Highlights of PSA testing guidelines

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University of South Australia, South Australia, Australia.


Abstract

These guidelines aim to provide the evidence that is available to guide clinicians managing men who, after the risks of benefits of Prostate-Specific Antigen testing are explained them, choose to have the Prostate test. Two large population studies have defined risks and benefits but have conflicting results. The guidelines commissioned by the Prostate Cancer Foundation of Australia in collaboration with Cancer Council Australia suggest that men who ask for testing should be tested every two years from the ages of 50 to 69. No survival benefit occurs until seven years. A Prostate-Specific Antigen of 3 ng/ml triggers further testing, with a biopsy for a Prostate-Specific Antigen greater than 5.5 ng/ml with lesser Prostate-Specific Antigen concentrations triggering biopsies in younger men. Low risk patients may have the option of active surveillance which delays their definitive treatment, while for those where cure is not a goal, watchful waiting may be suggested, with symptoms being the reason for further treatment.


The controversy over whether asymptomatic men should be screened by a prostate-specific antigen (PSA) test for prostate cancer arose because some men who had the test were subsequently found to have aggressive prostate cancer at a time when they could be cured. However, many more asymptomatic men who had an elevated PSA test were diagnosed and treated for an indolent prostate cancer, which would never have led to their deaths if left undetected, yet they were exposed to the same side effects of possible impotence and incontinence. The PSA test itself is not specific for prostate cancer and so false positives can occur (87 of 1000 will have a false positive PSA that will lead to a biopsy.1 False negatives also occur.

Advocates for screening have argued that maximising the lives saved should be the major consideration. However, two large randomised studies to determine the benefit of PSA screening, the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO) from the US and the European Randomised Study of Screening for Prostate Cancer (ERSPC) yielded conflicting results.2,3 PLCO showed no survival advantage for the men who were screened by PSA testing (in fact a non-significant 13% decrease at 13 years). The ERSPC showed a mortality advantage of 21%.

The 13 year follow-up of ERSPC gives a good idea of the balance between benefits and harms.4 For every 1000 men tested, 1.28 deaths were prevented, and 27 cancers were diagnosed to prevent one death. These results show why population screening, which would recommend that every man be tested, is not being pursued. However, guidance is needed for how to manage men who, having had the potential risks and benefits of PSA testing explained, request a PSA test. The National Health and Medical Research Council (NHMRC) released a document explaining the risks and benefits of testing to help general practitioners.5

The Prostate Cancer Foundation of Australia teamed with Cancer Council Australia, who produce treatment guidelines, to use strict evidence-based guidelines methodology to explore the question of PSA testing for those men who request it. This involved producing the guidelines to a standard that could be endorsed by the NHMRC. An expert multidisciplinary team to write the guidelines was selected. Structured clinical questions were identified and systematic literature reviews including searches for existing guidelines performed. The papers were screened against predefined eligibility criteria and then appraised for quality. The level of evidence was determined and then recommendations made, the strongest of which are evidence-based which can be distinguished from those based on consensus. Following is a summary of the key and evidence-based recommendations which were circulated for public discussion in December 2014.6

Recommendations are given levels of evidence depending on whether there were systematic reviews of randomised trials (level I), randomised trials (level II), non-randomised comparisons or single arm studies (level III) or case reports (level IV). The evidence is graded from A to D, where A is evidence that can be trusted to guide practice, and D is weak evidence applied to practice with caution.

Recommendations

The guidelines did not attempt to provide guidance about the decision of whether to have a PSA test. That will be covered by a decision aid to be produced subsequently. There is evidence that such aids improve knowledge and satisfaction and reduce distress at having to make the decision about whether to have a PSA test.7

PSA testing

For men, who after considering the potential benefits and harms of PSA testing, decide to have a PSA test, what should the frequency of testing be? It is recommended that regular testing is offered every two years from age 50 to 69 and further testing if the PSA is greater than 3 ng/ml (grade C).8 In a consensus-based recommendation, it was considered that in men with a risk 2.5-3 times higher than average (e.g. a brother with prostate cancer diagnosed before 60 years) who decide to undergo testing, the testing can start earlier at 45 years. For those at even greater risk, 9-10 times average (e.g. by having a father and brother with prostate cancer) and who choose to be tested, they can start at 40 years.9 In those studies which showed a mortality benefit from the early diagnosis of prostate cancer due to PSA testing, the benefit is not seen until about seven years after the PSA test.10 Therefore if a man has concomitant illnesses and is unlikely to survive seven years, then there is no possible benefit that can be gained from PSA testing, and so it is not recommended (grade C). In fact, you may see the short-term harms from resulting therapy without the possibility of survival benefit.

Digital rectal examination

An interesting result of reviewing the evidence is that in the primary care setting in an asymptomatic man where a PSA has been performed, digital rectal examination (DRE) on balance will not add anything meaningful and is not recommended (grade C). This may be a relief to both men and their general practitioners! However, a urologist may gain useful information from a DRE prior to biopsy.

Biopsy

When should a decision be made to biopsy? In the 50 to 69 age group, the evidence suggests that if the PSA is greater than 3 ng/mL, a repeat PSA should be done in one to three months, along with a free to total PSA percentage if the reading had been 3.0 to 5.5 ng/mL (grade D). The consensus view is that if the PSA is greater than 5.5 ng/mL, a biopsy is warranted. A further indication for biopsy is if the PSA remains from 3.0 to 5.5 ng/mL but the free to total PSA percentage is below 25%.12 The use of PSA velocity (grade D) or prostate health index is not known to increase the specificity.13 If a man in this age range with a PSA of greater than 3 is not offered or refuses biopsy, the consensus is that he should be advised to repeat the PSA in two years as there is a small chance of missing a significant cancer.

For men 45 to 69 years with a PSA in the range of 2.0 to 3.0 ng/ml, a biopsy should be considered if the free to total PSA is less than 25% (grade D).14
In terms of the yield of the biopsy, there is level I evidence that 24 cores nearly double the odds of detecting cancer as compared to six, therefore in addition to the sextant biopsies, directing an additional 15-18 biopsies to the peripheral zones of the prostate is recommended (grade B).15 There is insufficient evidence to make an informed choice between the transrectal and transperineal approaches.

If the biopsy is negative, what is the follow up? There is evidence that for each additional year after a negative biopsy, there is a 1-10% greater risk of prostate cancer at re-biopsy (level 1), so men should continue to be followed.16 Men should be monitored more closely if they had an abnormal pre-biopsy DRE, or biopsy finding of either atypical small acinar proliferation or high-grade prostatic intra-epithelial neoplasia. As well as repeat PSA, follow-up imaging to help target a tumour for follow-up biopsy should be considered (grade D). A multiparametric MRI (magnetic resonance image), in centres with expertise in performing these tests, should be considered for men with a negative ultrasound-guided transrectal biopsy, to determine if another biopsy is needed. If negative, no further biopsy will be required unless there are the higher risk features that warrant the closer monitoring above (grade D).17,18

Active surveillance

Patients who on biopsy have a low risk prostate cancer can have immediate treatment or opt for active surveillance, where they are followed up regularly so that potentially curative treatment can be offered when there are signs of progression. The evidence for what constitutes low risk suggests that patients with a PSA less than or equal to 20 ng/mL, clinical stage T1-2 or Gleason score 6, can be offered active surveillance (grade C). Others should be offered treatment unless they refuse, when it may be appropriate to re-biopsy them.16,19

The consensus is that the follow-up on active surveillance should be a PSA every three months with a DRE every six months. Repeat biopsies could be offered every two or three years or earlier if there were signs of progression.

Watchful waiting

Watchful waiting is a strategy in asymptomatic men for delaying definitive treatment until symptoms occur or the disease progresses, when the aim is to palliate the symptoms, not cure the disease. For men with potentially curable prostate cancer, the risk of developing advanced prostate cancer and dying is greater than if they have immediate treatment, however they are unlikely to have a diminished quality of life in the medium to long-term (grade C). Given that the literature shows that a survival advantage resulting from PSA testing is only seen after seven years, if due to concomitant illness a man’s life expectancy was less than seven years, watchful waiting would be a reasonable strategy.

The consensus is that initially these men should be followed by their general practitioners with PSA testing every three to four months for the first year, and if little change every six months thereafter, and referred back for specialist opinion for sudden progression of PSA or symptoms.20,21

Conclusions

These guidelines serve to show where current recommendations around the risks and benefits of PSA testing are based on evidence and where there is consensus. They are working towards maximising the benefits of PSA testing for men, while reducing the harms to individuals which would occur from unselected population testing. They show where more data would be desirable, particularly in being able to select those whose lives would be saved by immediate treatment. They will help plan for how best to test and follow-up men who after the risk and benefits of PSA testing are explained, wish to be tested.

The guidelines have been produced on a wiki platform, so that they are easy to update as new evidence becomes available and easy to disseminate. Decision aids based on the evidence available will follow.

References

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