- 1 Variable course of prostate cancer
- 2 Tests for prostate cancer
- 3 Treatment following early detection
- 4 Potential benefits and harms of prostate cancer screening
- 5 References
For many types of cancer, finding and treating the disease early, before it has spread, can improve health and lengthen life. However, early detection of prostate cancer by screening asymptomatic men with the prostate specific antigen (PSA) test is a complex and controversial issue.
Complicating factors include: the variable course of the disease; the limitations of the PSA test as a screening tool; the lack of a clear consensus on the optimal treatment of screening-detected early-stage prostate cancers; and the risk of significant adverse effects associated with treatment.
Accepted criteria for systematic use of a screening test in people without symptoms of disease include evidence that early detection of the disease, with subsequent early treatment, has benefits to health and can lengthen life, and that the benefits of screening and any subsequent treatment outweigh any known or possible harm resulting from screening. This is consistent with the principles of screening published by the WHO in 1968 and supported in subsequent recommendations, such as those published by the US Preventive Services Taskforce and the UK National Screening Committee, and in an update of the WHO principles published in the Journal of the American Medical Association. For more information, see the Principles of screening chapter of the National Cancer Prevention Policy.
There is, however, ongoing controversy, both in Australia and internationally, about the balance of benefit and harm from screening for prostate cancer using the PSA test.
Variable course of prostate cancer
Some prostate cancers are life-threatening; early detection and treatment has the potential to offer a survival benefit to affected men. However, many prostate cancers do not require treatment, especially in older men, because they grow slowly and do not progress sufficiently to cause harm, or even to cause any symptoms, in a man’s lifetime. Early detection of prostate cancer in these cases (known as over-diagnosis) may cause harm by exposing affected men to unnecessary treatments that carry substantial risk of important side effects, such as urinary incontinence and impotence. No current test (including the PSA test) distinguishes adequately between cancers that are likely to impair health or shorten life and those that are not.
It has been estimated that prostate cancer is present in 30% to 40% of men aged more than 50 years, but that only one in four of these cancers will result in clinical symptoms and only one in 14 will cause death.
Tests for prostate cancer
There are two tests commonly used to detect possible signs of prostate cancer: the PSA blood test, and digital rectal examination (DRE). These two tests are often used together to try to detect prostate cancer early.
Prostate-specific antigen test
The PSA test measures the amount of prostate specific antigen, a chemical produced by the prostate gland, in blood. However the test has limitations.
Increased PSA levels may indicate prostate cancer, but they may also indicate benign (non-cancerous) conditions such as benign prostatic enlargement, urinary tract infections and prostatitis. Most men who have a positive PSA screening test result do not have prostate cancer.
The concentration of PSA usually used as a guide for recommending biopsy is 4 ng/ml. This is referred to as a positive PSA result. However, at this level the PSA test is both relatively insensitive (cannot reliably identify the presence of prostate cancer) and relatively non-specific (it often produces a positive result in men who do not have prostate cancer).
In a large European trial of prostate cancer screening in men aged 50-74 years, 16% of all PSA tests were declared positive, but three out of four men with positive PSA screening tests did not have prostate cancer on biopsy. This is an indication of the PSA test’s lack of specificity.
The PSA test is also relatively insensitive – a low PSA result does not always correctly exclude the presence of prostate cancer.
The PSA test’s lack of specificity and lack of sensitivity make it difficult to establish an accurate threshold – i.e. a cut-off level of PSA concentration in the blood used to guide further clinical investigation.
Problems establishing a threshold were highlighted in a US study published in the Journal of the American Medical Association in 2005 and thought to be the best available data on the test’s performance. The study, involving 18,880 healthy men observed over seven years, found that if a PSA test was considered positive at 4.1 ng/ml, it would only identify 20.5% of men who had asymptomatic prostate cancer.
If, however, the threshold for grading a PSA test as positive was reduced to 2.6 ng/ml, 40.5% of men with asymptomatic prostate cancer would be correctly diagnosed, but 18.9% of men without prostate cancer would be incorrectly identified as possibly having prostate cancer and therefore requiring further investigation.
PSA as a predictor of risk
Serum PSA concentration measured in younger men can predict risk of future prostate cancer. A US study found that men aged 40-49 years with PSA levels higher than the median for their age were nearly four times as likely as men with lower levels to develop prostate cancer over the following 25 years, although most men with elevated PSA levels did not go on to develop prostate cancer. A Swedish study found that a single PSA test at age 44 to 50 years could be used to estimate the probability that a man would be later diagnosed with prostate cancer, with the probability increasing with higher PSA levels.
As a result, some groups advocate for a baseline PSA test at or after age 40 so that men with higher PSA levels (e.g. levels above the median) can be screened more frequently. However, there is no consensus on this approach and no clear evidence of benefit to guide clinical practice. There is also the risk of adverse psychological outcomes for men deemed 'at risk'.
Digital rectal examination
DRE involves manual examination of the prostate gland through the rectum to check any abnormality in size, shape or texture. However, it is not possible to feel the entire prostate. A cancer that is in a part of the prostate gland out of the doctor’s reach – estimated to be 25% to 35% of the prostate – may be missed. In addition, small cancers cannot be felt.
The combination of DRE and PSA testing has been shown to improve prostate cancer detection rates compared to either test used alone. One study found that the positive predictive value (the proportion of those with positive test results who have prostate cancer) of both tests combined was 56% compared to 28% for an elevated PSA level alone and 18% for an abnormal DRE alone.
Transrectal ultrasound and biopsy
If abnormalities are detected by a PSA test or DRE, a biopsy is usually performed using transrectal ultrasound (TRUS) imaging for more accurate spatial positioning of biopsy needles. The needle biopsy procedure involves eight to 10 or more cores of tissue being removed for examination under a microscope. Even though tissue is taken from a number of locations, and most invasive cancers will be detected, some cancers are missed and repeat biopsies may be required. The test is often painful and carries significant risks of infection and bleeding.
Future prospects for screening tests
Other candidate biomarkers for prostate cancer are being investigated, including novel tests for human kallikrein 11 from seminal plasma. Genetic tests are also being investigated. A summary of cross-sectional studies of men’s anticipated interest in having a genetic test for prostate cancer susceptibility, if available, can be found here.
Treatment following early detection
The treatments following diagnosis of prostate cancer consist of watchful waiting or active surveillance (monitoring with further biopsies), or active treatment including surgical removal of the prostate, radiotherapy or hormonal treatments.
Men undergoing active treatments may experience adverse effects, including significant rates of urinary incontinence and erectile dysfunction. For example, in a study of men diagnosed with localised prostate cancer in NSW in 2000-2002, three years after treatment 12% of men in the largest treatment group, radical prostatectomy, had some urinary incontinence (compared to 2% before diagnosis) and 77% were impotent (21% before diagnosis). Their likelihood of having these outcomes after three years of follow-up was much higher than that in a sample of men of the same age who had not been diagnosed with prostate cancer.
There is currently no consensus on optimal treatment for men with screening-detected early-stage prostate cancer.
Randomised controlled trials conducted before prostate cancer was commonly detected by screening showed that survival was better in men who had a radical prostatectomy than in men who did watchful waiting. In the most recent of these studies, 14.6% of men who had prostatectomies died within 15 years compared with 20.7% of men who did not have the procedure. However, it is uncertain whether this level of treatment benefit would apply to early-stage prostate cancers detected through screening.
The Prostate Cancer Intervention Versus Observation (PIVOT) study showed no benefit from prostatectomy in low-risk, early-stage prostate cancer patients. The study of 731 men with stage I or stage II prostate cancers, observed over 12 years from 1994, showed that radical prostatectomy produced reductions in all-cause and prostate cancer mortality that were not significant and less than 3% in absolute terms over 12 years.
A sub-group analysis, however, found a reduction in prostate cancer mortality in men treated with radical prostatectomy whose PSA at the time of diagnosis was >10 ng/ml. This was not evident in men with a lower PSA. These results, together with other recent results, suggest that watchful waiting or active surveillance is an appropriate choice for some men with early, low-grade prostate cancer.
International evidence shows, however, that 58% to 90% of men with PSA detected prostate cancer opt for early active treatment.
There is no definitive proof that any specific approaches to managing early-stage prostate cancer differ in effectiveness. Therefore, the incorporation of patient preferences into treatment decisions is widely endorsed.
Potential benefits and harms of prostate cancer screening
The key potential benefit of prostate cancer screening would be a lower risk of death from prostate cancer in those who are screened systematically than in those who are not. However, while it is clear that prostate cancer screening detects cancers at an earlier stage, it is not yet clear that it reduces the risk of dying from prostate cancer.
Two large randomised trials of prostate cancer screening using the PSA test and DRE in Europe and the US have reported conflicting prostate cancer mortality results. The European study reported a reduction in prostate cancer mortality of 21% attributable to screening, although at a high risk of over diagnosis. However, the US study found prostate cancer mortality to be a little higher in screened men than in unscreened men, although this difference was not statistically significant.
The studies included approximately 162,000 men aged 55 to 69 (Europe) and 77,000 men aged 55 to 74 (US). Both trials reported increased prostate cancer incidence in the screened group. In the European study, 6,963 prostate cancers were detected in the screened group and 5,396 in the control group; in the US study, 2,820 cancers were detected in the screening group compared with 2,322 cases in the control group.
The European study showed that 1055 men would need to be screened and 37 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer.
One of the centres participating in the European trial (Goteborg, Sweden) has reported its results separately and included in its analysis a larger number of participants (all those born from 1930 to 1944) than were included in the European trial (those born 1930-39). The study had been initiated separately from the European trial and added later. It reported a 44% reduction in prostate cancer mortality due to screening over 14 years of follow-up. It found that 293 men would need to be screened and 12 additional men diagnosed with prostate cancer to prevent one prostate cancer death.
The improved mortality due to screening seen in this sub-trial compared to the full European trial could be due to: the younger cohort of men in the trial (who were not included in the European trial); the absence of pre-screening; the shorter screening interval adopted; and longer follow-up. If participants from the Goteborg trial are excluded from analysis of the European trial, the estimated mortality benefit due to screening in the European trial falls from 21% to 16%.
Meta-analyses pooling the results of these and other trials have found no significant reduction in mortality as a result of screening, despite increased detection of early-stage prostate cancers. These analyses have been criticised, however, because of heterogeneity in the quality of the studies pooled.
In 2011, the US Preventative Services Task Force reviewed prostate cancer screening data and found convincing evidence that there was no mortality benefit from screening men aged 70 years or older, and that the mortality benefit 10 years after screening in men aged 50-69 was small or non-existent. The task force also concluded with 'moderate certainty' that the harms of PSA-based screening outweighed the benefits.
Screening for prostate cancer using PSA, with or without DRE, can cause harm in a number of ways.
The main harms attributable to PSA testing are caused by overdiagnosis, due to the test's inaccuracy (inadequate specificity and sensitivity). Neither the PSA test nor DRE, alone or together, are accurate tests for prostate cancer: most men with elevated PSA levels do not have cancer (a 'false positive') while cancers that are present may be missed (a 'false negative'). Consequently, significant numbers of men undergo unnecessary investigations following a false positive test result, with the attendant risks, financial costs and anxiety. Alternatively, they may be falsely reassured that they do not have prostate cancer.
Screening using PSA testing produces a high rate of false positives. Prostate cancer screening trials in the US and Europe have found that 12-13% of screened men had false positives after three or four screening rounds. Men with false positive results experience psychological harm, including anxiety and worry about their prostate cancer risk, and problems with sexual function up to at least one year after the test.
Abnormal or elevated PSA will normally lead to a biopsy (See Threshold problems). However, as many as three out of four men with elevated PSA levels on screening who undergo biopsy do not have prostate cancer. Potential harm from biopsies includes pain and discomfort as well as infection, bleeding and urinary difficulties. Serious infections or urinary difficulties occur in 0.5-1.0% of biopsies.
Less serious harm is probably much more common. In a recent British study, 33% of 850 men who had a prostate biopsy after a positive PSA screening test experienced moderate or major problems as a result.
A major harm of prostate cancer screening is over-diagnosis, because currently available tests do not distinguish between aggressive cancers and indolent cancers that are unlikely to cause harm during a man’s lifetime and therefore require no treatment. PSA testing can result in unnecessary treatment, with the attendant high risk of serious adverse effects and reduced quality of life for men screened. Rates of over-diagnosis with prostate cancer screening have been estimated to be up to 50%.
Adverse effects from prostate cancer treatment are serious and common. Although the level of harm reported across different studies varies, a recent data synthesis found that one in three men treated with prostatectomy would experience erectile dysfunction, while one in five would experience urinary incontinence. Radiation therapy would result in urinary incontinence in one out of seven men treated and was also associated with bowel problems. Levels of impotence, urinary incontinence and bowel problems of up to 79%, 15% and 18% respectively have been recorded five years after treatment. Although rare, death and serious complications from surgery may also occur.
International data shows that 58% to 90% of men with PSA-detected prostate cancer opt for early treatment.
In addition to the quality-of-life costs of over-diagnosis incurred by individual men, the economic costs to the health system of treating large numbers of indolent cancers detected by PSA testing would be significant.
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