Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study
BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c4521 (Published 14 September 2010) Cite this as: BMJ 2010;341:c4521
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Numerous PSA-based studies have produced conflicting outcomes
regarding the morbidity and mortality from prostate cancer. This is not
surprising because serum PSA is measured using immunoassays, a technique
known to suffer from significant analytical inaccuracy1,2 when compared
with other common routine laboratory tests such as U&E, LFT, FBC et
cetera. Published data on analytical error rate of immunoassays ranged
from 0.4% to 4.0%. This analytical error rate is largely caused by
interference from endogenous immunoglobulin antibodies which can lead to
erroneous results (falsely high or falsely low) dependant on the nature of
interfering antibodies and immunoassay format1. Furthermore, in these
studies, the focus was on identifying false results which have the
potential to confuse diagnosis and/or management3. Inaccuracy which caused
significant numerical error but nevertheless remained correctly within
their appropriate category (e.g. normal/reference range) were considered
benign and without clinical sequelae4. This can occur despite significant
numerical inaccuracy (e.g. 200% or more)4 introducing potential error in
risk straitfication
Another issue which is not commonly appreciated is the impact of
analytical error on augmenting clinical error rate which additionally
takes disease prevalence/incidence into account. Bayesian theorem can be
used to calculate such impact5. For example, in 60 years old asymptomatic
men in whom the prevalence of prostate cancer is ~ 1 in 2500, an
analytical rate of 0.4% can makes ~ 90% of raised PSA results potentially
false and inaccurate.
The prescriptive use of cut-off points for analyses carried out by
immunoassays is unfortunate. Almost all literature reports have focused on
misdiagnosis and mismanagement of cases caused by wrong immunoassay
results3,5. However, the impact of immunoassays' inaccuracy also appears
not to be fully appreciated in clinical research either, and this may have
contributed to the confusing outcome of PSA studies. Improving the
integrity of immunoassays tests can be achieved by additional affirmative
tests1,5 allowing more robust evaluation and conclusion (for diagnosis or
research) to be derived from data obtained by immunoassay analyses.
Adel A.A.Ismail
Retired consultant in clinical
biochemistry and chemical endocrinology
Wakefield; West Yorkshire
Email: Adel.A.A.Ismail@aol.com
Competing interests: None to declare
(1) Ismail AAA. Interference from endogenous antibodies in automated
immunoassays: what laboratorians need to know. J Clin Pathol 2009; 62: 673
-8
(2) Ismail AAA, Barth JH. Wrong Biochemistry results. BMJ 2001;
323:705-6
(3) Ismail Y, Ismail AA, Ismail AAA. Erroneous laboratory results:
what clinicians need to know. Clin Med 2007; 7: 357-61
(4) Ismail AAA, Walker PL, Barth JH, Lewandowski C, Jones R, Burr WA.
Wrong biochemistry results: two case reports and observational study on
5310 patients on potentially misleading thyroid-stimulating hormone and
gonadotropin immunoassay results. Clin Chem 2002; 48: 2023-29
(5)Ismail AAA, Ismail AA, Ismail y. Probabilistic Bayesian reasoning
can help identifying potentially wrong immunoassays results in clinical
practice "Even when they appear "not-unreasonable". Ann Clin Biochem.
Accepted for publication
Competing interests: No competing interests
Exhausting PSA
To the editor
RE:
Vickers AJ, Cronin AM, Bjork T, Manjer J, Nilsson PM, Dahlin A, Bjartell
A, Scardino PT, Ulmert D, Lilja H. Prostate specific antigen concentration
at age 60 and death or metastasis from prostate cancer: case-control
study. BMJ. 2010;341:c4521. doi: 10.1136/bmj.c4521.
To improve its performance, PSA's use in the diagnosis of prostate
cancer (CaP) has moved from the original single cut-off level of 4ng/ml,
to PSA density, various age and racially adjusted ranges, PSA velocity,
free/total ratio, PSA kinetics, and various combinations of the above.
Here, it is back to a single cut off value, but for the specific age of 60
y(1).
This article's recommendation drops the mark of 'normality' from the
previously accepted 'reference range', to the median value; and into a new
era, namely predicting CaP in the future.
The authors do not attempt to explain the association between PSA
levels and the clinical events that might happen more than a decade later.
Do they suggest that CaP is already present at 60, and the time lapse is
due to the slow progression of CaP; or are they postulating that a high
PSA expression is somehow a precursor of a disease that is yet to develop?
The implications are important. If it is the former, then prostate biopsy
would be the logical next step, and the management would be that of the
diagnosed CaP and not its prevention. If it is the later, then screening
for the 'at risk' group, and prevention, if possible, might be justified.
In that case a well-balanced dividing line needs to be drawn, weighing-in
the benefits, drawbacks, and the financial implications, and working out a
defined surveillance programme.
The authors propose that the application of their findings will have
the advantage of being able to reassure 50% of men. In reality, applying
the new lower threshold will heighten the fear of future CaP for a larger
proportion of the population than before, for longer, and without a clear
idea of what to do next.
The magnitude of the risk also needs some scrutiny. In this paper,
the estimated risk of death before 85 was 0.28%, 0.9%, 5.6% and 11% for
PSA level of 0.65, 1.06, 2.12 and 3.4 ng/ml at the age of 60. This does
not seem to as serious as the statement that "men with a prostate
specific antigen concentration >2 ng/ml at age 60, have, on average, 26
times the odds of dying from prostate cancer than men with a concentration
<2 ng/ml". Although all estimations are mathematically correct, they
paint very different pictures, taking into consideration the age at death.
The authors chose to draw the dividing line at 1 ng/ml. Arguably, the
right balance lies at a higher level taking into consideration that the
estimated population centiles for the mentioned 4 levels are 25, 50, 80
and 90, respectively.
The recommendation for chemoprevention is not supported by any new
findings. To imagine that androgen deprivation can 'prevent' prostate
cancer is over-simplistic. A literature review by the AUA and ASCO showed
no cancer-specific or overall survival advantages for 5ARIs. It noted the
reduction in the risk of 'diagnosing' prostate cancer on the medium term,
albeit with an increase in the proportion of high grade disease, the later
is of disputed significance (2).
The advantages of screening for CaP are marginal at best (3,4). PSA
is not, and will never be, a cancer specific test, and its use should be
thoughtful to avoid doing more harm than good. Nearly all guidelines
recommend a good upfront discussion with men considering PSA testing. The
AUA has updated its advice regarding the use of PSA in early
diagnosis/screening for CaP to recommend individualised risk assessment
and warn against acting on the basis of a single test or the use of rigid
arbitrary cut-off points (5), and we should all bear that in mind.
References:
1. Vickers AJ, Cronin AM, Bj?rk T, Manjer J, Nilsson PM, Dahlin A, et
al. Prostate specific antigen concentration at age 60 and death or
metastasis from prostate cancer: case-control study. BMJ. 2010;341:c4521.
doi: 10.1136/bmj.c4521.
2. Kramer BS, Hagerty KL, Justman S, Somerfield MR, Albertsen PC,
Blot WJ, et al. Use of 5_-Reductase Inhibitors for Prostate
Cancer.Chemoprevention: American Society of Clinical Oncology/American
Urological Association 2008 Clinical Practice Guideline.. J Urol
2009;181,:642-1657.
3. Andriole GL, Crawford ED, Grubb RL 3rd, Buys SS, Chia D, Church
TR, et al. Mortality results from a randomized prostate-cancer screening
trial.N Engl J Med 2009;360:1310-9.
4. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V,
et al. Screening and prostate-cancer mortality in a randomized European
study. N Engl JMed 2009;360:1320-8.
5. Prostate-Specific Antigen. Best Practice Statement: 2009 update.
http://www.auanet.org/content/media/psa09.pdf (accessed 14.10.2010)
Mr Magdi M Kirollos. FRCS (Urol), FEBU.
Consultant Urological Surgeon. Torbay Hospital. South Devon Healthcare
Trust. Urology Department. Lawes Bridge. Torquay TQ2 7AA, Devon. UK.
e-mail: magdi.kirollos@nhs.net
Competing interests: No competing interests