NZ MEDICAL Journal papers on screening

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: brian.cox@otago.ac.nz

References:
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).

Prostate cancer screening: is it possible to explain diametrically opposed views?

NZ Medical Journal, February, 2005

To see original, click HERE>

Ann Richardson, Associate Professor, Department of Public Health and General Practice, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch

Prostate cancer screening is controversial. Clearly, the views of those who support and actively offer prostate cancer screening are very different from the views of those who see no justification for screening at present. How can we understand and explain such opposing views?
 
It is likely that differences of opinion about prostate cancer screening reflect differences in the way people assess the benefits and risks of screening. By examining each of these in turn, it is possible to understand the controversy, but also determine whether prostate screening is ethical.
Benefits
Underlying the discrepant views on screening is the extent to which people assume that screening is beneficial. If men and their doctors assume that screening must be beneficial, then irrespective of the outcome of prostate-specific antigen (PSA) testing, both the man and his doctor will be positively reinforced:

A physician is positively reinforced for recommending screening, regardless of the test result, because a negative result makes the patient grateful for reassurance and a positive result makes a patient grateful for early detection. A patient who is impotent and incontinent after a decision for curative treatment may attribute his survival to surgery and be grateful for having his cancer cured. Individual experience provides almost no negative feedback that early detection and aggressive treatment may not work.

But is prostate cancer screening beneficial? Intuitively it seems obvious; surely picking up disease earlier must be good? Unfortunately we know that screening is not always beneficial. Randomised controlled trials (RCTs) have revealed that some screening procedures (for instance, screening for lung cancer using chest radiography and sputum cytology in high-risk individuals, and screening for breast cancer with breast self-examination), which were previously assumed to be beneficial, are not.

Using methods such as survival comparisons, observational studies, or ecological studies to assess screening is dangerous, these studies are vulnerable to biases, which can cause any benefit of screening to be overestimated, and at worst, can make screening appear beneficial even when it is not (Table 1).

Only an appropriately designed and analysed RCT can avoid these biases, and determine whether screening for prostate cancer really is beneficial.

At present, we do not know if there is any benefit from prostate cancer screening, because there is not yet evidence from appropriately designed and analysed randomised controlled trials. Two large RCTs are presently underway.

Table 1. Why do we need randomised controlled trials of prostate cancer screening?

Bias is a defect in study design or analysis that causes results to deviate from the truth. The following biases can affect the assessment of prostate cancer screening:

Lead time bias
Screening can detect prostate cancer early, thereby extending the interval between diagnosis and death, even if the time of death is unchanged. Because survival time is measured from time of diagnosis to death, men whose prostate cancer was detected by screening will have longer survival times than men diagnosed clinically, even if screening does not actually extend life.

Length bias
Fast growing prostate tumours, which tend to have the worst prognosis, are less likely to be detected by screening, because they grow so rapidly that the period when the tumour could be detected by screening before signs or symptoms develop, may be very short. Screening will therefore detect a disproportionate number of slow growing tumours with a good prognosis. Comparisons of outcome between men with screen-detected prostate cancer and men with clinically-diagnosed prostate cancer are likely to be invalid because of this.

Selection bias
Men who take up the offer of screening may differ in their underlying risk of dying from prostate cancer, so that their prognosis would have differed from non-participants even in the absence of screening. Thus, comparing the outcome for men who have been screened with men who have not may be inappropriate. Selection bias can be avoided in a randomised-controlled trial by appropriate (intention to treat) analysis.

Over-diagnosis bias
Screening may detect abnormalities that are of questionable malignancy and cancers that would not have been diagnosed in the absence of screening. Although some of these abnormalities and cancers may never have been diagnosed, nor affected a man’s life in the absence of screening, they will be counted as ‘screen-detected’ cancers. Because of the inclusion of these cancers, the outcome for a group of screened men with prostate cancer will appear better than the outcome for unscreened men with prostate cancer.
Risks
People who are unwell are often prepared to take risks in order to get better. Many patients will accept treatments that carry risks; for instance, drugs that have potential side effects, and radiotherapy or surgery despite their possible complications.

Clinicians are used to interacting with people who are unwell and who tolerate potential harm in order to get better. Clinicians may transfer this tolerance of harm to the screening situation, hence urologists may be more likely to support prostate cancer screening than public health physicians.

But people who are well may not share the same tolerance towards potential harm, especially if the benefit is uncertain. If there is no benefit, the net effect of screening will be to harm those who take part. Apart from the obvious harms related to false negative and false positive screening results, over-diagnosis is likely to be a major problem in prostate cancer screening.

Autopsy studies, where prostate biopsies were taken from men who had died of causes other than prostate cancer, have shown that the histological evidence of prostate cancer in such men is much higher than the lifetime incidence and mortality from prostate cancer. In other words, histological evidence of prostate cancer can be found in far more men than would ever be expected to suffer from or die from the disease.

Further evidence of over-diagnosis comes from the Finasteride Trial, which was designed to find out whether the drug Finasteride could prevent prostate cancer.

Men aged 55 years and over were randomly allocated to an intervention group (which took Finasteride) and a control group (which took a placebo). All the men had normal digital rectal examinations (DRE) and PSA results at entry to the trial. During the trial, the men underwent annual DRE and PSA tests.

At the end of the trial, all men who had not been diagnosed with prostate cancer during the trial were offered an end-of-study prostate biopsy. Of 4692 men in the control group who had prostate biopsies, nearly a quarter (24.4%) had histological evidence of prostate cancer at the end of the seven years’ follow-up.

The investigators had expected 6.0% of the men to be diagnosed with prostate cancer during the trial, and the expected lifetime prevalence in these men was 16.7%. The trial investigators themselves stated ‘The rate of 24.4% suggests the possibility of over-diagnosis of disease.’

The results from autopsy studies and the Finasteride trial are a warning.

If healthy men have PSA tests, some will be diagnosed with prostate cancer that they would otherwise never have known about, and that would never have threatened their lives. This would be bad enough, but many men who are diagnosed with prostate cancer are offered treatment such as radiotherapy or surgery, and these treatments have significant side effects. The potential side effects include impotence, incontinence, diarrhoea, and death.

Some of the men who suffer these side effects would never have known they had prostate cancer in the absence of screening, so they will have been directly harmed as a consequence of being screened.
Conclusion
Although it is possible to understand and perhaps explain opposing views on prostate cancer screening, examining the risks and benefits shows that prostate cancer screening is not justified at present.

Whether there is any benefit from prostate cancer screening is unknown. It is inappropriate to support screening in the hope that it will be found to be beneficial, since this would be gambling with men’s health.

Prostate cancer screening fails to meet criteria for screening, and carries potentially serious risks. In the absence of conclusive evidence of benefit, it is entirely possible that prostate cancer screening could cause more harm than good. Therefore, at present, it is unethical to offer prostate cancer screening.

 In the future, screening should only be offered if the randomised controlled trials of prostate screening that are currently underway, demonstrate a benefit.

Author information: Ann K Richardson, Associate Professor, Department of Public Health and General Practice, Christchurch School of Medicine and Health Sciences, University of Otago, PO Box 4345, Christchurch

Correspondence: Dr Ann Richardson, Department of Public Health and General Practice, Christchurch School of Medicine and Health Sciences, University of Otago, PO Box 4345, Christchurch. Fax: (03) 364 3614; email: ann.richardson@chmeds.ac.nz

Prostate cancer screening—finding the middle road forward

NZ Medical Journal, February, 2005 – Editorial by David Lamb, Brett Delahunt

To see original, click HERE>

The viewpoint paper on prostate cancer screening in this issue of the New Zealand Medical Journal raises some interesting questions about the medical rights of individuals, and precisely what is unethical behaviour in medicine (Richardson A. Prostate cancer screening: is it possible to explain diametrically opposed views? URL: http://www.nzma.org.nz/journal/118-1209/1289.

The author immediately gets into difficulties by posing a question in the title of the paper, and then failing to address it in the subsequent text. The truth is that diametrically opposed views are rarely both right, and are often both wrong.

The middle position, or moderate view, is usually shown in time to be the correct one. The extreme positions in prostate cancer screening are, at one end, that no one should be screened (the author’s position); and at the other end, that all men over the age of 50 years should be enrolled in systematic population-based screening programmes.

This latter extreme is a position unsupported by nearly all health professionals active in the treatment of prostate cancer. The middle position, which currently available evidence suggests is a reasonable one to hold, is that screening should be accessible to those younger men most likely to have the disease, and to those men most likely to benefit from early diagnosis, such as men aged 70 years or less.

In adopting a paternalistic approach to all prostate cancer screening, the author fails to recognise that there are important differences between population-based screening (PBS) and self-requested screening (SRS).1 The value of PBS is determined by measuring the net benefit for the population screened, and this requires levels I and II evidence from well designed randomised controlled trials (RCTs).

At present, such evidence is not available, but absence of evidence is not evidence of absence. Unless the biological behaviour of prostate cancer is completely different to that of other cancers, and we have no reason to believe that it is, then it is a reasonable premise that earlier detection and treatment of the disease will be associated with survival advantages for at least some patients.

Backing this belief is the fact that, after treatment, the survival of patients presenting with locally advanced tumours extending through the prostate capsule falls to approximately 20% at 10 years, compared with 85% for early confined tumours.

Most clinicians do not believe that lead time bias can be the sole explanation for this difference, as the cancer control curves for patients presenting with non-metastatic tumours have reached a plateau by 10 years after treatment, indicating that patients who have not relapsed at this time are cured. If diagnosis as early as possible in the natural history is to be abandoned as one of the key goals for improving outcomes, RCTs will therefore need to produce some surprising results.

The situation with SRS is very different to PBS. Here it is the individual man who is making a value judgement on whether or not they perceive there are advantages in being screened.

Given the uncertainties that currently exist, it is not appropriate for others to make this decision on his behalf. The individual does require access to adequate educational literature to make an informed decision, and this material is currently not freely available to the public of New Zealand.

Most importantly, the public needs to know which people are most likely to develop prostate cancer, and which people are most likely to benefit from earlier diagnosis, as well as details of the screening process, and its side effects.

Those who are found to have prostate cancer need additional information on the implications of their particular cancer, the management options open to them, and the possible side effects of treatment.

The correct response is to provide this missing literature, not to withdraw all rights to screening. The suggestion that SRS is not ‘ethical’ is curious, as SRS is widely practised throughout New Zealand, and it is usually the majority opinion that determines what constitutes ethical behaviour.

Those men at particularly high risk of developing prostate cancer deserve a special mention. The risk of developing prostate cancer rises by up to 11 times that of the general male population when a man has one or more first-degree relatives with the disease.5 Surely these men with genetic risks comprise a group that should be actively encouraged to present for screening?

The utility of the prostate cancer screening process has been described in detail in a recent New Zealand publication.6 This paper addresses how the pathology report on prostate biopsies can be used to obtain a better understanding of whether or not the cancer is a clinically significant one.

A recent Swedish report showed that unsuccessful treatment, or no treatment, of cancers considered ‘low risk’ at diagnosis led to a high mortality rate from cancer by the time 15 years follow-up had elapsed.7 The mortality rate was particularly high for those patients aged 70 years or less at diagnosis.

The incidence of prostate cancer in the Finasteride Trial,8 referred to by the author of the opinion paper that follows, is certainly higher than might have been anticipated, but this is probably due to the inclusion of some low-grade tumours that most expert pathologists would regard as being of dubious clinical significance. The absence of any outcome data from this trial makes it impossible to interpret the data further.

The low mortality ratio (incidence/mortality) of prostate cancer seen in New Zealand9 and other Western countries is unlikely to be due solely to a high proportion of ‘trivial’ cancers allowing death from other causes to intervene. Effective treatment for early tumours is also probably a factor, but until the New Zealand Health Information Service (NZHIS) is able to monitor cohorts of patients with full clinical data, we will struggle to understand the relative contribution of treatment and natural history to patient outcomes.

In conclusion, there are large gaps in our knowledge and understanding of prostate cancer, and we look to the results of large RCTs to fill these gaps. Until then, some assumptions have to be made based on the generic behaviour of cancer. Prostate cancer is a major cause of male death, so deserves the respect of all medical disciplines, as well as governments responsible for funding our health services.

Author information: David Lamb, Associate Professor; Brett Delahunt, Professor, Department of Pathology and Molecular Medicine, Wellington School of Medicine and Health Sciences, University of Otago, Wellington South.
Associate Professor David Lamb is Head of the Radiation Service at the Wellington Cancer Centre. He is a Principal Investigator in the first large prostate cancer trial run by the Trans-Tasman Radiation Oncology Group (TROG 96.01). He is the New Zealand Chair of the RADAR prostate cancer trial (TROG 03.04), currently recruiting patients in Australia and New Zealand.
Professor Brett Delahunt is Professor of Pathology and Molecular Medicine at the Wellington School of Medicine. He is a member of the WHO Tumour Classification Working Group on Classification of Urological Pathology, and Secretary of the International Society of Urological Pathology. He is the review pathologist for the RADAR trial (TROG 03.04).

Regarding ‘Prostate cancer screening—finding the middle road forward’ editorial

NZ Medical Journal, February, 2005

Response from Ann Richardson, Associate Professor, Department of Public Health and General Practice, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch

To see original, click HERE>

The Editorial in the 11 February 2004 issue of this Journal1 was written in response to my Viewpoint article in the same issue: Prostate cancer screening: is it possible to explain diametrically opposed views?

The authors of the Editorial, David Lamb and Brett Delahunt, found some difficulty with the answer to this question, which was provided in the Viewpoint article.

To summarise, it is possible to explain diametrically opposed views by weighting the benefits and risks of screening differently. Those who support prostate cancer screening assign great weight to the benefits of screening (despite the lack of evidence), and little weight to the risks.

Those who do not support screening acknowledge the risks and recognise that, given the lack of evidence of benefit, these risks could outweigh any benefits of screening.

Recognition of these risks has led to caution even from previous supporters such as Professor Thomas Stamey, one of the initial advocates for PSA screening for prostate cancer in the 1980s, who wrote last year:

What is urgently needed is a serum marker for prostate cancer that is truly proportional to the volume and grade of this ubiquitous cancer, and solid observations on who should and should not be treated which will surely require randomized trials once such a marker is available.

Since there is no such marker for any other organ confined cancer, little is likely to change the current state of overdiagnosis (and over-treatment) of prostate cancer, a cancer we all get if we live long enough.

Finally, lowering the cutoff indication for prostate biopsy from 4.0 to 2.5 simply compounds the tragedy by adding millions of men to the biopsy list.

In their Editorial, Lamb and Delahunt argued that “absence of evidence is not evidence of absence.”

This argument could be a valid argument for screening only if there were no harm associated with screening.

Then, even if PSA screening turned out not to be beneficial, at least no men would have been harmed. Unfortunately we know that there is harm associated with screening, so if PSA screening turns out not to be beneficial, the net effect of screening will be to have caused harm to thousands of men. Even if it transpires that there is a benefit from screening, the harm must still be considered.

The point is, at the moment we do not know:

    * Whether there is any benefit from prostate cancer screening, and
    * If there is, whether the benefit outweighs the harm.

This information can only be obtained from the randomised controlled trials that are currently in progress.

Finally, and most importantly, Lamb and Delahunt suggested that I regard “self-requested screening” as unethical.

In fact, my Viewpoint article did not address self-requested screening at all, but discussed the ethical implications of offering prostate cancer screening to men. I addressed this issue specifically because many readers of this Journal are health professionals who need to decide whether to offer PSA screening to their patients.

This issue is not confined to population screening, since screening can also be offered opportunistically. It is the offer of prostate cancer screening that I believe to be unethical, because we do not know whether the harms of screening outweigh the benefits.

It would not (and should not) occur to most men that their doctor would offer them an unproven and possibly harmful screening test. Thus, men are likely to regard an offer of prostate cancer screening from a doctor as a recommendation to be screened, or at the very least an endorsement of screening.

That is why I believe it is inappropriate for doctors to offer prostate cancer screening at present, especially because, as doctors, we should “first do no harm”. The Editorial by Lamb and Delahunt, in focusing on self-requested screening, addressed a completely different issue.

The difference between offering screening and responding to a request for screening was recognised by the National Health Committee (which also recommended against offering screening), in its recommendation:

“men who request a PSA test and/or DRE be provided with information which clearly explains the possible harms and benefits of screening and subsequent treatment. This is to ensure that men reach a fully informed decision”.

Screening for prostate cancer: a survey of New Zealand general practitioners

NZ Medical Journal, June 20, 2003 – John Durham, Melissa Low and Deborah McLeod 

To see paper: click HERE>

Abstract

Aim: To determine the views of general practitioners (GPs) in relation to screening for prostate cancer.

Methods: A questionnaire was sent to a random, national sample of 575 New Zealand general practitioners, stratified to include equal numbers of rural and urban GPs.

Results: The response rate to the questionnaire was 66.3%. A 55-year-old man presenting for an annual checkup or requesting advice about screening for prostate cancer would be given a prostate specific antigen (PSA) test by 74% of GPs.

If the same man had a family history of prostate or breast cancer, 93% of GPs would carry out a PSA test. Most GPs overestimated the effectiveness of screening tests for prostate cancer and were uncertain about the importance of associated risk factors. Some form of screening for prostate cancer is performed by 97.5% of GPs, and 50% of GPs support a national population-screening programme.

‘Watchful waiting’ is considered to be a reasonable treatment option for a man with localised prostate cancer and less than 10 years’ life expectancy by 40% of GPs compared with 2% for a man with more than 10 years’ life expectancy.

Conclusion: Most GPs undertake screening for prostate cancer, even though there is no evidence that screening improves life expectancy and quality of life. 

MAIN PAPER

Prostate cancer is an important health issue for New Zealand men.

In 1999, the latest year for which complete figures are available, the age-standardized rate for prostate cancer registrations was 98.2 per 100 000 population.1

It is the third most common cause of cancer deaths in males, following lung and colorectal cancer, and accounted for 14% of all male cancer deaths and 3.85% of all male deaths in 1999, with an age-standardized mortality rate per 100 000 population of 18.5.2

There has been a rapid increase in the rate of new registrations for prostate cancer since about 1991. New registrations increased by 63% between 1993 and 1994, and 23% between 1994 and 1995. From 1995 to 1997 there was a 6.2% decrease in the annual rate of new registrations but the rate increased again in 1999.1

The great majority of new registrations in 1999 were based on a histological diagnosis. It is likely that the specimens provided for most of these patients were taken from needle biopsies of the prostate gland performed because of abnormal findings on digital rectal examination (DRE) or prostate specific antigen (PSA) testing.

More than 58% of all new registrations were in men aged more than 70 years. Prostate cancer had a fatality/case ratio of 0.21, with nearly five times more registrations than deaths.

In 1999 there were a total of 552 deaths from prostate cancer; 81.9% of these deaths were in men older than 70 years and 38.9% in men older than 80 years.2

It is possible that this sudden and rapid increase in the incidence of prostate cancer is a result of screening using the PSA test.

‘Screening’ refers to the application of a test to people who are as yet asymptomatic for the purpose of classifying them with respect to their likelihood of having a particular disease.3

In 1996, the New Zealand National Health Committee (NHC) sponsored a review by an independent Prostate Cancer Screening Working Party of the potential risks and benefits that might arise from prostate cancer screening.

The Working Party reported that there were significant potential risks associated with confirmatory tests and treatment, and that these risks outweighed the as yet unproven benefits of earlier intervention that would be achieved by screening asymptomatic men for prostate cancer.

A joint policy statement advising against routine prostate screening for men without symptoms was issued publicly by the NHC in New Zealand and the Minister for Human Sciences and Health in Australia on 12 August 1996.

The NHC recommended that: “Because screening has not been demonstrated to improve the quality and length of men’s life through early diagnosis, a systematic prostate cancer screening programme for men without symptoms should not be introduced. The matter should be kept under review.”4

At about the same time as the 1996 NHC recommendations, a survey of 500 New Zealand general practitioners (GPs) reported the views and practices of GPs in relation to screening for prostate cancer.5

This study found that approximately one third of GPs believed that no one should be screened using either the PSA test or DRE and 40% of GPs felt that all men over 50 years in age should be screened with one or other test. These results were similar to surveys in other countries where primary care physicians had high and increasing rates of PSA testing, with PSA tests forming part of the routine examination of men more than fifty years of age.6,7

The aim of the current study was to determine whether the rapid increase in the incidence of prostate cancer was consistent with GPs continuing to undertake PSA screening, and to identify current practice with respect to prostate cancer screening.
Methods
Medimedia, who have a commercially available database of 2684 New Zealand GPs, provided a computer-generated, random, national sample of 600 GPs. The sample was stratified on the basis of postcodes to include equal numbers of rural and urban GPs.

The full Medimedia database consisted of 1603 GPs with an urban postcode and 1081 GPs with a rural postcode. Twenty five GPs from the initial sample were ineligible for the study, leaving a final sample of 290 urban and 285 rural GPs.

The reasons for exclusion of GPs from the sample were that 10 had left general practice, four were on long-term leave and 11 were no longer at the address provided.

The questionnaire used was developed specifically for this study and was piloted on a different sample of 10 GPs to ensure that it was understandable and had face validity. Screening behaviour was measured using closed questions about practice screening programmes, a series of case vignettes of typical screening situations, the performance of screening tests, risk factors for prostate cancer, and treatment options.

The questionnaire defined ‘population screening’ as offering a test to all men of a certain age, ‘opportunistic screening’ as offering a test to men presenting with an unrelated problem, and ‘selective screening’ as testing men with specific symptoms or risks.3

Distribution of the questionnaire was initially by post. Non-responders received two reminder questionnaires; the first of these was posted and the second was sent by fax.

The following are examples of the case vignettes used when asking GPs to indicate which screening tests, if any, they would use for some of the different possible presentations of men who might have prostate cancer:

1. Mr. Smith (aged 55 years) is fit and well and presents to you for his annual checkup. He has no significant medical or family history.
2. Mr Jones (aged 55 years) is well but is concerned that he is at risk of getting cancer. His brother was diagnosed with cancer of the prostate this week and his aunt died in her forties of breast cancer.
3. Mr Green (aged 55 years) is fit and well and has reluctantly arrived to see you at your surgery. His wife has persuaded him to attend after she saw a documentary on television about prostate cancer. He has come to ask your advice about whether he should have a test done.

The full questionnaire is available on request from the authors.

The responses to all quantitative questions were coded and entered directly into a database. The results are presented as a frequency analysis of responses to each question.

Where appropriate, statistical tests of independence of the categories in the frequency tables used were the chi-square test and the generalised Fisher exact (Fisher-Freeman-Halton) test.

In order to account for the different proportions of urban and rural GPs, the response frequencies in each sample were weighted using the respective sampling fractions, and 95% confidence intervals (CI) were calculated when making inferences about the responses of all GPs.

Results

Response rate Responses were received from 381 (66.3%) of the eligible GPs. The demographic information for the responding population is shown in Table 1. Table 1. Demographics of the responding population

The responders and non-responders were compared for gender and year of registration. There were no significant differences in these parameters between the responders and the non-responders.

Rural GPs were significantly more likely to work in a group practice of four or more doctors compared with urban GPs (p = 0.0455).

Otherwise, there was no statistically significant difference between rural and urban GPs for gender, age, years in practice or number of sessions worked per week. Female GPs were significantly more likely than male GPs to be younger (p <0.0001), and to have worked in general practice for a shorter period (p <0.0001), with fewer GPs in the same practice (p = 0.0008) and for fewer sessions per week (p <0.0001).

All responses were analysed for differences between urban and rural GPs, and between male and female GPs. No statistically significant differences were found except in the response to the question about the value of the NHC guidelines. In the responses to this question female GPs were significantly more likely not to have seen the guidelines (p = 0.0088).

Screening for prostate cancer

GPs were asked which tests they would perform for: a man presenting for a general checkup with no significant family or medical history; a man concerned about his risk of prostate cancer who has a brother with prostate cancer and an aunt who had died of breast cancer in her forties; and a man presenting for advice about prostate screening.

Respondents could choose to do more than one test and also had the option to do no tests. Answers to these questions are shown in Table 2. The responses suggest that 73.7% (95% CI 69.3–78.2%) of GPs would do a PSA test as part of a health checkup and 74.5% (95% CI 70.1–78.9%) would do a PSA for a man asking about prostate screening.

This figure increased to 93.2% (95% CI 90.6–95.8%) of GPs who would do a PSA test for the same man with a family history of prostate and breast cancer.

Table 2. Use of screening tests indicated by responders

In order to estimate how effective GPs felt that the screening tests were in identifying asymptomatic prostate cancer, the questionnaire asked respondents to provide an approximate estimate of the positive predictive value (PPV) of these tests.
Of respondents who replied, 27% provided an estimate of the PPV for the PSA and DRE tests that agreed with the levels reported in the literature.8 A majority of the respondents (56.2%) overestimated the PPV for DRE, and more than one third (36.0%) overestimated the PPV of the PSA test.

Screening programmes in general practice

The questionnaire asked GPs to indicate which, if any, groups of patients they currently screened for prostate cancer and which types of screening programmes they thought should be performed in New Zealand (Table 3).

Table 3. Screening programmes used and preferred in general practice

This suggests that some form of screening programme is offered by 97.5% (95% CI 96.0–99.0%) of all GPs and 50.0% (95% CI 45.0–55.2%) support a population-screening programme for prostate cancer.

Twenty six GPs claimed that they used all three types of screening in their practice and only 25 GPs mentioned that there was no demonstrated benefit of population screening for prostate cancer.

Thirty six GPs said that their practice offered screening for prostate cancer by the practice nurse, but only nine of these GPs said that this involved a specific protocol for the use of prostate cancer screening tests.

There was a range of opinion about which age groups should be screened for prostate cancer in New Zealand. Most GPs thought it appropriate to include men between 50 and 70 years, and relatively few GPs wanted to screen men under 40 years or over 80 years (Table 4).

Table 4. Age groups felt to be appropriate for screening by GPs

Fifty six per cent of the respondents thought that the screening interval should be two years and only 6% greater than two years.

GPs were also asked how useful they had found the NHC guidelines on prostate screening. The guidelines were thought to be of some use or better by 35% of the GPs who replied to the questionnaire, but 36% reported not having seen the guidelines.
Risk factors for prostate cancer

Selective screening programmes depend on being able to identify asymptomatic individuals who may be at risk of developing the target disorder.

The questionnaire asked GPs to identify a range of factors as either being of no risk, low risk, or high risk in the development of prostate cancer.

Most respondents correctly identified increasing age (86.9%) and a first-degree relative with prostate cancer (82.9%) as being associated with an increased incidence of prostate cancer, but only 29.7% recognised the association with breast cancer.

High dietary fat intake was thought to be a risk factor by 45.9% of respondents but smoking (62.9%) and benign prostatic hyperplasia (63.6%) were incorrectly identified as risk factors by many GPs.

The majority of respondents were not sure about the significance of Maori (52.5%) and Asian (63.5%) ethnicity as risk factors.

Follow up of abnormal tests or after diagnosis of prostate cancer

Two vignettes asked GPs which tests they would use in men returning for follow up.

The first of these was a man returning one year after radiotherapy for prostate cancer, and the second was a man returning after an abnormal PSA result of 6 ng/ml and a free PSA of 28%.

In the latter scenario, the PSA test would be repeated by 64% of the GPs, and the other GPs would investigate the abnormal test by some combination of DRE, trans-rectal ultrasound (TRUS) examination or specialist referral. More than 90% of the respondents would order a PSA test as part of the follow up one year after radiotherapy. A TRUS would be ordered by 27% of the GPs as part of the investigation of the abnormal PSA.

Management of prostate cancer

An important part of any screening programme is the information given to participants about their treatment options if they are found to have the target disorder.

The GPs were asked to suggest the most appropriate treatment for men who had been found to have localised prostate cancer and were thought to have either more or less than 10 years’ life expectancy (Table 5). ‘Other therapy combinations’ all included radical prostatectomy and/or radiotherapy and hormone treatment.

Table 5. Suggested treatment of a man with localised prostate cancer and less or more than 10 years’ life expectancy

For a man with less than 10 years’ life expectancy and localised prostate cancer 68.5% (95% CI 63.8–73.2%) of GPs thought that non-curative treatment (watchful waiting or hormone therapy) would be appropriate.

For the same man with more than 10 years’ life expectancy only 11.1% (95% CI 7.9–14.3%) thought that this would be appropriate management.
Discussion
This survey found that 74% of GPs in New Zealand say that they will do a PSA screening test for prostate cancer when a 55-year-old man either asks about prostate cancer screening or has a routine, annual health check.

Ninety three per cent of GPs would do a PSA test if this same man had a family history of prostate cancer.

The survey also found that nearly all GPs offer some form of prostate cancer screening and 50% supported a national screening programme for prostate cancer.

This increase in the number of GPs who believe in the value of prostate cancer screening, since the earlier survey by Morris,5 is consistent with the observed sustained increase in the rate of new registrations for prostate cancer.

Between 1993 and 2002 there have been at least 19 published, systematic reviews of prostate cancer screening.9 These reviews have consistently concluded that there is no evidence that screening for prostate cancer will reduce mortality, and that radical treatment of prostate cancer has a risk of significant increased morbidity.

It appears that the majority of New Zealand GPs support a screening programme with no proven benefit and the potential to cause considerable harm.

Pressure from groups outside general practice may be one reason for this high level of screening. In responding to the questionnaire, some GPs commented that the Prostate Awareness Society, the media and urologists encouraged men to actively seek screening for prostate cancer.

Another possible explanation for the increased level of screening is that GPs feel that they would be exposed to an increased risk of medical litigation if they discouraged patients from having screening tests and these patients were subsequently found to have prostate cancer.

A study in Australia found that 61% of GPs thought that they would be at risk if they did not screen an asymptomatic man requesting a PSA test and that national evidence-based guidelines against prostate cancer screening provided only limited medicolegal protection.10

The best available estimates for disease-specific survival for localised prostate cancer are in the region of 90% after 10 years.9

In the only reported randomized controlled trial comparing radical prostatectomy with watchful waiting in early prostate cancer there was no statistically significant difference in overall mortality between the two groups after eight years of follow up.11

his survey found that 42% of GPs would recommend screening for men aged 70–79 years and only 2.9% of GPs would consider watchful waiting for men with prostate cancer and more than 10 years’ life expectancy.

These figures suggest that the information about disease-specific survival for localised prostate cancer may not be well known or understood by many GPs. However, there was a strong trend towards watchful waiting in those men with a short life expectancy, and a more active approach of prostatectomy and radiotherapy in those men with a greater life expectancy.

GPs may find it difficult to diagnose a condition and not treat it actively unless there was a likelihood that the disease was not going to be the ultimate cause of mortality.

Other results from this survey also suggest that GPs need more information about the effectiveness of population screening for prostate cancer.

A few GPs expressed concerns about the accuracy of the available screening tests, but only 27% were able to give a reasonable estimate of the positive predictive value of the PSA test and DRE, and most overestimated the accuracy of these tests.

Age and a positive family history of prostate cancer were correctly identified as risk factors by most GPs, but the majority were uncertain about the relevance of other potential risk factors. The variation in the responses to a PSA result of 6 ng/ml with a free-to-total PSA of 28% implies some lack of understanding of the significance of the free-to-total PSA result and the ‘normal’ range of the PSA test when used in a screening programme.12

This result implies a reduction in the probability of having prostate cancer from 1-in-5 with the PSA result alone, to 1-in-12 with the additional free-to-total PSA result. It is doubtful if this reduction in risk would persuade many men not to have a prostate biopsy.

The spontaneous variation in the PSA level between consecutive measurements within a 90-day period can be as much as 1 ng/ml.13 Repeating the screening test would still produce a result above the generally accepted cut-off point of 4 ng/ml and no change in the risk of prostate cancer indicated by the original test.

In general, this survey suggests that there is a clear need for good, easily accessible information for both GPs and their patients about the value of screening for prostate cancer and the interpretation of the results of the available screening tests.

Author information: John Durham, Senior Lecturer; Melissa Low, Medical Student; Deborah McLeod, Research Manager, General Practice Department, Wellington School of Medicine and Health Sciences, University of Otago, Wellington

Acknowledgements: This survey was carried out as a summer studentship by Melissa Low, funded by the New Zealand Guidelines Group. We are grateful to all GPs who completed the questionnaire.

Correspondence: Dr John Durham, Ora Toa Medical Centre, 227 Bedford Street, Cannons Creek, Porirua. Fax: (04) 237 5925; email: john.durham@oratoa.co.nz

References:
1. New Zealand Health Information Service. Cancer: new registrations and deaths 1999. Wellington: New Zealand Health Information Service; 2003. URL: http://www.nzhis.govt.nz/publications/Cancer.html Accessed June 2003.
2. New Zealand Health Information Service. Mortality and demographic data 1999. Wellington: New Zealand Health Information Service; 2003. URL: http://www.nzhis.govt.nz/publications/Mortality.html Accessed June 2003.
3. Beaglehole R, Bonita R, Kjellstrom T. Basic Epidemiology. Geneva: The World Health Organization; 1993.
4. National Health Committee. Screening for prostate cancer. Fifth Annual Report, Personal Health Services. Wellington: National Health Committee; 1996. URL: http://www.nhc.govt.nz/publications/annual5/prostate.html Accessed June 2003.
5. Morris J, McNoe B. Screening for prostate cancer: what do general practitioners think? NZ Med J 1997;110:178–82.
6. Voss JD, Schectman JM. Prostate cancer screening practices and beliefs. J Gen Intern Med 2001;16:831–7.
7. Fowler FJ Jr, Bin L, Collins MM, et al. Prostate cancer screening and beliefs about treatment efficacy: a national survey of primary care physicians and urologists. Am J Med 1998;104:526–32.
8. US Preventive Service Task Force. Guide to clinical preventive services. 2nd edition. Washington, DC: US Department of Health and Human Services; 1996.
9. Durham J. Population screening for prostate cancer. A systematic review. Wellington: New Zealand Guideline Group; 2002. URL: http://www.nzgg.org.nz/development/documents/Prostate_Cancer_review.pdf Accessed June 2003.
10. Girgis S, Ward JE, Thomson CJH. General practitioners’ perceptions of medicolegal risk. Using case scenarios to assess the potential impact of prostate cancer screening guidelines. Med J Aust 1999;171:362–6.
11. Holmberg L, Bill-Axelson A, Helgesen F, et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002;347:781–9.
12. Hoffman RM, Clanon DL, Littenberg B, et al. Using the free-to-total prostate-specific antigen ratio to detect prostate cancer in men with nonspecific elevations of prostate-specific antigen levels. J Gen Intern Med 2000;15:739–48.
13. Pickens GJ, Roehrborn CG. Variability of repeated prostate specific antigen measurements within less than 90 days in a well-defined patient population. Proc Am Urol Assoc 1995;153:936A. 

Screening for prostate cancer

NZ Medical Journal, June 20, 2003 – Peter Davidson, Urologist, Department of Urology, Christchurch Hospital, Christchurch

To read original, click HERE>

The article Screening for prostate cancer: a survey of New Zealand general practitioners by Durham, Low and McLeod appears in this issue of the NZMJ.

This important paper looks at New Zealand general practitioners’ attitudes, habits and understanding around this complex issue. In so doing, a number of areas are highlighted where there are discordant views between GPs and the evidence from the literature.

Of the GPs surveyed, 42.3% would screen men between the ages of 70 and 79 years and 12.3% would screen men of 80 years or greater.

Most recommendations on screening would not advise the screening of men over the age of 75 years and many would not recommend screening men over the age of 70 years.

Risk factors for carcinoma of the prostate are a family history, advancing age, a diet high in animal fat and, to a lesser degree, a family history of breast cancer.

Also implicated have been low UV sunlight exposure and low selenium intake.

Benign prostatic hyperplasia is not a risk factor for carcinoma of the prostate and indeed prostate cancer is detected in no greater frequency in men with symptoms than men without symptoms of bladder outflow obstruction. Nevertheless, if one is considering treatment of benign prostatic hyperplasia, exclusion of malignancy is important, as that may alter the treatment administered.

As far as ethnicity is concerned, African-Americans seem to have the highest incidence and Asians the lowest incidence. Little is known about the relative risk in Maoris. It should be noted, however, that Asians who live in a Western environment start to develop a risk more akin to that of a Western population.

This article highlights the fact that there is wide variation in the screening tests used to detect prostate cancer.

The most common combination, however, is digital rectal examination (DRE) and prostate specific antigen (PSA) testing. This would remain the recommendation of the urological community if a PSA cut-off point of 4 were to be used as the threshold for advancing to prostate biopsies.

There is evidence, however, that lowering the cut-off point to 3 may negate the need for the rectal examination in an organised screening programme.

Further, a number of urologists have recommended the screening cut-off point to be lowered as far as 2.5. To date, there is no evidence that the outcomes in men who have a PSA between 2.5 and 4 are any worse than in men with a PSA between 4 and 10.

Thus, it is generally recommended that a PSA of 4 be a trigger point for further investigation.

The role of free-to-total PSA is still debated. As pointed out by Durham et al, while this may reduce the probability of having prostate cancer on a biopsy, it is unlikely to result in a difference sufficient to persuade men not to have a biopsy.

This paper points out that there is a 90-day spontaneous variation of up to 1ng/ml. With fully automated testing this may be greater and certainly in clinical practice it is not uncommon to find greater spontaneous variations of PSA.

Accordingly, repeating the PSA is preferable prior to proceeding to biopsy of the prostate, as recommended in a recent publication by Eastham et al.

The majority of GPs overestimated the positive predictive value of both the PSA and DRE. These positive predictive values are around 35%.

In discussing the results, Durham et al state: “These reviews have consistently concluded that there is no evidence that screening for prostate cancer will reduce mortality, and that radical treatment of prostate cancer has risk of significant increased morbidity.”

To date, there are no results from randomized controlled trials of screening. The results of the American and European screening studies should be available within the next five years. Until these results are available the question of whether or not prostate cancer screening will reduce mortality remains unanswered.

Nevertheless, there is a considerable body of evidence, including the Quebec study, the Tyrolia study, and the Olmstead County study, as well as the analysis of the SEER data, which would suggest a possible effect, without being conclusive.

Furthermore, in Western countries, where widespread PSA testing has become common, the age-adjusted mortality rate of prostate cancer is falling. Thus, to date, whilst there is no proof that prostate cancer screening will reduce mortality, there is also no proof that it will not!

Finally, the findings of the controlled trial performed in Sweden by Holmberg et al, comparing radical prostatectomy with watchful waiting, require comment. This trial was reported after eight years of follow up and there was no statistically significant difference in overall mortality between the two groups.

There is, however, a statistically significant difference in prostate cancer mortality between the two groups. It is widely expected that as the trial matures this may translate into a difference in overall mortality.

Thus, it seems highly likely that an effective treatment is available for the treatment of prostate cancer.

The question of prostate cancer screening remains complex and requires discussion between GP and the individual patient.

The study by Durham et al highlights some of the deficiencies in the understanding of GPs around a number of issues related to the discussion about screening. An understanding of these issues should help GPs to better advise their patients about the benefits and risks associated with prostate cancer screening, and in so doing help them in making their individual decisions.

Correspondence: Dr Peter Davidson, Department of Urology, Christchurch Hospital, Private Bag 4710, Christchurch. Fax: (03) 364 0936; email: peter@urology.co.nz

Durham J, Low M, McLeod D. Screening for prostate cancer: a survey of New Zealand general practitioners. NZ Med J 2003;116(1176). URL: http://www.nzma.org.nz/journal/116-1176/476/