- The condition should be an important health problem.
- There should be a treatment for the condition.
- Facilities for diagnosis and treatment should be available.
- There should be a latent stage of the disease.
- There should be a test or examination for the condition.
- The test should be acceptable to the population.
- The natural history of the disease should be adequately understood.
- There should be an agreed policy on whom to treat.
- The total cost of finding a case should be economically balanced in relation to medical expenditure as a whole.
- Case-finding should be a continuous process, not just a "once and for all" project.
Prostate cancer is the most common cancer in men, it is therefore an important health problem. Treatments exist for all stages of the disease, and diagnosis is readily available in most large regional centres.
The main screening tests for prostate cancer are:
- Digital rectal examination
- Prostate Specific Antigen (usually > 4)
The arguments against prostate cancer screening are many, and it is no longer recommended by several cancer bodies.
- The PSA can be falsely elevated in benign conditions or falsely negative in high grade, high risk disease
- A number of men diagnosed with prostate cancer will never die from their disease, so there is a high 'overdiagnosis' risk
- Diagnostic tests for prostate cancer have potential complications (infection, pain, false negative)
- Treatment of prostate cancer is associated with numerous complications and reduced quality of life
- Randomised controlled trials of prostate cancer screening have given conflicting results and small benefits.
Nevertheless, most patients who present for radiation therapy have been diagnosed by a screening PSA or, less commonly, digital rectal examination.
PSA is encoded by the gene KLK3. It forms an component of the semen and its exact function is to be determined. Some of the protein leaks into the bloodstream; in prostate cancer the production of PSA is increased and it is also released into the serum more readily.
The large screening studies typically use a cut-off of 4 for PSA. Levels between 4 and 10 are considered intermediate risk and over 10 high risk.
- The sensitivity (true positives / true + false negatives; i.e. positive test when cancer is present) is about 20-50%
- The specificity (true negatives / true negatives + false positives; ie. negative test when cancer is not present) is about 90%
- The positive predictive value (likelihood of a positive biopsy if PSA is elevated) is 30-50% (over 75% for PSA over 10)
- The negative predictive value (likelihood of no cancer if PSA is low) is 85%
Patients with 'normal' PSA values may still develop prostate cancer; about 15% of patients included in screening trials were diagnosed with prostate cancer despite normal PSA and DRE. Lower cutoffs for 'abnormal' PSA leads to worse sensitivity (ie. more patients with false negatives) but better specificity; the value of 4 is considered an acceptable mean.
Although prostate cancer produces higher levels of PSA per unit volume, it has not been well validated as a measure to predict prostate cancer. Using a value of 0.15 ng/mL/cm3 would miss 50% of cancers in men with abnormal PSA (4-10) and normal DRE. It also requires rectal ultrasound or MRI of the prostate for accurate measurement and this is much more complex to obtain.
PSA rises more quickly in patients with cancer. However, it adds little value in the screening setting in addition to the PSA value itself. This has been validated in randomised trials.
PSA in men with prostate cancer is more commonly bound to serum proteins; in benign conditions 'free PSA' is higher. Men with a normal free PSA to bound PSA ratio still have an 8% risk of cancer in the 4-10 bracket; making this test not as accurate enough to rule out prostate cancer with accuracy.
Digital rectal examination is the original 'test' for prostate cancer. It only reliably picks up advanced cases and is not suitable, by itself, as a screening tool. DRE in combination with PSA may improve the overall sensitivity and specificity of the each test; however the randomised trials into prostate cancer screening did not require DRE (ESPRC) or did not demonstrate a survival benefit (PLCO).
The difficulty with a modern study of PSA testing is the widespread use of the test in the community already; this tends to contaminate results (i.e. patients with high PSA might be picked up before entry into the study, and patients on 'control' arms often have PSA tests).
The European Randomised Study of Screening in Prostate Cancer (ERSPC) assigned patients to screening with PSA (on average every 3-4 years) to normal care. Patients with PSA above 2.5-4 (depending on the site) were referred for biopsy. The results were:
- Relative risk reduction of 21% for prostate cancer specific mortality
- Absolute risk reduction of 0.1 per 1,000 person years; ie: 1000 patients need to be screened for 10 years to prevent one death)
- No effect on all cause mortality
The benefit of the European study is that PSA testing is not as ubiquitous in Europe than in USA where the PLCO study was performed. Accounting for the use of PSA testing in the 'control' group, the actual reduction in prostate mortality may have been 30%.
The PLCO study performed various screening tests for prostate, lung, colorectal and ovarian cancers in the US. It did not find a survival difference between the two groups. The study was complicated by high rates of PSA testing in the control arm and prior to trial entry, potentially contaminating the results.
Two meta-analyses have examined the available evidence, and found that screening increases the numbers of cancers detected but does not effect survival outcomes.
There are differing recommendations from professional organisations.
- The American Urological Association recommends discussion of screening with patients who should make an informed decision about participating in screening
- The US Preventitive Task Force recommends against screening as the benefit is questionable and the potential harms are great
- The Urological Society of Australia and New Zealand (USANZ) recommends that patients are offered screening from 50 or from 40 with a family history
There are some debate in the media on the issue. Some are critical that the urology societies recommend PSA screening to increase the numbers of patients needing their services with no survival benefit. Even in the European randomised trials, 35 patients need to be treated to prevent one prostate cancer death - a significant number of these patients will suffer complications of treatment with reduced quality of life.
I believe it is difficult with the current evidence to recommend introduction of a blanket screening policy (ie. all men at 50 get PSA tests) as the potential benefit versus risk has not been fully established. Men at the age of 50 with a normal life expectancy should have PSA screening discussed. They should be advised of the potential benefit (possible slight reduction in mortality) and potential risks (risks of diagnostic tests, risk of overdiagnosis, risk of treatment). Men with a family history of prostate cancer should be considered for a PSA test at the age of 40.