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PSA Testing for Prostate Cancer in Asymptomatic Men: Information for Health Practitioners submission

ID: 
14
This submission reflects the views of
Organisation Name: 
Royal College of Pathologists of Australasia
Personal Details
General Comments
18. Considering the Information Document is for Health Practitioners, do you have any other comments?: 

RE: Draft NHMRC PSA testing in asymptomatic men: Evidence evaluation Report 2013 and Information for Health Practitioners

  1. In Australia, the Royal College of Pathologists of Australasia (the College) is the peak organisation representing specialist pathologists; amongst whom chemical pathologists arresponsible for the quality and guidance for the PSA test and histopathologists are responsible for the assessment of prostate biopsies and the diagnosis of prostate cancer. Their role in prostate cancer testing is therefore vital but often under-recognised.
  2. The College appreciates the opportunity to review this important document. The document is generally a detailed and balanced summary that compares the benefits and risks of PSA testing for prostate cancer and the Committee and the NHMRC should be commended for undertaking this important but controversial and monumental task. The College does however have concerns about some aspects of the review.

Evidence Evaluation Report:

  1. The College is disappointed that the Committee, while evaluating in detail a number of trials of variable quality, has not been able to use that evaluation discriminatingly to reach a conclusion about the value of PSA testing for early prostate cancer. It appears to give equal weight to trials labelled as having good or poor data quality and further gives undue prominence to the PLCO study as good data quality while later voicing a large number of concerns about the data which largely negate its ability to compare PSA screening to no screening. It is hardly surprising if a meta-analysis containing a number of poor studies showing no effect, combined with a numerically large study with little difference in PSA testing or intervention between the screening and control arms, is inconclusive, as any better conducted study which does show an effect will be effectively swamped.
  2. All of the trials have some problems and even the recent Cochrane review could be criticised for its handling of the Goteborg trial data. The long follow up required in prostate cancer means that inevitably there have been refinements in PSA testing, biopsy protocols and treatments since the trials were designed about 20 years ago so those data reflect to a great extent the clinical practice of the 1990s, yet the median follow up is significantly less at 10-14years.
  3. The PLCO trial was set up with normal care, which included community PSA testing and DRE rather than no testing, as its control arm. This was reflected in the very large level of testing of the control group of 52% as compared to 85% in the screening arm.1 There was also a very low rate of compliance with biopsy 30-40%2 in mmen with a raised PSA in the screening arm severley limiting the effectiveness of screening. The most recent PLCO report3 states "After 13 years of  follow-up, there was no evidence of a mortality benefit for organised annual screening in the PLCO trial compared with opportunistic screening, which forms part of usual care". As this trial is not now even claiming to address the question of PSA testing vs no testing this trial should not be eligible for inclusion in the meta-analysis.
  4. It is noted that this trial scored more highly on some of the epidemiological criteria than other trials but these did not include consideration of criteria which may have been relevant to a prostate cancer trial, such as appropriateness of age and population screened, screening intervals, PSA levels determining biopsy, biopsy protocols, compliance with interventions and completeness of follow-up. The PLCO would have scored poorly for both compliance and followup with only 52% followed up at 13 years, which is why the latest PLCO data was not included in the Cochrane review.
  5. If the Norkopping, Stockholm and Quebec trials are considered of poor quality, their findings should be given less weight. This leaves only the ERSPC and Goteborg trials of at least fair quality on epidemiological grounds and addressing the question of PSA screening vs no testing. The College believes therefore that the indefinite, even negative, conclusion reached in the Evidence Statement on effects of PSA testing on mortality should be re-considered as at least 2 well conducted large trials have now shown a significant effect in reducing prostate cancer specific mortality. The College agrees with the Evidence Statement on overall mortality and that on reduction of metastases. With respect to harms, the Evidence Statement appears to imply that the adverse effects of androgen deprivation therapy (ADT) is a harm arising from PSA testing while noting this is used as a treatment for advanced prostate cancer. As there is evidence now that metastasis is reduced by PSA testing, advanced prostate cancer is more likely therefore to be a complication of not PSA testing. The reduction in morbidity from the metastases themselves and the avoidance of associated ADT should be added to the positive side of the equation.

Information for Health Practitioner

Page 1: Benefits and harms of PSA testing.

The use of false positive and negative to describe a PSA ignores the fact that this is not a qualitative but a quantitative test that also has a continuous, rather than dichotomous, risk profile. This is actually partly recognised on a page 3 underline that states: There is no fixed level that designates a normal test result and that other factors such as age, must be considered when assessing risk. Similarly there is no reference to family history in risk assessment other than as a factor in repeating a PSA that falls in the ‘upper end of the reference range’(page 4). For a health practitioner audience it could be explained that, in this case, the authors are using this as a surrogate diagnostic test. Rather, an elevated PSA result implies an increased risk of prostate cancer. Even if the test is ‘positive’ and no prostate cancer is found, the patient remains at increased risk of harbouring or developing prostate cancer. This is complicated by the imperfect sensitivity and negative predictive value of trans-rectal biopsy. The PSA result itself cannot be considered as ‘false positive’ in fact, a repeat analysis of the serum sample will almost always give the same result; ie an elevation in PSA.

  1. Page 1: Frequency of Benefits and harms of PSA testing. There is no justification in this section for the assumption that a 60 year old man is the best illustrative example. The current evidence suggests that if a 60 year old man has a PSA below the median (about 1.1ug/L) he may never need to be tested again let alone yearly. Furthermore if a 60 year old man has a PSA above average, but below the age related upper reference limit (about 3.5ug/L), there is no proof that yearly testing has any advantage over 2 yearly or 4 yearly testing in low risk men. These issues have a major impact on potential harms of testing and treatment. This is skimmed over on page 4 where it states ‘some doctors may suggest a time to the next PSA test based on the patients test result’ and this is a vital aspect that warrants more detail.
  2. The statement that “8.7% of these men will have a false positive result” is difficult to justify on the evidence. If an age related upper 97.5th percentile for this population is used, only 2.5% will be ‘false positive’. Furthermore as all positive PSA results should be confirmed, when 30% of them fall to within normal limits on repeat testing so that even 2.5% is likely to be an overestimate of current practice.
  3. Regarding the risks of over-diagnosis and overtreatment; these two terms should not be considered synonymous. The reference to the USPTF with 10% active surveillance or watchful waiting is inappropriate. Firstly in Australia the treatment profile according to the Victorian Prostate Cancer Registry has about 40% opting for active surveillance4. There is also major difference between active surveillance4 (monitoring with curative intent) and watchful waiting (monitoring with palliative intent) and the document, rather than clarifying this issue makes the confusion worse. This bracketing of the two concepts together is also found at the top of column 2 on page.
  4. Regarding the uncertainty about which cancers need to be treated, the purpose of biopsy interpretation is to guide this decision and consensus on criteria for active surveillance is being developed. Many men will still make the choice to be treated for low risk disease and the factors that lead to this choice need to acknowledged, such as concerns about risks of under grading or under staging using current diagnostic methods. Not all men make this decision based on ignorance but will choose this path in a fully informed manner, accepting the risk of surgical morbidity and mortality and the uncertainty of any potential survival benefit. Note that, on the current evidence, a ‘small’ protective effect cannot be excluded (see below).

Page 2: Research on the effectiveness of PSA testing

  1. This section could be revised (see comments on the Evidence Evaluation Report). Importantly, the many trials use none of the enhancements in the use of PSA over the last 15 years including: Age related reference intervals, Age related medians, PSA forms (Total PSA, Free PSA, Prostate Health Index), PSA kinetics (PSA velocity / PSA doubling time / %change PSA.
  2. The Medicare Schedule has specifically allowed these enhancements to be used since 2009:
  3. In the question at the top of column 2, page 2, the statement is made that one trial found ‘PSA testing does lead to a small reduction in death from prostate cancer,…'The use of the word ‘small’ is ambiguous as it is a comparative term and potentially seen as being biased as it implies either (i) it is not significant statistically (which it was) or (ii) not significant clinically (where even this reduction would equate to thousands of men saved from this second most common cause of death from cancer in men).
  4. In the second question: Does PSA testing reduce the overall mortality? Is it necessary to say that PSA doesn’t save men from other causes of death (eg cardiovascular death, colorectal cancer remembering that the studies were conducted in the USA and Europe)? I can imagine some relationships eg getting men interested in prostate health may also increase their awareness of their other health problems, or DRE may pick up some colorectal cancers. Diagnosing and treating many less common causes of death (type 1 diabetes, Addison’s disease) wouldn’t impact the overall mortality rate in a country but that doesn’t necessarily mean we should not detect and treat those conditions.

 Page 3: Information to help men and their families

  1. A PSA test doesn’t detect prostate cancer, it assesses the risk of possible prostate cancer. Ideally we should avoid the use of the word detect.
  2. While it is generally true that the PSA test cannot determine which cancers are aggressive or not (unlike the Gleason score on biopsy), the refinements of PSA including the fractions of PSA, including PHI, and its rate of rise can be used in the assessment of the risk of aggressive cancer.
  3. The statement that the DRE should be avoided for 1 week prior to a test seems excessive and should be evidence based.
  4. The PCA3 test and MRI tests should not be mentioned as these are unlikely to ever be first line tests whereas PSA fractions (eg free PSA & PHI) are mentioned in the supporting documents and have been proven as having better diagnostic performance, but are not mentioned in the summary document – even though the Medicare schedule supports them.
  5. On Page 4, the term ‘ reference range' is no longer recommended and the term reference interval should be used. Range implies the full range of results seen in the reference population whereas interval implies the central 95% confidence interval.

In summary:

  • The College believes therefore that the indefinite, even negative, conclusion reached in the Evidence Statement on effects of PSA testing on mortality should be re-considered as at least 2 well conducted large trials have now shown a significant effect in reducing prostate cancer specific mortality.
  • The College agrees with the Evidence Statements on overall mortality and that on reduction of metastases.

  • Family history, DRE, refinements to the PSA test (including age-related reference intervals and PSA forms and kinetics) are useful adjuncts to the clinical decision-making process but none are diagnostic therefore comments about false positive and false negative PSA results do not reflect the purpose of the test.

 The College looks forward to the next Draft of the document and fully supports the efforts of the NHMRC to assist doctors and men in making informed decisions about their health care while awaiting more definitive evidence.

References:

1. Andriole GL, Grubb RL et al “Mortality Results from a Randomised Prostate Cancer Screening Trial”. N Engl J Med 2009; 360:13109

2. Grubb RL, Pinsky PF et al “Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomised trial BJU Int 2008; 201:152430

3. Andriole GL, Crawford ED et al “Prostate Cancer Screening in the Randomised Prostate, Lung, Colorectal and Ovarian Cancer Screenign Trial: Mortality Results after 13 Years of Follow up. J Natl Cancer Inst 2012;104:125132

4. Evans SM, Millar, JL et al “Patterns of care for men diagnosed with prostate cancer in Victoria from 2008 to 2011. MJA

2013 198 3 June 540-5

 

Page reviewed: 4 March, 2014