Testing with variants of PSA to improve sensitivity after an initial total PSA ≤ 3.0 ng/mL
For asymptomatic men with an initial total PSA below or equal to 3.0 ng/mL does measuring free-to-total PSA percentage improve the detection of prostate cancer or high-grade prostate cancer without resulting in unacceptable numbers of unnecessary biopsies, when compared with a single total PSA result below or equal to 3.0 ng/mL? (PICOi question 6.1a)
For asymptomatic men with an initial total PSA below or equal to 3.0 ng/mL does measuring PSA velocity improve the detection of prostate cancer or high-grade prostate cancer without resulting in unacceptable numbers of unnecessary biopsies, when compared with a single elevated total PSA result below or equal to 3.0 ng/mL? (PICOi question 6.2a)
For asymptomatic men with an initial total PSA below or equal to 3.0 ng/mL does measuring the Prostate Health Index (PHI) improve the detection of prostate cancer or high-grade prostate cancer without resulting in unacceptable numbers of unnecessary biopsies, when compared with a single elevated total PSA result below or equal to 3.0 ng/mL? (PICOi question 6.3a)
Guidelines developed in partnership with
This resource has been developed, reviewed or revised more than five years ago. It may no longer reflect current evidence or best practice.
Published: 2015
National Health and Medical Research Council 
These guidelines (recommendations) in the web-version of this guideline were approved by the Chief Executive Officer of the National Health and Medical Research Council (NHMRC) on 2 November 2015 under section 14A of the National Health and Medical Research Council Act 1992 In approving the guidelines (recommendations), NHMRC considers that they meet the NHMRC standard for clinical practice guidelines. This approval is valid for a period of five years. NHMRC is satisfied that the guidelines (recommendations) are systematically derived, based on the identification and synthesis of the best available scientific evidence, and developed for health professionals practising in an Australian health care setting.
This publication reflects the views of the authors and not necessarily the views of the Australian Government.Background
For men without a diagnosis or symptoms of prostate cancer who, after being informed of the benefits and harms of testing, wish to undergo regular PSA testing, the following strategy is recommended because it is associated with reduced risk of death from prostate cancer: offer PSA testing every 2–4 years from age 50 to age 69, and offer further investigation if the PSA is greater than 3.0 ng/mL (see 2.2. PSA testing strategies).
In asymptomatic men without a diagnosis of prostate cancer, a single total PSA test result above 3.0 ng/mL fails to detect a substantial proportion of cancers.[1] There is a particular interest in detecting prostate cancer when PSA is in the range 2.0–2.9 ng/mL, as these cancers are more likely to be clinically significant than cancers found when PSA levels are below 2.0 ng/mL. Moreover, men with increased genetic risk of prostate cancer have a significantly higher risk of having prostate cancer with total PSA levels below 3.0 ng/mL.[2]
The use of a total PSA threshold of 3.0 ng/mL will not be equivalent in all circumstances because of different analytical biases between assays. Day-to-day biological variability of 15% in a man’s PSA level also means that, for a man with an average level of 3.0 ng/mL, the levels on consecutive days can be as high as 3.9 ng/mL (upper 95th percentile) or as low as 2.1 ng/mL (lower 95th percentile). Therefore, we also included studies of men with total PSA levels in the broader range of 2.0 ng/mL to 4.0 ng/mL. Nevertheless, in studies that included men with total PSA levels of 2.0–4.0 ng/mL, most participants will actually have total PSA levels between 2.0 ng/mL and 3.0 ng/mL.
Free-to-total PSA percentage
PSA is a serine protease and its active form is bound by antiproteases (particularly alpha 1 anti-chymotrypsin). Bound PSA is the main form of PSA in serum. Inactive forms of PSA, such as nicked PSA and proPSA, are not bound and represent the free forms of PSA in serum. For at least two decades it has been known that men with the lowest proportion of free PSA (e.g. less than 10%) are likely to have prostate cancer. Measurement of free PSA expressed as a percentage of total PSA (free-to-total PSA%) has been used as a method of improving the predictive efficiency of PSA testing. For example, free-to-total PSA% might be used in men with total PSA below 3.0 ng/mL to improve sensitivity. The Finnish centre of the ERSPC trial found that free-to-total PSA% was a strong predictor of the later diagnosis of prostate cancer in men with a total PSA level below 3.0 ng/mL.[3]
PSA velocity and other measures of PSA kinetics
The rate of increase in serum total PSA has been identified as a risk indicator for prostate cancer.[4] PSA velocity has been defined as the absolute increase in total PSA per year, and changes of over 0.75 ng/mL/year were initially identified as representing a threshold for increased risk. Other PSA change calculations have also been proposed and applied. These include total PSA doubling time (e.g. using a doubling time less than 3 years as an indicator of increased risk) or total PSA percentage change (e.g. using a threshold of more than 25% per year as an indicator of increased risk).
The calculations of PSA kinetics including PSA velocity, PSA doubling time or PSA percentage change, are complicated by the high day-to-day variability of total PSA levels, which is generally about 15%. Therefore, a rise of 20–30% is required before the PSA level can confidently be said to have risen. The confidence in whether a PSA has risen is improved when three or four PSA levels are taken over an extended period of months, rather than days. Guidelines for PSA kinetics measurement require at least three levels measured by the same assay, with each measurement separated by at least 3 months.[5]
Prostate Health Index (PHI)
PHI testing differs from total PSA testing and free-to-total PSA% testing in identifying whether the free PSA proportion in serum contains an abnormally high component of proforms of PSA, specifically pro2PSA. The PHI is calculated as follows:
([-2]proPSA/free PSA) × √ total PSA
The threshold values for the PHI test can be reached in a situation where the proportion of free PSA present as pro2PSA is very high and the total PSA levels are low, such as when total PSA is below the 3.0 ng/mL threshold. Therefore, the use of PHI might be expected to improve the sensitivity of PSA testing.
Evidence
The search strategy, inclusion and exclusion criteria, and quality assessment are described in detail in the Technical report.
Free-to-total PSA percentage
Four diagnostic accuracy studies were identified that reported the numbers of additional cancers detected and biopsies undertaken as a result of free-to-total PSA% testing of men with total PSA levels less than the threshold for biopsy.[6][7][8][9] All were assessed to be at risk of bias.ii
All four studies used a total PSA threshold of 4 ng/mL and found that using free-to-total PSA% at total PSA levels below the total PSA threshold detected additional cancers. However, the numbers of extra unnecessary biopsies varied depending on free-to-total PSA% threshold, the population, and the total PSA range in which the free-to-total PSA% test was used.[6][7][8][9]
In a Japanese study[6] of men aged 50–79 years, the use of a free-to-total PSA% threshold of < 12% for men with a total PSA of 2.0–4.0 ng/mL increased detection by approximately 10%, at an incremental cost of 2.1 extra unnecessary biopsies for each additional cancers diagnosed. These results were assessed to be non-generalisable to the Australian population of men who may consider prostate cancer testing, because the cancer detection rate for men with a total PSA greater than 4.0 ng/mL was 43.1%.
A Finnish study[9] conducted in a cohort of men aged 55–67 years participating in a screening trial found that the use of a free-to-total PSA% threshold of < 16% for men with a total PSA of 3.0–4.0 ng/mL increased detection by approximately 10%, at an incremental cost of 3.9 extra unnecessary biopsies for each additional cancer diagnosed. The cancer detection rate in this study was 24.5% for a total PSA threshold of 4.0 ng/mL, which was more typical of screening populations. However, this study was not directly relevant to testing protocols using a total PSA threshold of 3.0 ng/mL, as it did not seek to improve on the sensitivity at total PSA levels below 3.0 ng/mL.[9]
Another small (n = 40) study[8] showed that for men at increased risk of prostate cancer (African American, family history of prostate cancer, or BRCA1 positive) aged 41–69 years at biopsy and with total PSA levels less than a threshold of 4 ng/mL, the use of a free-to-total PSA% threshold of less than 27%, increased cancer detection by a factor of 2.3, with one additional unnecessary biopsy for each additional cancer detected.
The other study[7] did not provide evidence as to the improvement in sensitivity.
PSA velocity
No diagnostic accuracy studies were identified that reported the numbers of additional cancers detected and biopsies undertaken as a result of measuring the PSA velocity of men with total PSA levels less than or equal to 3.0 ng/mL.
Prostate Health Index
No diagnostic accuracy studies were identified that reported the numbers of additional cancers detected and biopsies undertaken as a result of PHI testing of men with total PSA levels less than or equal to 3.0 ng/mL.
Evidence summary and recommendations
| Evidence summary | Level | References |
|---|---|---|
| Free-to-total PSA%
A study in men aged 41–69 years at high risk of prostate cancer (African American, family history of prostate cancer, or positive for BRCA1 gene), found that the use of free-to-total PSA < 27% as the criterion for biopsy in those with total PSA between 2.0 and 4.0 ng/mL, more than doubled the number of cancers detected, compared with the use of a total PSA threshold of 4.0 ng/mL alone, and resulted in approximately one extra unnecessary biopsy for each additional cancer detected. One study in a screening population found that the additional biopsy criterion of low free-to-total PSA (< 12%) for men with a total PSA of 2.0–4.0 ng/mL increased prostate cancer detection by approximately 10% and resulted in two extra biopsies per additional prostate cancer detected, compared with the use of a single biopsy indication of a total PSA > 4.0 ng/mL. The results of this study may not be generalisable to the Australian population, because a high cancer detection rate was observed with a total PSA threshold of 4.0 ng/mL. In a second study in a screening population the use of a free-to-total PSA% threshold of < 16% for men with a total PSA of 3.0–4.0 ng/mL increased detection by approximately 10%, at an incremental cost of 3.9 extra unnecessary biopsies for each additional cancer diagnosed. However, this study was not directly relevant as it did not seek to improve on the sensitivity at total PSA levels below 3.0 ng/mL. A third study in a screening population reported an increase in prostate cancer detection when using free-to-total PSA% as an additional indication for biopsy however the actual increase in sensitivity with the addition of the free-to-total PSA% test was not reported. |
III-2 | [6], [7], [8], [9] |
| PSA velocity
There was no evidence for whether or not measuring the PSA velocity of men with a PSA less than or equal to 3.0 ng/mL improves the detection of prostate cancer, compared with PSA alone. |
N/A | |
| Prostate Health Index
There was no evidence for whether or not PHI testing men with a PSA less than or equal to 3.0 ng/mL improves the detection of prostate cancer, compared with PSA alone. |
N/A |
N/A: non-applicable
Evidence-based recommendation
|
Grade |
|---|---|
 |
D |
| Consensus-based recommendation
|
|---|
|
Do not use PSA velocity or the PHI test as adjuncts to total PSA testing in determining whether or not to offer prostate biopsy, except in the context of research conducted to assess their utility for this purpose. |
Health system implications
Clinical practice
The use of free-to-total PSA% as an adjunct to total PSA testing in high risk men with total PSA levels between 2.0–3.0 ng/L is not currently a routine approach. Misuse or new safety concerns from these recommendations are not envisaged. An increase in litigation alleging malpractice is possible if the Evidence-based recommendation is not followed in practice. This potential legal risk will be mitigated by robust efforts to ensure that knowledge of the guideline is disseminated to all relevant health practitioners and the development of aids that will assist them in practising according to the guideline. The Consensus-based recommendation could mitigate risk of litigation for practitioners who practice in accordance with the evidence with respect to PSA velocity or the PHI test.
Resourcing
Implementation of the recommendations about free-to-total PSA% tests for men at high risk of prostate cancer and total PSA levels between 2.0–3.0 ng/mL will not have any resource implications.
The free-to-total PSA% test is reimbursable in Australia and extensively used. These recommendations should increase appropriateness of existing use.
Barriers to implementation
There are no apparent barriers to the implementation of these recommendations.
Footnote
i Clinical questions were translated into the PICO framework: population, intervention (or exposure), comparator and outcome (see Appendix 3).
ii The tool for assessing risk of bias for this type of research question classified studies as being ‘at risk’ or ‘not at risk’ (see Technical report).
References
- ↑ Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, et al. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA 2005 Jul 6;294(1):66-70 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15998892.
- ↑ Nordström T, Aly M, Eklund M, Egevad L, Grönberg H. A genetic score can identify men at high risk for prostate cancer among men with prostate-specific antigen of 1-3 ng/ml. Eur Urol 2014 Jun;65(6):1184-90 Available from: http://www.ncbi.nlm.nih.gov/pubmed/23891454.
- ↑ Finne P, Auvinen A, Määttänen L, Tammela TL, Ruutu M, Juusela H, et al. Diagnostic value of free prostate-specific antigen among men with a prostate-specific antigen level of <3.0 microg per liter. Eur Urol 2008 Aug;54(2):362-70 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18006214.
- ↑ Carter HB, Pearson JD. PSA velocity for the diagnosis of early prostate cancer. A new concept. Urol Clin North Am 1993 Nov;20(4):665-70 Available from: http://www.ncbi.nlm.nih.gov/pubmed/7505974.
- ↑ Arlen PM, Bianco F, Dahut WL, D'Amico A, Figg WD, Freedland SJ, et al. Prostate Specific Antigen Working Group guidelines on prostate specific antigen doubling time. J Urol 2008 Jun;179(6):2181-5; discussion 2185-6 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18423743.
- ↑ 6.0 6.1 6.2 6.3 Ishidoya S, Ito A, Orikasa K, Kawamura S, Tochigi T, Kuwahara M, et al. The outcome of prostate cancer screening in a normal Japanese population with PSA of 2-4 ng/ml and the free/total PSA under 12%. Jpn J Clin Oncol 2008 Dec;38(12):844-8 Available from: http://www.ncbi.nlm.nih.gov/pubmed/18941125.
- ↑ 7.0 7.1 7.2 7.3 Rowe EW, Laniado ME, Walker MM, Patel A. Prostate cancer detection in men with a 'normal' total prostate-specific antigen (PSA) level using percentage free PSA: a prospective screening study. BJU Int 2005 Jun;95(9):1249-52 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15892810.
- ↑ 8.0 8.1 8.2 8.3 Uzzo RG, Pinover WH, Horwitz EM, Parlanti A, Mazzoni S, Raysor S, et al. Free prostate-specific antigen improves prostate cancer detection in a high-risk population of men with a normal total PSA and digitalrectal examination. Urology 2003 Apr;61(4):754-9 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12670560.
- ↑ 9.0 9.1 9.2 9.3 9.4 Mäkinen T, Tammela TL, Hakama M, Stenman UH, Rannikko S, Aro J, et al. Prostate cancer screening within a prostate specific antigen range of 3 to 3.9 ng./ml.: a comparison of digital rectal examination and free prostate specific antigen as supplemental screening tests. J Urol 2001 Oct;166(4):1339-42 Available from: http://www.ncbi.nlm.nih.gov/pubmed/11547069.
Discussion
Supporting attachments
