conformal external beam radiotherapy and radical prostatectomy treatments for men with localised prostate cancers who attend a GP practice, randomised to PSA testing in the CAP trial. Both trials are measuring outcomes of prostate cancer-specific mortality as well as overall survival, costs and quality of life.

Long-awaited results from the CAP93 and ProtecT91 trials will be reported in 2016 which will provide key information needed to manage localised prostate cancer as well as quantifying the potential harms of over-detection and overtreatment compared to the survival gains in PSA-detected prostate cancer after 10 years of follow-up. There have been calls for a national screening programme for prostate cancer, just as there are for bowel, breast and cervical cancers. However, there is insufficient evidence to support PSA-based screening as recently reviewed by the UKNSC2. The current published data is insufficient to recommend the adoption of population screening for prostate cancer as a public health policy due to the large overtreatment effect. None of the published randomised controlled trial studies (ERSPC17, PLCO63, The Norrkoping94 and Stockholm95 studies in Sweden and the Quebec study in Canada96) used UK-comparable screening protocols, nor have the impacts on men’s symptoms and quality of life or costs been published for these studies, so care must be exercised in applying these results to any decisions about a screening programme in this country.

15.1 UK National Screening Committee (UK NSC) recommendation

A 2015 review by the UK NSC2 shows advances have been made in our understanding of prostate screening but there is no updated evidence to justify introducing a national screening programme. Despite the benefit of PSA screening to reduce prostate cancer mortality by at least 21% (ERSPC trial)17, there are still significant gaps in our knowledge of overdiagnosis and overtreatment of clinically insignificant prostate cancers as well as identifying the optimum treatment. The potentially harmful effects of prostate screening are significant. While some early cancers would be detected and lives saved, the introduction of a PSA-based screening programme at this stage would undoubtedly lead to some men with indolent disease unnecessarily experiencing the side-effects of radical treatment, including sexual dysfunction, urinary problems and, in extreme cases, death.

The UK NSC has therefore recommended against a prostate cancer screening programme in the UK at this time. Instead, the PCRMP exists so that asymptomatic men who ask about a PSA test can make an informed choice, based on good quality information from their GP or Practice Nurse, about the advantages and disadvantages of having the test. An online patient decision aid has been developed to help men make a decision which is right for them.

16. PSA testing patient decision aid option grid

  Having the PSA Test Not having the PSA Test
HEALTH If you have the PSA test and follow-on treatment you are less likely to die of prostate cancer than men who do not have the test. Having an abnormal PSA test result means you may be offered further tests and treatments, which may harm your health. If you do not have the PSA test you are more likely to die of prostate cancer than men who do have the PSA test. You are also more likely to experience the complications of advanced incurable prostate cancer.
TEST RESULTS The PSA test may reassure you if the result is normal. But it can miss cancer and provide false reassurance. If you have prostate cancer, you are more likely to be diagnosed and treated early. But an abnormal test result may also lead to unnecessary worry and medical tests when there is no cancer. The test cannot tell the difference between fast-growing cancers and slow-growing cancers that may not cause symptoms or shorten your life. If you do not have the PSA test you may avoid unnecessary worry and tests after an abnormal result when there is either no cancer or a slow-growing cancer. If you have prostate cancer, you are less likely to be diagnosed and treated early.
ACCURACY OF TEST About 75 out of every 100 men who have an abnormal PSA test result do not have prostate cancer. This is called a false positive result. About 15 out of every 100 men who have a normal PSA test result do have prostate cancer. This is called a false negative result. If you do not have a PSA test, you will not get a false positive or a false negative result but the chance of early detection may be missed.
FOLLOW-UP TESTS About 17 out of every 100 men who are tested have an abnormal test result. About 82 out of every 100 men who have an abnormal result will have a biopsy. Some men have problems or complications after a biopsy for prostate cancer. The most common complications are bleeding and infections. If you do not have a PSA test, it is unlikely you will need to have a biopsy unless you get symptoms of prostate cancer, at which stage the cancer might be more advanced.
TREATMENT If you are diagnosed with prostate cancer, you will need to decide about treatment. Potential treatments can include surgery, radiotherapy and hormone therapy. Side effects of treatments for prostate cancer can include problems with erections, loss of fertility and incontinence. If you do not have a PSA test, it is unlikely you will need treatment for prostate cancer, unless you get symptoms. This means you are less likely to have any complications from treatments.

17. Conclusions

Prostate cancer is a significant health problem, mainly affecting older men. There are problems surrounding the early diagnosis and treatment options for the disease, and to date there is no evidence to say whether the introduction of a population screening programme would reduce mortality in the UK without significant numbers of men being overtreated.

Due to the uncertainties surrounding PSA testing and treatments for prostate cancer, it is imperative that men who request a PSA test receive balanced information about the pros and cons to assist them in making an informed choice about being tested.

17.1 Resources

The following organisations have more information on prostate cancer and PSA testing:

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