Discussion

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Prostate Cancer Foundation of Australia and Cancer Council Australia PSA Testing Guidelines Expert Advisory Panel. Clinical practice guidelines PSA Testing and Early Management of Test-Detected Prostate Cancer. Sydney: Cancer Council Australia. [Version URL: http://wiki.cancer.org.au/australiawiki/index.php?oldid=122831, cited 2017 Nov 17]. Available from: http://wiki.cancer.org.au/australia/Guidelines:PSA_Testing/Testing/Discussion.

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. expand arrow

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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.

Chapter 2 Testing

Discussion

Men’s expectations for prostate cancer testing

It is important to note that the expectations of men’s gain in life (mean months of life gained per man diagnosed) in these protocols and the comparisons between them are of the same order of magnitude as the survival times men have expressed willingness to trade off for freedom from quality-of-life impacts that may follow definitive treatment for prostate cancer. Table 2.9 extracts data from a discrete choice experiment conducted among participants in the NSW Prostate Cancer Care and Outcomes Study.[1] Men were willing to trade off survival increments of between 3.25 months (for freedom from mild fatigue) and 27.69 months (for freedom from severe urinary leakage) when symptoms were considered individually. Therefore, mean months of life gained per man diagnosed with prostate cancer provides a meaningful measure of the balance between benefits and harms.

Table 2.9. Additional months of life needed to compensate men for each persistent treatment-related adverse effect of diagnosis of prostate cancer in excess of a base case of mild loss of libido with no other problems and 12-year life expectancy
Treatment related adverse effects Additional months of life needed to compensate
Mild fatigue 3.25
Severe impotence 4.00
Mild urinary leakage 4.22
Mild urinary blockage 4.91
Severe loss of libido 5.02
Mild bowel symptoms 6.22
Severe fatigue 13.30
Severe urinary blockage 21.96
Severe bowel symptoms 25.31
Severe urinary leakage 27.69

Source: King et al (2012)[1]

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Unresolved issues

PSA testing strategies

Notwithstanding the size and logistic complexity of the five randomised controlled trials that have studied whether PSA testing reduces mortality from prostate cancer, they provide little or no evidence for the comparative performance of different strategies (or protocols) for PSA testing.[2][3][4][5][6][7][8][9][10][11] The most we have been able to conclude from them is that for men aged 50–69 years without a prostate cancer diagnosis or symptoms that might indicate prostate cancer, PSA testing every 2–4 years and a total PSA threshold for biopsy of > 3.0 ng/mL may reduce prostate cancer mortality. There is little or no additional evidence in the randomised controlled trials that would allow us to determine whether this combination of age at testing, interval between tests and criterion for biopsy achieves the optimal balance between the benefits and harms of PSA testing.

Although the best-quality evidence (results of randomised controlled trials) supports biennial PSA testing of men aged 50–69 years, with total PSA of ≥ 3.0 ng/mL as the criterion for further investigation, one model[12] based on the ERSPC results suggests that the criterion of total PSA > 95th percentile for age may improve the balance of benefits to harms. It also suggests that the extent of the benefit and the balance of benefits to harms are similar when testing men aged 40–49 years as it is when testing men aged 50–59 years. While the apparently small additional benefit gained with beginning testing at age 40 years would probably lie with testing in the age-group 45–49, this has not be adequately assessed in the models.

While these guidelines have recommended against PSA testing at age 40 years as a means of estimating future risk of prostate cancer death, it is nonetheless true that the PSA level when measured in the forties or early fifties is a strong predictor of risk. It has been suggested, in this context, that a man’s future screening protocol could be modified in light of the first PSA test result. For example, the Royal College of Pathologists of Australia’s (RCPA’s) position statement Prostate specific antigen testing: age-related interpretation in early prostate cancer detection[13] has recommended that ‘If the PSA level is not above the age-related median, the patient should be reassured that their risk is low and be re-tested in 4 years’ (not 2 years as in the protocol recommended in this guideline and RCPA’s recommendation for men with a PSA above the age-related median). Such tailoring of the testing protocol to risk as assessed by PSA level has the potential to appreciably reduce the harms of PSA testing while preserving the benefits and would justify early consideration using a PSA testing model developed specifically for Australian men.

Quality-of-life outcomes have not been reported to any material extent in the randomised controlled trials designed to evaluate PSA testing. Observational quality of life studies suggest that persisting consequences of definitive therapy, such as urinary incontinence, impaired sexual function, bowel problems are the most common quality-of-life issues that men diagnosed with prostate cancer experience.[14] In principle, these can be reduced if over-diagnosis can be reduced. The broader impairment of quality of life due to androgen deprivation therapy and advanced cancer is also important and, in principle, both can be reduced by earlier diagnosis of cancers that would go on to become symptomatic in the absence of measures that achieve earlier diagnosis, such as PSA testing. The modelling studies addressed outcomes relevant to quality of life only indirectly, by estimating rates of over-diagnosis and false positives on biopsy. There would be value in extending this modelling to include a more comprehensive assessment of quality-of-life issues, as it is unlikely that they will ever be adequately addressed by randomised controlled trials.

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Australian population PSA reference data

Data from modelling studies suggest that the use of an age-based PSA test criterion for biopsy may reduce rates of false positive tests and over-diagnoses, and achieve a better balance of benefits to harms than a fixed value criterion (e.g. > 3.0 ng/mL). As PSA testing models based on Australian data become available within the next 5 years, these recommendations may be revised to specify more widely biopsy criteria based on percentiles of total PSA, most likely the 95th percentile for age.

Recommendations based on total PSA percentiles for age would require data for each year of age, or for age brackets not wider than 5 years. Laboratories should routinely report these data for PSA tests on men without a prostate cancer diagnosis or symptoms that might indicate prostate cancer. There should be a single, authoritative Australian source of data on the distributions of PSA concentration in suitable age categories in Australian men.

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PSA modalities for improving sensitivity and specificity

It is uncertain how repeat total PSA and free-to-total PSA% work together in avoiding unnecessary biopsies while maintaining sensitivity. Furthermore it is not known how these diagnostic changes impact on clinical outcomes. To the extent possible, their impact on overall outcome for men having PSA testing should be evaluated in the proposed Australian model for PSA testing.

The present evidence allows two discrete recommendations when initial total PSA is greater than 3.0 ng/mL in men aged 50–69 years:

  • Measure free-to-total PSA% if initial total PSA is greater than 3.0 ng/mL and up to 5.5 ng/mL. If free-to-total PSA is less than 25%, offer prostate biopsy.
  • Offer repeat PSA within 1– 3 months. If repeat total PSA is greater than 3.0 ng/mL, offer prostate biopsy.

However, the evidence does not indicate how these could be integrated into a practical recommendation or sequence of steps that could be implemented in clinical practice, given that a patient may meet one or both of the independent criteria for biopsy. Evidence was not available from any studies that used a clinical algorithm based on both these parameters. The use of ‘either total PSA greater than 3.0 ng/mL or free-to-total PSA% less than 25%’ as the criterion for biopsy may result in the loss of specificity gains achieved by using these tests individually. Logic and the findings of modelling studies (see 2.2 PSA testing strategies) suggest that it would be more reasonable to reserve biopsy for those who meet both criteria, acknowledging that this more stringent threshold could reduce sensitivity.

Clinical considerations are also relevant to guidance based on this body of evidence. The result of a free-to-total PSA% measured at the time of an initial slightly elevated total PSA could be misleading (e.g. if the PSA was raised due to prostatitis, this may also affect PSA fractions). Therefore, it seems reasonable to consider the result of a free-to-total PSA% test performed after an interval of 1–3 months. In practice, clinicians request measurement of free-to-total PSA% at the same time as repeat total PSA.

In consideration of all these factors, the Expert Advisory Panel elected to make an evidence-based recommendation on the timing and choice of these tests, and to make a consensus-based recommendation on how their results should be interpreted.

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Studies currently underway

Several of the prospective studies evaluating PSA testing strategies are still underway. Longer-term follow-up data may influence future recommendations.

Modelling of PSA testing protocols in the Australian context is also underway. When available, the data may enable better prediction of outcomes for Australian men and subgroups, and may result in revision of the recommendations.

Prostate Cancer Foundation of Australia has commissioned researchers at the Australian National University to develop a tool for estimating life expectancy in men using Australian data. When available, this tool would provide doctors with much of the information needed to discourage offers of PSA testing to men with less than 7 years’ life expectancy.

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Future research priorities

Future research priories include:

  • effects of PSA testing strategies (using different combination of age at testing, interval between tests, and criterion for biopsy) on outcomes of prostate cancer-specific mortality outcomes, disease- and treatment-related morbidity, and quality of life
  • Australian population reference data to establish PSA normal values for various age groups
  • the interaction between multiple PSA testing modalities (e.g. PHI, repeat total PSA and free-to-total PSA%) used in conjunction with a total PSA threshold of 3.0 ng/mL, especially for men aged 50–69 years and those at high risk
  • more research-based information on the RR of prostate cancer conferred by different risk factors is needed to be able to determine, with confidence, the age at which a man with one or more risk factors should consider beginning PSA testing. Currently, even for family history (probably the best known risk factor) there is considerable uncertainty in the estimates of RR, particularly with different degrees of family history (see Chapter 1 Risk). It will be important that potential confounding with PSA testing is taken into account in studies done to fill this information gap.

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References

  1. 1.0 1.1 King MT, Viney R, Smith DP, Hossain I, Street D, Savage E, et al. Survival gains needed to offset persistent adverse treatment effects in localised prostate cancer. Br J Cancer 2012 Feb 14;106(4):638-45 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22274410.
  2. Kilpeläinen TP, Tammela TL, Malila N, Hakama M, Santti H, Määttänen L, et al. Prostate cancer mortality in the Finnish randomized screening trial. J Natl Cancer Inst 2013 May 15;105(10):719-25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23479454.
  3. Kjellman A, Akre O, Norming U, Törnblom M, Gustafsson O. 15-year followup of a population based prostate cancer screening study. J Urol 2009 Apr;181(4):1615-21; discussion 1621 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19233435.
  4. Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church TR, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012 Jan 18;104(2):125-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22228146.
  5. Bokhorst LP, Bangma CH, van Leenders GJ, Lous JJ, Moss SM, Schröder FH, et al. Prostate-specific antigen-based prostate cancer screening: reduction of prostate cancer mortality after correction for nonattendance and contamination in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. Eur Urol 2014 Feb;65(2):329-36 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23954085.
  6. Hugosson J, Carlsson S, Aus G, Bergdahl S, Khatami A, Lodding P, et al. Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010 Aug;11(8):725-32 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20598634.
  7. Labrie F, Candas B, Cusan L, Gomez JL, Bélanger A, Brousseau G, et al. Screening decreases prostate cancer mortality: 11-year follow-up of the 1988 Quebec prospective randomized controlled trial. Prostate 2004 May 15;59(3):311-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15042607.
  8. Roobol MJ, Kranse R, Bangma CH, van Leenders AG, Blijenberg BG, van Schaik RH, et al. Screening for prostate cancer: results of the Rotterdam section of the European randomized study of screening for prostate cancer. Eur Urol 2013 Oct;64(4):530-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23759326.
  9. Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012 Mar 15;366(11):981-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22417251.
  10. Sandblom G, Varenhorst E, Löfman O, Rosell J, Carlsson P. Clinical consequences of screening for prostate cancer: 15 years follow-up of a randomised controlled trial in Sweden. Eur Urol 2004 Dec;46(6):717-23; discussion 724 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15548438.
  11. Sandblom G, Varenhorst E, Rosell J, Löfman O, Carlsson P. Randomised prostate cancer screening trial: 20 year follow-up. BMJ 2011 Mar 31;342:d1539 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21454449.
  12. Gulati R, Gore JL, Etzioni R. Comparative effectiveness of alternative prostate-specific antigen--based prostate cancer screening strategies: model estimates of potential benefits and harms. Ann Intern Med 2013 Feb 5;158(3):145-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23381039.
  13. The Royal College of Pathologists of Australasia. Prostate specific antigen testing: Age-related interpretation in early prostate cancer detection. Revised position statement.; 2011 [cited 2014 Nov 20] Available from: http://www.rcpa.edu.au/getattachment/37efcb2a-0844-4250-b9e7-a53a26eeafec/Prostate-Specific-Antigen-Testing-Age-related-inte.aspx.
  14. Smith DP, King MT, Egger S, Berry MP, Stricker PD, Cozzi P, et al. Quality of life three years after diagnosis of localised prostate cancer: population based cohort study. BMJ 2009 Nov 27;339:b4817 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19945997.

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