JUNE 4: PROSTABLOG NZ: Any hopes the NZ Prostate Cancer Foundation and some top urologists may have that the government will change its mind any time soon about promoting prostate cancer screening among men are not helped by a new NZ Medical Journal article. READ ARTICLE HERE>
There has been world-wide renewal of the debate about population-based screening campaigns since publication in the New England Journal of Medicine in March of the results of a couple of long-term studies into whether PSA testing saves more lives.
The authors of the NZ article think the results support a long-held fear that PSA testing leads to “over diagnosis” and unnecessary treatment of slow-growing prostate tumours that were never going to do any harm.
The Otago University researcher and epidemiologist say:
“The results of the randomised controlled trials might optimistically be considered to indicate that: eventually there will be a reduction in prostate cancer mortality from PSA testing of asymptomatic men 55–69 years of age; the considerable harms from such testing are bearable by patients and the health care sector, and; PSA testing of asymptomatic men should be facilitated.
“Another view would be that we now have inconclusive evidence from randomised controlled trials of any decrease in prostate cancer mortality and unequivocal evidence of major harms, mainly from over-diagnosis and consequent overtreatment, so much so, that good health care should involve advising asymptomatic men against PSA testing at this time.”
The article is timely, since the Ministry of Health is due to release an updating statement on its prostate screening policy.
Its stance has been that a campaign like those for cervical and breast cancer screening is not appropriate for prostate cancer, given widely held views that it may do more harm than good.
This is a view shared by the Cancer Society, but not the prostate cancer foundation, whose president, Barry Young, has called the stance scandalous.
His opinion appears to be backed by statistics showing the death rate among Maori men from prostate cancer is twice that for non-Maori. The cervical and breast cancer campaigns feature TV advertisements clearly aimed at Maori and Pacific Island women.
Recent US studies show poorly educated men in lower socio-economic groups fare worst from prostate cancer, as do black Americans.
The NZ Medical Journal article seems at odds with the American Urological Association’s recently updated guidelines, which urge men of 40 to be PSA-tested so a baseline for later comparison can be established (level change and speed of change are significant).
However, the AUA is equivocal about what the two studies reveal and stops well short of recommending population-based screening. It advises “well-informed” men to seek individual assessment by their physicians, a view held by the NZ Ministry of Health.
The ministry has been reviewing the studies. One of its committees discussed them on May 18 and has made a recommendation on screening to the Director General of Health, who is expected to make a statement as early as Monday.
This will undoubtedly assist the new Minister of Health, Tony Ryall, who contradicted himself when he announced new health targets in May. He made no mention of prostate cancer, despite his January statement that it would be a top priority for the new Government.
NZ Medical Journal, June 5, 2009:
PSA testing in asymptomatic men to diagnose prostate cancer remains experimental
By Brian Cox, Mary Jane Sneyd
The recent reductions in prostate cancer mortality seen in some countries have been attributed to earlier detection of the cancer by PSA testing.
However, the randomised controlled trials show that if any benefit from PSA testing exists it would not be seen within 7 years of its introduction.(1,2)Therefore, the mortality reductions observed are likely to be due to more cases being offered curative therapy or the availability of better treatment.
In 1996, PSA testing of asymptomatic men was considered experimental and the major potential for over-diagnosis and subsequent overtreatment with major sideeffects was highlighted3 and now the results of two studies have become available.
These results provide conflicting evidence of the effectiveness of PSA testing in reducing mortality from prostate cancer.
The results of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial in the United States were published because, at this time, the study’s monitoring board raised concerns about the harms they identified from PSA testing in asymptomatic men,(2) whereas the European Randomized Study of Screening for Prostate Cancer (ERSPC) study protocol precipitated publication when a statistically significant result was obtained from analyses conducted at regular intervals.(1)
A summary of the design of these two studies is shown in Table 1.
The ERSPC study was conducted in 7 countries, used various PSA cut-off points for recommendation for biopsy, varying screening intervals, and different age eligibility, with screening ceasing when the upper age of eligibility was reached.
In the PLCO trial, men aged 55–74 years were offered annual PSA testing for 6 years, combined with digital rectal examination for 4 years, or in the control arm received usual care.
Active annual follow-up by questionnaire and linkage to the National Death Index was undertaken with a median duration of follow-up of 11.5 years (range
7.2–14.8). The PSA assays for each PLCO trial centre were performed by one laboratory. A cut-off of 4ng/ml was used to recommend referral to their usual doctor.
Table 2 summarises the main results of these studies.
The results of the ERSPC study suggested a 20% reduction in prostate cancer mortality from PSA testing, along with other screening tests such as digital rectal examination (DRE) and transrectal ultrasonography (TRUS), in asymptomatic men after a median of 9 years of follow-up (RR=0.80, 95%CI 0.65–0.98).
Table 1. Summary of the design of the PLCO trial and the ERSPC study
The PLCO trial observed a non-significant 13% increase in prostate cancer mortality in those offered annual PSA tests (RR=1.13, 95%CI 0.75–1.70) after 7 years of follow-up for all subjects.
This was not significantly altered by inclusion of available data to 10 years of follow-up (67% of subjects) or if confined to those with one PSA test, or 2 or more tests, in the previous 3 years at baseline.
The chance of a diagnosis of prostate cancer increases with the number of biopsies taken.
In the ERSPC study the number of biopsies after a positive screening test varied between countries, but standardisation was recommended in 1996, whereas in the PLCO trial the decisions about biopsy and treatment were left to the man’s usual health care provider.
This meant that, in the PLCO trial, any further assessment procedures and treatment were expected to be similar for both the intervention and control group.(4)
Table 2. Summary of the PLCO trial and ERSPC study results of PSA screening for prostate cancer
In Finland, Sweden, and Italy, randomisation of the offer of screening occurred after selection from population registers – a study of the effect of the introduction of prostate screening in the general population (the effectiveness of screening).
In the Netherlands, Belgium, Switzerland, and Spain, randomisation occurred after acceptance of the invitation to participate—a study of screening in those who accept it (the efficacy of screening).
Efficacy is greater than effectiveness and effectiveness measures the overall benefit of offering PSA testing to asymptomatic men in the population.
Therefore, the ERSPC study estimate of benefit is greater than would be achieved from population-based PSA testing in asymptomatic men.
In the PLCO trial 40% of the control subjects had at least one PSA test by the second year of follow-up (contamination of the controls) and this increased to 52% by the sixth year of follow-up.
The contamination of the control group in the ERSPC study was not reported in the recent publication but varied from 6.7% to 36.6% among centres during 1996–2001.(5)
This resulted in a smaller relative increase in prostate cancer diagnoses between intervention and control groups in the PLCO trial (22%) compared to the ERSPC study (71%).
Detailed analyses of both the similarities and differences among the different trials included in the ERSPC study are likely in the future.
The beneficial effects from randomised controlled trials of screening almost always exceed what is obtained when the technology is introduced into routine health care, as the tight controls for the decision making process and management protocols of trials tend to be lost.
A greater length of follow-up of the trials will be required before more conclusive results are available. However, the contamination of the control groups in both studies may not have occurred equally among different risk groups for prostate cancer death, resulting in unresolvable bias.
What is now unequivocal from these two trials is the magnitude of over-diagnosis and subsequent overtreatment resulting from the PSA testing of asymptomatic men.
Overdiagnosis is the detection of prostate cancer that would not become clinical disease in a man’s natural life.
This is sometimes referred to as indolent prostate cancer and has been known for a long time to be very common.
This over-diagnosis has been estimated to be 48% (95%CI 44%–55%) for annual screening and 50% (46%–57%) for 4-yearly screening in men aged 55–67 years.(6)
The treatment of prostate cancer by either radical prostatectomy or radiotherapy carries significant risks such as chronic incontinence (urinary or faecal), impotence, or, in some instances, death.
In addition to significant side-effects, the treatment of many men who will not benefit produces increased waiting times and reduced accessibility to radiotherapy and surgery for other patients who may benefit from them.
For example, if we accept the ERSPC study results, 1480 men would need to be screened and 48 additional cases of prostate cancer treated for each death from prostate cancer prevented over a 10-year period.
Moreover, about 24 of the additional cases treated would receive treatment for a condition that would not have become clinical prostate cancer in their lifetime, and of these about 4 would have chronic incontinence or impotence.
The decision about the value of PSA testing in asymptomatic men is not solely determined by the magnitude of any reduction in prostate cancer mortality but by the balance of harms versus benefits.
Despite previous claims of effectiveness,(7,8) it now appears that if there is a reduction in prostate cancer mortality from PSA testing in asymptomatic men, it is likely to be small.
The current results of the trials assist in resolving the controversy regarding the value of PSA testing of asymptomatic men.
The results of the randomised controlled trials might optimistically be considered to indicate that: eventually there will be a reduction in prostate cancer mortality from PSA testing of asymptomatic men 55–69 years of age; the considerable harms from such testing are bearable by patients and the health care sector, and; PSA testing of asymptomatic men should be facilitated.
Another view would be that we now have inconclusive evidence from randomised controlled trials of any decrease in prostate cancer mortality and unequivocal evidence of major harms, mainly from over-diagnosis and consequent overtreatment, so much so, that good health care should involve advising asymptomatic men against PSA testing at this time.
It is easy to understand the belief that the early detection of cancer must result in a reduction in the mortality from the disease.
Historically, many clinicians and patients have been seduced by this idea many times for a variety of cancers.(9)
However, the current randomised controlled trial evidence suggests that claims of benefit from PSA testing in asymptomatic men have probably been overstated and that, as indicated by the authors of one of the trials,2 the recognised harms must be more rigorously considered to protect many men from iatrogenic illness.
Author information: Brian Cox, Associate Professor; Mary Jane Sneyd, Research Fellow; Hugh Adam Cancer Epidemiology Unit, Department of Preventive and Social Medicine, University of Otago, Dunedin.
Acknowledgement: Associate Professor Cox and Dr Sneyd were funded by the Director’s Cancer Research Trust.
Correspondence: Brian Cox, Hugh Adam Cancer Epidemiology Unit, Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin, New Zealand. Fax: +64 (0)3 4797164; email: email@example.com
1. Schroder FH, Hugosson J, Roobol MJ, Tammela TLJ, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. New England Journal of Medicine. 2009;360(13):1320–8.
2. Andriole GL, Crawford ED, Grubb RL, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. New England Journal of Medicine. 2009;360(13):1310–9.
3. Cox B. Prostate cancer screening is experimental. The New Zealand Medical Journal. 1996;109(1017):63–4.
4. Barry MJ. Screening for prostate cancer – the controversy that refuses to die. New England Journal of Medicine. 2009;360(13):1351–4.
5. Ciatto S, Zappa M, Villers A, Paez A, Otto SJ, Auvinen A. Contamination by opportunistic screening in the European Randomized Study of Prostate Cancer Screening. BJU International. 2003;92 (Suppl. 2):97–100.
6. Schroder FH. Detection of prostate cancer: the impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The Canadian Journal of Urology. 2005;12 (Suppl. 1):2-6.
7. Lamb DS, Slaney D, Smart R, Nacey JN, Russell G, Scott B, et al. Prostate cancer: the new evidence base for diagnosis and treatment. Pathology. 2007;39(6):537–44.
8. Smart R. PSA testing and DRE, TRUS scanning with sector biopsy, improved histology, curative treatments, and active surveillance for prostate cancer: asuccess story for men’s health. New Zealand Medical Journal. 2008;121(1287):57–68.
9. Richardson AK. Prostate cancer screening: is it possible to explain diametrically opposed views? New Zealand Medical Journal. 2005;118(1209).
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