Perspectives
Men's health
Volume 198 - Issue 10

Should we screen for prostate cancer? A re-examination of the evidence

Authors:  Chris B Del Mar, Paul P Glasziou, Geoffrey H Hirst, Robert G Wright and Tammy C Hoffmann

Med J Aust 2013; 198 (10): 525-527. || doi: 10.5694/mja12.11576
Published online: 3 June 2013
Experts remain divided on the benefits and harms of screening for prostate cancer, but Del Mar and colleagues argue that prostate-specific antigen testing does little to reduce mortality from prostate cancer, and advise caution about the adverse effects of diagnosis and treatment.
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The potential harms from diagnosis, overdiagnosis and treatment must not be overlooked

Despite the results of two large, but conflicting, trials published side by side in 2009, whether prostate cancer screening is beneficial or harmful (or indeterminate) remains unresolved.1,2 Those on either side of the debate read the same information but interpret it differently, declaring that it supports their unchanged positions.

That prostate cancer is important is not at issue: it is the ninth-ranked cause of disease burden in men in Australia, representing the loss of 36 000 disability-adjusted life-years (DALYs), or 2.7% of the total Australian loss, in 2003.3 This is about two-thirds of the loss resulting from breast cancer in women (60 000 DALYs; 4.8%). A positive family history of prostate cancer is associated with increased risk (typically a risk ratio of about 2),4 although this risk may be exaggerated by detection bias (men with a positive family history are more likely to have a screening test).5 Associations with family history of other conditions are less certain.5

The rate of prostate-specific antigen (PSA) testing is high enough to represent a de facto screening program (in the same order as breast screening). It has increased from about 200/1000 per year (age standardised) in the 1995–96 financial year to more than 400/1000 in 2010–11, although it may now be declining, following the United States Preventive Services Task Force recommendations to stop screening for prostate cancer.6-8 The rate of radical prostatectomy among men aged 50 years or older in Australia has increased in line with this from less than 1/1000 in the 1995–96 financial year to more than 2.5/1000 per year in 2007–08.8 Tumour size and age at prostatectomy have decreased in the US.9 But mortality from prostate cancer has changed little in Australia in 20 years, decreasing overall from 0.6/1000 in 1985 to just under 0.5/1000 in 2007.8 The even greater surge in screening among men aged 50 years or older in the US, from 35% in 1987 to 90% in 1992, has meant that symptomatic presentation of localised prostate cancer has dropped from 77% to 60% over the same period.10

Why is prostate cancer screening so difficult?

PSA, a protease that breaks down the ejaculate coagulum in mammalian species, is a weak test for prostate cancer.11 Its protein is highly specific for prostatic tissue, both benign and malignant, so it is useful in identifying prostate tissue in tumours of uncertain origin.12 However, PSA in the blood is detected in patients with a wide variety of benign and malignant disorders, and also increases normally with age, making it difficult to develop useful reference ranges to predict prostate volume.13 The test characteristics of PSA testing (sensitivity and specificity) are uncertain because determining prevalence requires histological testing. Indirect evidence suggests that it is a poor screening test; a German study found the total PSA level of 131 men with benign prostate hypertrophy could not be distinguished from that of 79 men with localised prostate cancer suitable for radical prostatectomy.14 US studies show that PSA testing contributes little to the diagnosis of early prostate cancer.9 It may be better at ruling out prostate cancer, although the optimal PSA cut-point is uncertain.

The search to find better screening markers has produced other tests, such as measuring the ratio of free PSA to total PSA (which is little better14), and following the change in PSA levels over time to determine the rate of increase in PSA (which requires multiple testing).

While the PSA blood test can potentially detect some early, low-volume and localised prostate cancer, allowing its eradication by radical prostatectomy,15 digital rectal examination (DRE) occasionally detects some of the cancers missed by PSA testing alone, which is why those recommending PSA screening advocate DRE as well.15

Are there benefits of screening?

Men with negative results on the screening test will be reassured (although sometimes falsely). Two large RCTs were published in 2009 looking at the effects on mortality in men with positive results on PSA testing. A US trial found no benefit,1 while a European trial found a small statistically significant reduction in mortality.2 A subsequent report from one centre (Gothenburg, Sweden) within the European trial, which followed the study cohort for 12 years, found a greater reduction in mortality, which increased after a decade.16 Nevertheless, two systematic reviews including all reported trial data concluded that screening is not effective.17,18

The trials described in the systematic reviews may be criticised for deficiencies in compliance — the US trial in particular was compromised because about half of the control group of men undertook some screening,1 while conversely, in the European studies, some men assigned to the screening group did not receive screening.2

We attempted to perform a correction for compliance, which suggested that after correction, a relative risk reduction of death from prostate cancer from being screened is still not statistically significant at 12% (95% CI, − 1% to 23%) (Box).22

What are the downsides of screening?
Downsides of treatment

After radical prostatectomy, erectile dysfunction affects most men — fewer among younger men, those with a lower PSA level and perhaps those undergoing special nerve-sparing surgical techniques.23 Other complications are common too, including urinary incontinence (which is very common in the months after treatment, returning to normal in 75%–90% of men after 2 years, depending on surgical technique) and, with less frequency, urinary irritation and bowel symptoms.24 General feelings of “vitality” are lost in about 10% of men.25

Harms from diagnosis

Prostatic biopsy after abnormal PSA or DRE results may cause severe bleeding and infection (about 1% each). One-quarter of the 1% admitted with infection after biopsy require intensive care treatment for severe sepsis.26

The rates of suicide and cardiovascular disease (CVD) increase enormously immediately after men are given a diagnosis of prostate cancer (a retrospective cohort study in Sweden found that the relative risk of suicide increased eight times, and the risk of CVD increased 11 times).25 These risks level off after 1 week, but remain high for years afterwards.27

Related to this problem is the issue of lag-time, which is the time between diagnosis by screening and the time when the cancer would have become manifest symptomatically without screening. Lag-time yields benefit if it allows a cancer to be cured by radical surgery. But it causes harm also, because it means patients live longer under the cloud of the diagnosis of a malignancy, with the harmful effects mentioned above. Lag-time has been estimated to be as long as 11 years.28

Harms from overdiagnosis

It is said that “More men die with prostate cancer than from it”.29 However this is difficult to quantify because of the variation in the threshold for men submitting themselves for prostate cancer testing. The best available data come from autopsy studies of men dying from other causes whose prostates have been examined histologically. The literature is confused by different histological definitions of prostate cancer, but at least one well conducted study suggests that rates of latent prostate cancer are as high as more than 50% in men aged over 60 years — so that it might even be called “normal” at that age,27 and a review of data from several countries confirms this.30 In other words, only a minority of cancers lead to symptoms and mortality. Latent cancers are indolent (“lazy”) cancers that look like, but do not behave like, metastasising ones. Unfortunately we can only poorly distinguish them histologically using relatively crude methods such as the Gleason score. The consequence is overdiagnosis. The more we test for prostate cancer, the more we will detect it, harvesting more and more latent cancers whose effects would never have become manifest — leaving only the adverse effects of diagnosis and treatment on the harms–benefits scale. Modelling studies using data from results of recent trials suggest that as many as 50% of detected prostate cancers are overdiagnosed latent tumours.28

A response to this is the emerging management option of “active surveillance”, in which cancers with a better prognosis are initially managed conservatively.

How should patients be informed?
Should clinicians raise the topic . . .

Before ordering a PSA test? Although all authorities agree that informed consent should be obtained before ordering a PSA test, these are often ordered without any discussion at all,31,32 and when discussions do occur, they are often unbalanced, with the pros of screening emphasised more than the cons.33

When not ordering a PSA test? Most authorities have proposed that clinicians should raise the topic of prostate cancer screening with all men as part of general disease prevention and health promotion, provide relevant information, and then together with the patient make an informed decision about prostate cancer screening. However, the information is difficult to present and process. Moreover the media, and some well publicised charities, often portray the debate confusingly, over-simplifying the issues so that the takeaway message is often that prostate screening is beneficial. In particular, it is difficult to justify raising this form of prevention, which is not accepted as effective, over the legion of others that are. A more justifiable approach is to avoid raising prostate cancer screening unless a patient does. When it is raised, it should be discussed in a balanced manner with the relevant information given.

What information can clinicians provide?

Decision aids present balanced information and help patients to participate in decision making. They can improve knowledge, increase patients’ desire to be more actively involved in decision making, decrease interest in PSA testing, and decrease PSA testing rates in patients as part of routine care (if not among those men specifically seeking screening). Such aids include videotapes, written materials or educational sessions.34 They can be computer-based and interactive (eg, http://www.prosdex.com).35

However, decision aids alone are not enough. They should supplement discussions between patient and doctor — before, during and/or after. Most decision aids do not appropriately consider patients with low health literacy, and patients often find them too long — even interactive online decision aids, where patients need to invest only about 20 minutes.36,37

When patients raise the topic of prostate cancer screening, a clinician might initially discuss the main issues — the uncertainty of benefit, and the potential harms as well as the potential benefits. It is important for patients to digest these issues before further discussions, perhaps using a decision aid.

Not rushing the decision is important. In primary care it is usually possible to suggest that patients take away information to consider, perhaps in conjunction with their family, before taking a blood test slip to the laboratory.

Results of meta-analysis of five randomised controlled trials (RCTs) of screening for prostate cancer, adjusted for adherence to the screening protocol

Trial/group

Participants

Death from prostate cancer

RRR (95% CI)

Adherence to screening protocol

Adherence-adjusted RRR (95% CI)

Stockholm19

Control

24 772

506

− 0.093 (− 0.45 to 0.18)

100%*

− 0.093 (− 0.45 to 0.18)

Screening

2 374

53

100%*

Quebec20

Control

15 353

75

− 0.006 (− 0.33 to 0.24)

93%

− 0.037 (− 4.3 to 0.80)

Screening

31 133

153

24%

Norrköping21

Control

7 532

130

− 0.16 (− 0.73 to 0.22)

100%*

− 0.16 (− 0.73 to 0.22)

Screening

1 494

30

100%*

PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial)1

Control

38 350

85

− 0.15 (− 0.54 to 0.14)

54%

− 0.39 (− 1.6 to 0.25)

Screening

38 343

98

85%

ERSPC (European Randomized Study of Screening for Prostate Cancer)2

Control

99 184

522

0.16 (0.04 to 0.27)

100%

0.20 (0.052 to 0.33)

Screening

82 816

364

82%

The five RCTs combined

Control

—

—

0.086 (− 0.012 to 0.17)†

—

0.12 (− 0.01 to 0.23)§

Screening

—

—

—

RRR = relative risk reduction. * Adherence data are not available for the Stockholm and Norrköping trials. † Meta-analysis combining the data (giving a non-significant RRR of 8.6% of deaths from prostate cancer). § Meta-analysis adjusted for degree of adherence to screening that may have influenced the trials (giving a relative non-significant reduction of 12% of deaths from prostate cancer).

Authors

  • Chris B Del Mar MD, FRACGP, FAFPHM1,2
  • Paul P Glasziou PhD, MB BS1
  • Geoffrey H Hirst MB BS, FRACS3
  • Robert G Wright BSc(Hons), MB ChB, FRCPA1
  • Tammy C Hoffmann PhD, BOccThy(Hons)1
  • 1. Bond University, Gold Coast, QLD.
  • 2. Royal Australian College of General Practitioners Red Book Committee, Melbourne, VIC.
  • 3. Department of Urology and Continence, Mater Health Services, Brisbane, QLD.

Correspondence: cdelmar@bond.edu.au

Competing interests

No relevant disclosures.

Acknowledgements

Tammy Hoffmann is supported by a National Health and Medical Research Council (NHMRC) and Primary Health Care Research, Evaluation and Development Career Development Fellowship (1033038) with funding provided by the Department of Health and Ageing. Paul Glasziou is supported by a NHMRC Australia Fellowship (527500). The funders had no role in the preparation, review and approval of the manuscript.

References

Provenance: Not commissioned; externally peer reviewed.

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