Screening for prostate cancer: have you had your cholesterol measured?

Abstract

Screening for prostate cancer has become one of the most common topics of conversation at urological oncology meetings. Most people have a bias as to whether there should or should not be a national screening programme. Unfortunately there are many unanswered questions, which may or may not be possible to answer definitively. In a balanced and scholarly review of the subject, Professor Peter Boyle indicates several flaws in the agreement for screening, but feels that PSA testing will continue unabated.

The authors from the University of Stellenbosch review the plentiful literature relating to testicular torsion and functional recovery. They also review the mechanism of injury and the effect on the contralateral testis.

INTRODUCTION

It is hard to imagine a single topic in cancer research at present which provokes so much polarization of scientists and clinicians in the field as does prostate cancer. Particularly important questions revolve around the usefulness of early diagnosis and the treatment of early-stage tumours. The ‘prostate world’ is split between those who advocate that every man should be ‘screened’ and those who equally vehemently insist that no asymptomatic man should ever be screened. This article presents a blunt evaluation of the current situation.

PROSTATE CANCER SCREENING TESTS

Three tests have been proposed as being potentially useful in population screening for prostate cancer, the DRE, PSA and TRUS. The latter can be quickly dismissed as being too invasive to be considered a simple screening test, and is more a procedure to be used in the diagnostic evaluation of a suspected case of prostate cancer. Until recently, the DRE was the only widely available screening test and is generally used as a routine health check for asymptomatic men in many parts of the world, particularly the USA.

In an important study [1], all 173 men who died from prostate cancer in Rochester County between 1976 and 1991 were identified. For each case, two control men were identified and the medical records examined for up to 10 years before death. Cases were less likely than control subjects to have had a DRE in the 10 years before diagnosis (odds ratio 0.51, 95% CI 0.31–0.84) and the authors concluded that if further research showed that this association is causal, screening DREs may have prevented as many as 50–70% of deaths from prostate cancer that might have occurred in the absence of screening [1].

However, this finding has not been replicated and the evidence to support screening by DRE is poor. In a case-control study conducted among members of a large health maintenance organization, a history of a screening DRE during the 10 years before the date on which cancer was diagnosed did not reduce the mortality from prostate cancer to any appreciable degree [2]. In a previous similar study, in the 10 years before initial diagnosis (excluding the last 3 months) the mean number of examinations for routine screening (2.45 vs 2.52) or to evaluate intestinal or rectal symptoms (0.44 in both) were similar in cases and controls. After adjusting for racial differences, the relative risk of metastatic prostatic cancer for men with one or more DREs compared with men with none was 0.9 (95% CI 0.5–1.7) [3]. An essentially similar conclusion emerged from the European Randomized Trial [4].

The PSA test was approved by the USA Food and Drug Administration in 1986 to monitor the disease status in patients with prostate cancer and, in 1994, to aid in detecting prostate cancer. However, after 1986, the test was used in many men who had not been previously diagnosed with prostate cancer, apparently resulting in the diagnosis of a substantial number of early tumours. PSA is being widely proposed as a screening test for prostate cancer and has the two advantages of being an easy and a cheap assay. However, elevated PSA levels are not a sure indicator of prostate cancer as they can be high the presence of benign enlargement. Also, some men with prostate cancer can have low levels of PSA. For any given definition of what represents a ‘normal’ result, there will be associated false-positive and -negative outcomes; although progress is being made, there is still much research work on the compromise between gains in sensitivity and losses in specificity.

In April 1991, Catalona et al.[5] published the results from a large series of men in whom they measured PSA, concluding that the screening programme ‘identifies patients at high-risk for prostate cancer’. As a study of the outcome of screening it had several important limitations, principally the lack of a randomized design, a parallel control group and mortality comparisons as an endpoint. Although its conclusions favoured screening, the study did not provide conclusive evidence.

Although the general use of PSA for screening was not widely practised or advocated by the urological community at the time of the report by Catalona et al., a significant proportion of the medical community acted on this report. For example, the number of PSA blood tests increased three-fold in the Group Health Cooperative of Puget Sound in the 3-month period immediately after publication. In the Health Professionals Follow-up Study, a prospective study involving over 50 000 men, the incidence of organ-defined cancers rose abruptly by 86% (95% CI, 36–256) and regionally advanced cancers increased by 73% (95% CI, 12–267). Giovannucci et al.[6] attributed this to PSA testing of asymptomatic men following the publication of an inconclusive but well-publicised study advocating screening.

IS PSA AN EFFECTIVE TEST FOR PROSTATE CANCER?

A nested case-control study with stored serum samples collected from 49 261 men resulted in 265 initially asymptomatic men who subsequently developed clinical prostate cancer; these cases were matched with 1055 controls [7]. PSA levels were significantly higher in men who subsequently developed prostate cancer than in the controls. In the first 3 years after blood collection, the median concentration was 23 times higher in cases than in controls of the same age in the same centre. A smaller difference persisted thereafter; fourfold 3–6 years after sampling, 3.6-fold at 6–10 years and 1.8-fold after 10 years. In the first 3 years, using a raised level as being 12 times the median, the sensitivity was 81% (54–91%) and the proportion of men who did not develop prostate cancer but who had levels this high was 0.5%. Thus, PSA measurement was shown to be a highly discriminatory screening test for prostate cancer in healthy men. In the general population, 60–74 year-old men who had 12 times the normal median level would have about an even chance of developing clinical prostate cancer within the next 3 years. The authors concluded that measuring PSA is a good enough screening test to justify a randomized controlled trial to determine any reduction in mortality from prostate cancer [7].

In a similar study conducted in Finland, 104 prostate cancers were identified between 1968 and 1991 in a cohort of men. The estimated sensitivity of the PSA test was 44% and specificity 94% at a threshold of 4.0 ng/mL. The sensitivity improved to 86% in patients diagnosed 5 years after the taking the blood sample. The test had a better sensitivity (93%) and specificity (96%) in men aged < 65 years at the time of sampling than in those who were older. The sensitivity further improved to 100% with a threshold of 2.5 ng/mL and it was concluded that PSA is a valid screening test for prostate cancer, and compares favourably with mammography for breast cancer, although until an effect on mortality has been shown, routine screening cannot be recommended [8].

In summary, there is adequate evidence that serum PSA is increased in men with prostate cancer or who develop prostate cancer up to 10 years after testing.

PROSTATE CANCER MORTALITY

Will PSA screening reduce prostate cancer mortality? This is a key and still unanswered question. Also, the serious adverse effects of radical prostatectomy and radiotherapy on quality of life, notably incontinence and impotence, could change a modest mortality reduction obtained by PSA screening into a negative quality-of-life-adjusted years. Even assuming a reduction in mortality rates from prostate cancer, given the age distribution of the disease, an increase in life-expectancy would be very difficult to achieve. The SEER Report for 2002 noted that the median age at death from prostate cancer in the period 1993–99 was ≈ 79 and that a quarter of all deaths from prostate cancer occurred in men aged ≥ 85 years [9]. Of all sites where cancer screening has been proposed or examined, the situation in prostate cancer may well be unique in that ‘competing causes of death’ is an important issue in men in the age range of prostate cancer. Of course, it is a consideration that preventing death with complications of prostate cancer may well have a very positive effect of quality of life.

Examination of temporal trends in prostate cancer mortality is problematic and conflicting. ‘Although trends in prostate cancer screening and disease incidence differ substantially between the United States and England and Wales, trends in mortality are very similar’[10]. ‘Although it has been argued that the decrease in prostate cancer mortality rates began too soon to be explained by PSA testing, stage-specific survival rates indicate that a rapid decrease in mortality may be explained by the large number of high-grade prostate cancers detected before metastasis. If recent decreases in US prostate cancer mortality rates are due to early detection using PSA testing, randomised trials investigating PSA testing will show early evidence of a mortality benefit.’[11].

Hidden within these arguments is the conjecture that a change in mortality rate occurred too soon. In many respects this is simply conjecture and no one has been able to show how quickly or slowly a change could take place after the introduction of large-scale screening activity.

In 1993 PSA testing was made freely available to men aged 45–75 years in the Federal State of Tyrol, Austria [12]. At least two-thirds of all men in this age range were tested at least once in the first 5 years of the study. Initially only total PSA was measured but free PSA measurement was added in 1995; the same assay was used throughout. The DRE was not part of the screening examination. By comparing prostate cancer mortality in Tyrol, where PSA was tested at no charge, with the rest of Austria, where it was not introduced, the impact of screening could be monitored in a ‘natural’ experiment with a parallel control group reflecting developing clinical practice.

There was significant migration to lower stages since the introduction of this screening programme. There was a reduction in mortality rates in the rest of Austria from 1993 onwards but the reduction in Tyrol was much greater; mortality remained fairly constant between 1993 and 1995, and subsequently declined. Trends in prostate cancer mortality rates since 1993 differ significantly between Tyrol and the rest of Austria (P = 0.006). Based on the age-specific death rates averaged over 1986–90, the difference between the numbers of expected and observed deaths from prostate cancer in Tyrol was 22 in the age group 40–79 in 1998, and 18 the following year [12].

These findings are consistent with the hypothesis that the policy of making PSA testing freely available, and the wide acceptance of it by men in the population, is associated with a reduction in prostate cancer mortality in an area where high quality urology and radiotherapy are available freely to all patients. This latter situation makes Tyrol somewhat unique and is a sine qua non for considering implementation of such programmes. It is the authors’ opinion that most of this decline is probably a result of the aggressive down-staging and successful treatment, and any contribution from detecting and treating early cancers will become apparent in years to come.

Incidence and mortality from prostate cancer were increasing in most countries until the late 1980s [13]. After the introduction of the PSA test, there have been reports of declines in mortality in Canada, the USA and the UK. Trends in age-standardized death rates between 1979 and 1997 for men aged 50–79 years in 24 industrialized countries were compared using ‘join-point’ regression. During the period studied, age-standardized mortality increased at 1% to 2% per year in most countries. In seven countries (Canada, USA, Austria, France, Germany, Italy and the UK) there was a significant decrease in age-standardized mortality over the period 1988–91 [13]. Trends in age-specific rates within these countries support a period effect on prostate-cancer mortality, i.e. consistent with a sudden change which affected all age groups. Declines in mortality could result from any combination of either artefact, reduction in prostate cancer incidence (unlikely in view of increase in early detection methods), a rise in competing causes of death (again unlikely) or changes in the risk of death from prostate cancer.

However, great care is needed when examining and interpreting prostate cancer mortality rates in different countries. For example, in England a decrease has been noted by several authors since ≈ 1990 and has been interpreted as an argument against screening [10,13]. The real issue, however, is why the mortality rate in the England and Wales rose so rapidly from the early 1980s onwards, having been so constant for decades beforehand (Fig. 1). When this is further examined, it is evident that the increase is most prominent in men aged > 70 years (and hardly appears at all in men aged < 70; Fig. 2a) and is most pronounced in men aged ≥ 80 years (Fig. 2b).

Figure 1. Annual age-standardized mortality rates per 1200 000 from prostate cancer in men aged ≥ 50 years in the USA (green) and UK (red dashed).

Figure 2. Prostate cancer mortality in England in 5-year age groups (starting from 50 years).

In the mid-1980s, automatic coding of death certificates was introduced into England. The immediate impact was to reduce the mortality rate from pneumonia by 20%, as when presented with a vague cause of death in the first part of the death certificate, a firmer cause was sought in the second part. As many of these vague causes of death are in the very elderly, the greatest impact on inflating specific cause of death will be in that age group. Given that the median age of death from prostate cancer is nearly 80 in many countries [14], this form of cancer could be expected to be particularly affected by this phenomenon. The decline observed since 1990 could well be the effect of this error being corrected in national statistics.

All men with a diagnosis of prostate cancer who died in Olmsted County, Minnesota between 1980 and 1997 were identified and parts 1 and 2 of the death certificates were reviewed for a diagnosis of prostate cancer [15]. In addition, all men with biopsy-confirmed prostate cancer diagnosed between 1983 and 1995 were identified. The complete medical records of incident cases of prostate cancer were reviewed for signs and symptoms at diagnosis and for the first treatment received. Age-adjusted, community mortality rates from prostate cancer increased from 25.8/100 000 men in 1980–84 to a peak of 34/100 000 in 1989–92, and have since declined to 19.4/100 000 in 1993–97 (22% decline in mortality, 95% CI − 49% to + 17%). The overall age-adjusted incidence rates, which peaked at 209/100 000 person-years in 1992 as previously reported, declined to 108/100 000 in 1993 and 132/100 000 in 1995. The pattern was similar for organ-confined cancers. However, incidence rates for regional or distant disease were suggestive of a continuing downward trend from 1989 to 1992 compared with 1993–95 (12% decline per year, P = 0.07). These data show that despite the increase in prostate cancer mortality rates in the mid to late 1980s, mortality rates in 1993–97 were lower than in the years before serum PSA testing. While chance cannot be excluded, these data suggest that increased screening for prostate cancer, particularly through PSA testing, may have led to declines in mortality from prostate cancer [15].

Prostate cancer incidence data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program and mortality data from the National Center for Health Statistics were analysed [16]. The following findings are consistent with a screening effect: (i) the recent decrease since 1991 in the incidence of distant stage disease, after not having been perturbed by screening; (ii) the decline in the incidence of earlier stage disease beginning the following year (i.e. 1992); (iii) the recent increases and decreases in prostate cancer incidence and mortality by age that appear to indicate a calendar period effect; and (iv) trends in the incidence of distant stage disease by tumour grade and trends in the survival of patients with distant stage disease by calendar year that provide suggestive evidence of the tendency of screening to detect slower growing tumours. The decline in the incidence of distant stage disease holds the promise that testing for PSA might lead to a sustained decline in prostate cancer mortality. However, population data are complex, and it is difficult to confidently attribute relatively small changes in mortality to any one cause [16].

The incidence-based mortality method was applied to prostate cancer data from the Surveillance, Epidemiology, and End Results Program [17]. This method links data on patients diagnosed with cancer to vital status and cause of death, such that mortality can be evaluated by factors associated with disease at diagnosis. Prostate and ‘other cancer’ mortality rates were evaluated according to patient age at death, disease stage and grade at diagnosis, race and whether additional cancers involving other sites were present. Mortality from prostate cancer decreased from 37% in 1988 to 30% in 1995, largely as a result of a sharp increase in ‘other cancer’ mortality rates. The overall trend in prostate cancer mortality rates increased from 1988 to 1992 and then decreased. The increase and decrease in rates occurred across categories of age, race, grade and number of cancer primaries. However, the increase in rates did not occur in distant staged cases, nor did the subsequent decrease in rates occur in nondistant staged cases [17]. PSA screening appears to have influenced both the increase and decrease in prostate cancer mortality rates.

The potential confounding influence of changing treatment patterns and misattribution bias make a definitive conclusion about the link between PSA screening and mortality rates strongly suggestive but not proven. At least some of the mortality decline since 1991 appears likely to be a result of screening, but the precise magnitude of the screening effect is difficult to estimate [11,18].

In France, where practices to detection early prostate cancer are widespread, cancer incidence and mortality were investigated in five French administrative areas, covered by a population-based registry, having a total population of ≈ 1700 000 men [19]. Incidence data from these registries were studied for the period 1982–95, and mortality data were provided by the Institut National de la Sante et de la Recherche Medicale for the period 1982–96. Age-period-cohort models by Poisson regression were created to characterize these trends. Between 1982 and 1995, 14 699 cases of prostate cancer were registered by the five registries under consideration. After a slight intensification of the increase in 1987, undoubtedly caused by early detection (notably using PSA), the trend of the incidence seems to reverse from 1993. Mortality increased monotonically from 1982 to 1990 by an average of 1.8% per year, before decreasing annually by an average of 3.3% until 1996 [19]. Poisson regression indicated a period effect on both incidence and mortality data, each consistent with an impact of increased detection in the early 1990s.

All cases of neoplasms of the prostate (ICD-O, C61.9) diagnosed in Saskatchewan (Canada) from 1970 to 1997 inclusive, were identified in the Saskatchewan Cancer Registry [20]. The age-adjusted incidence of prostate cancer was 60.5 per 100 000 in 1970, rising gradually to 101.5 per 100 000 in 1989. In 1990, incidence increased much more sharply, reaching a peak of 163.1 per 100 000 in 1993, after which it began to fall. This sharp increase coincided with the introduction and increasing use of the PSA test in the province. The relative survival of patients with prostate cancer was stable from the late 1970s to the 1980s, then improved markedly in 1990–94. After the introduction of the PSA test, the relative risk of death from prostate cancer was only ≈ 60% of what it had been throughout the previous 15 years. Prostate cancer-specific death rates did not change from the early 1980s to the end of the study period [20].

Data from prostate cancer cases and deaths reported to the British Columbia Cancer Registry (Canada) during 1985–99 were used to examine trends in incidence and mortality in 88 ‘small health areas’ among men aged 50–74 years [21]. These areas were classified by the intensity of PSA screening (low, medium or high) according to their ranked age-standardized incidence rate of prostate cancer in 1990–94. Between 1985 and 1989 and 1990–94 the incidence of prostate cancer increased by 53.2% and 14.6% among men aged 50–74 and those aged ≥ 75, respectively. Between 1985 and 1989 and 1995–99, prostate cancer mortality declined by 17.6% and 7.9% in the two age groups, respectively. There appeared to be no association between the intensity of PSA screening and subsequent decreases in prostate cancer mortality [21].

In Western Australia from 1985 to 1996, after increasing steadily from 42 per 100 000 person-years in 1985 to 61 in 1992, the recorded incidence of prostate cancer more than doubled to 134 per 100 000 person-years in 1994, then decreased sharply to 87 in 1996 [22]. Among men aged ≥ 50 years, those aged 50–54 years had the largest annual increases, at 14% (95% CI, 10–19%) from 1985 to 1992 and 108% (84–134%) from 1992 to 1994. They also had the smallest annual decline between 1994 and 1996 (8%, + 1 to − 16%). The mortality rate showed no sudden increases or decreases. In men aged ≥ 60 years the mortality rate increased annually by 2.9% (2–4%) from 1985 to 1996. The number of Medicare reimbursements for PSA tests increased until May 1995, then declined. There was a significant correlation between the monthly number of PSA tests and new cases of prostate cancer (P < 0.01). The mortality rate has showed no systematic deviation from its long-term trend [22].

In Quebec (Canada), the change in prostate cancer incidence in the early 1990s, attributed largely to PSA screening, and the subsequent change in prostate cancer mortality was assessed by dividing the adult male population of Quebec aged ≥ 50 years into 15 birth cohorts. For each cohort the change in prostate cancer incidence between 1989 and 1993, and the change in prostate cancer mortality between 1995 and 1999, was computed [23]. Even though most birth cohorts showed an increase in prostate cancer incidence and a subsequent decrease in mortality, the sizes of these changes were not inversely correlated (Pearson's r 0.33, one-sided P = 0.89). Similarly, in the regional population study, there was a greater increase in prostate cancer incidence, which did not indicate a greater decline in mortality (Pearson's r 0.13, one-sided P= 0.68) [23].

Most recently, a comparison between the cohorts of men in the Seattle-Puget Sound Cancer Registry Area and the Connecticut Cancer Registry area showed that although there were substantial differences in the PSA testing rates and the prostate biopsy rates in both areas, there was little difference in prostate cancer mortality resulting from this increased activity [24]. The reasons for such discrepancies remain unclear, although it is important not to draw too many conclusions about screening intensity in the absence of knowledge of what was done with the findings of the test results.

COMPLICATIONS OF TREATING PROSTATE CANCER

Undoubtedly, early detection methods for prostate cancer will lead to an increase in unnecessary biopsies, in the incidence of the disease and, particularly, in the number of men with early disease who are candidates for radical therapy, either surgery or radiation. The three main approaches to treatment of prostate cancer can commonly have deleterious side-effects (see http://www.cancer.gov/cancerinfo/pdq/treatment/prostate/).

Complications of radical prostatectomy can include urinary incontinence, urethral stricture, impotence, and the morbidity associated with general anaesthesia and a major surgical procedure. An analysis of (USA) Medicare records on 101 604 radical prostatectomies performed from 1991 to 1994 showed a 30-day operative mortality rate of 0.54%, a re-hospitalization rate of 4.5%, and a major complication rate of 28.6%. Over the study period, these rates decreased by 30%, 8% and 12%, respectively [25]. Radical prostatectomy may also cause fecal incontinence and the incidence may vary with surgical method [26].

Definitive external-beam radiation therapy can result in acute cystitis, proctitis and sometimes enteritis, which are generally reversible but may be chronic, although rarely requiring surgical intervention. Potency, in the short term, is preserved with irradiation in most cases, but may diminish over time [27]. Radiation side-effects of three-dimensional conformal vs conventional radiation therapy using similar doses (total dose of 60–64 Gy) were compared in a randomized unblinded study [28]. There were no differences in acute morbidity, and late side-effects serious enough to require hospitalization were infrequent with both techniques. However, the cumulative incidence of mild or greater proctitis was lower in the conformal than in the standard therapy arm (37% vs 56%, P = 0.004). Urinary symptoms were similar in the two groups, as were local tumour control and overall survival rates at 5 years of follow-up [29].

Several different hormonal approaches can benefit men with various stages of prostate cancer. These include bilateral orchidectomy, oestrogen therapy, LHRH agonists, antiandrogens, ketoconazole, and aminoglutethimide. LHRH agonists lower testosterone to castrate levels. Similar to orchidectomy and oestrogens, LHRH agonists cause impotence, hot flushes and loss of libido.

RANDOMISED TRIALS OF PSA TESTING

There are three randomized trials of prostate cancer screening underway; the Quebec Trial, the Prostate, Lung, Colorectal, and Ovarian Cancer study (PLCO) in the USA and the European Randomized Study for Screening for Prostate Cancer (ERSSPC) in Europe [28]. The Quebec trial is a population-based trial that started in 1988. In all, 46 193 men aged 45–80 years were identified through electoral lists as residing in the area of Quebec; 30 956 were invited to be screened, of whom 7155 accepted and were screened. In the control group, 982 men were screened. The threshold was a PSA level of 3 ng/mL; re-screening is annual. Intention-to- treat analysis after a 10-year period found no reduction in mortality; there were 137 deaths from prostate cancer between 1989 and 1996 inclusively in the 38 056 unscreened men, while there were only five deaths among the 8137 screened individuals. Prostate cancer death rates are 48.7/100 000 in unscreened men and 15.0/100 000 in screened men for an odds ratio of 3.25 in favour of screening [30].

However, the only valid analytical strategy is the intent-to-screen analysis. If the death rates from prostate cancer are compared by intent-to-screen, the relative risk of death on the screening group is (97/204 710)/ (45/110 072) = 1.16, i.e. an excess of deaths in the invited group. This suggests that the difference in those complying with those not complying may be caused by selection bias.

The PLCO screening trial is based on volunteers aged 55–74 years who signed a consent form to be randomized (74 000); half will be randomized to receive annual PSA and DRE screening to a total of four screens and half to the usual care in the community. The PSA threshold is 4 ng/mL and results are expected by 2006. The ERSSPC is a multicentre trial initiated in 1994 that plans to enrol up to 239 000 men in 10 different countries. The method of recruitment, age of the enrolees, PSA thresholds and the frequency of screening will vary among the centres, and more than two-thirds of the target number was enrolled by July 1998; the trial is expected to be complete in 2008.

A problem of potentially major consequence for both trials is the ‘contamination’ of the control group. The sample size for a clinical trial is calculated to give the number of events required to achieve an appropriate level of statistical power. From this, the required sample size can be calculated. Zelen [31] showed that the effective sample size (ESS) is n(1 − p)², where p is the proportion of the control group who receive the treatment and n is the original number of events required. Thus if 25% of the control group have their PSA measured, the ESS is 0.56n. If p is 50%, then ESS is 0.25n. If the recruitment has been completed, the only way to achieve the required power is to increase the follow-up to get the increased number of events, resulting in a delay in obtaining meaningful results.

SCREENING RECOMMENDATIONS

From the available evidence various different recommendations have been made to the general public by professional groups. The American Cancer Society currently does not recommend mass screening but recommends that men should be given the opportunity for shared decision-making about testing. They recommend that healthcare professionals should offer the PSA test and DRE yearly, beginning at age 50, to men who have at least a 10-year life expectancy, by giving men the necessary information to make an informed decision. In the decision-making process, information should be provided to men about the potential risks and benefits of early detection and treatment of prostate cancer. Men who are members of high-risk groups, e.g. African-Americans and men who have a first-degree relative diagnosed with prostate cancer at an early age, should begin testing at 45 years.

The American Medical Association declares that launching mass prostate screening programmes is currently premature. Physicians should provide patients with information about the risks and benefits to make an informed decision about screening. When men are screened, it should include both a PSA test and a DRE, and men most likely to benefit include those who have a life expectancy of ≥ 10 years, who are aged ≥ 40 years and of African-American descent, who have an affected first-degree relative and those aged ≥ 50 years.

The United States Preventive Services Task Force initially recommended against routine screening using PSA or a DRE, but their position may have changed with their more recent evaluation [32] that the evidence is insufficient to recommend for or against routine screening using these two tests. Although they found that screening leads to early detection, and some men with prostate cancer benefit from treatment, there is uncertainty whether the potential benefits of screening justify the potential harms. If physicians chose to screen individual patients they should first discuss the uncertain benefits and possible harms. These recommendations are supported by the Centers for Disease Control and Prevention.

In the UK, the National Health Service (NHS) states that ‘until there is clear evidence that a national screening programme will bring more benefit than harm, the NHS will not be inviting asymptomatic men for prostate cancer screening’.

THE CURRENT SITUATION

The possible reduction in mortality from screening, while uncertain, must be weighed against the substantial decreases in treatment-specific health outcomes among men treated for clinically localized tumours typically detected by screening. Concurrent with the successful life-saving efforts in terms of prostate cancer diagnosis and treatment, some men who do not need treatment are receiving it [33]. These are men destined to die from causes other than prostate cancer. Unfortunately, at diagnosis, men needing treatment for prostate cancer cannot be differentiated from men who do not. Unless the likely date of death from prostate cancer and the likely date of death from other causes can be precisely determined for each patient, some men will always be over-or under-treated [33]. Conservative strategies result in the under-treatment of some patients who would benefit from treatment, while sparing other patients unnecessary treatment. Aggressive strategies result in the over-treatment of patients who do not need therapy, while curing other men of prostate cancer. Both strategies are correct, but only some of the time. There have been dramatic shifts in the incidence, grade, stage and age of men with prostate cancer with the advent of widespread PSA-based cancer detection in the USA [33]. Grade and stage trends suggest that more biologically relevant (the shift from well- to moderately differentiated tumours) and yet therapeutically amenable (earlier stage) tumours have been identified in many patients during the PSA era. Many men have been diagnosed and treated who will not benefit from such treatment. Given the long delay between treatment and mortality that is inherent in early prostate cancer, the full effects of treatment are probably not yet apparent in prostate cancer mortality data [33].

Population data and ongoing screening trials in the USA and Europe will be complementary in the final determination of the relative contribution of the impact of screening vs other causes on recent mortality trends. Unfortunately, it is not feasible for a physician to advise the patient requesting advice about PSA testing to return in 4–6 years when the results of randomized trials will (probably) be available.

So what should be done and what should be recommended at present? Imagine the outcome of the much awaited randomized trials; if the findings from both trials are in favour of PSA testing reducing prostate cancer mortality, then there would be an acceleration in the use of PSA testing and coverage of the population tested would increase. But what would happen if both trials were to report null findings, i.e. no reduction in prostate cancer mortality with PSA screening? It is highly likely that even if both trials are null, widespread PSA testing will continue.

There are several reasons for believing this. Trial results, for or against, have been contentious issues among supporters and opponents of screening ever since they were first undertaken. Specifically, there has recently been a situation where the utility of mammographic screening for breast cancer has come under strong attack [34,35]. Even with data available from nine randomized trials of reasonable methodology, claims were made strongly that there was no evidence to support mammographic screening. With fewer trials available for evaluating prostate cancer screening, and with contamination rates in the control group likely to be very high, questions will be posed about the reliability of the findings.

Second, and importantly, the PSA test is straightforward, cheap, readily available and easily acceptable by most men. PSA testing has already achieved a high penetration among men and their physicians. In 2000, in the USA it was estimated that 12 514 000 PSA tests were provided to the male population (135 000 000 in all) (http://www.cdc.gov/nchs/fastats/pdf/ad328.t15.pdf/).

Furthermore, PSA use among black and white Medicare beneficiaries aged > 65 years during the period from January 1991 to December 1998 was determined. PSA use stabilized among white men, reaching an annual rate of 38% by 1995 and remaining at this level to 1998. The annual rate of use among black men reached 31% by 1998, but was still increasing at that time. By 1996, at least 80% of tests in both blacks and whites were second or later tests. By the end of 1996, 35% of white men and 25% of black men were undergoing testing at least biannually or more frequently. In 1996, 83% of diagnoses in whites and 77% in blacks were preceded by a PSA test. In both race groups, an overwhelming majority of diagnoses are associated with a PSA test, whether for screening or diagnostic purposes [36].

An age-stratified population-based ‘random digit dial’ telephone survey determined prevalence of PSA testing among men in Alberta aged 40–74 years. The proportion of men who had ever had PSA testing was 4.5% at age 40–49, 13.1% at age 50–59, and 22.2% at age 60–74 years [37].

The extent of PSA testing outside North America is more surprising, e.g. > 2.2 million PSA tests were used in > 1.1 million Australians between 1989 and 1996. The annual number of men tested increased five-fold in this period and peaked in 1995. Of Australian men aged > 50 years, 27% had at least one PSA test in 1995 or 1996; 33% of men aged 60–69 years had a test in this period [38]. To document the extent of PSA testing in the general population at Getafe (Spain), 5371 PSA test records (1997–99) were reviewed and testing rates estimated per 1000 person-years [39]. The PSA testing rate in the general population was 21.6/1000 person-years; in those aged 55–69 years it was 86.8/1000 and increased to 152.6/1000 in men aged > 70 years [40]. In Milan, Italy, where there is no campaign publicising or encouraging prostate cancer screening, it has been estimated that 26.9% of men aged ≥ 40 years and with no history of prostate cancer had a PSA test in the 2-year period 1999–2000 [39]; in men aged ≥ 50 years the rate increased to 34%.

THE WAY FORWARD

The degree of enthusiasm for prostate cancer screening seems high even given the limitations of the evidence of benefit, and several reasons for this have been presented recently [41]. Given the current situation, there are several different strategies that could be introduced. For example, the (English) NHS Prostate Cancer Risk Management Plan recognises that more men are sufficiently anxious about prostate cancer to seek help by asking for a PSA test (http://www.cancerscreening.nhs.uk/prostate/informationpack.html). Under this plan any man considering a PSA test will be given detailed information to enable him to make an informed choice about whether to proceed with the test. Properly managed access to the PSA test has a significant part to play in empowering people to make decisions about their lives. If, having had access to this information, any man who still wishes to have his PSA tested can have this provided for him by the NHS.

Many sources of data show that prostate cancer incidence rates increased after the introduction of PSA testing. The average age at diagnosis has decreased, the proportion of advanced stage tumours has declined, the proportion of moderately differentiated tumours has increased, and patterns of care have changed accordingly [42]. A decline in mortality began in the USA and other countries in 1991. The decline in mortality is well established but this recent trend may only retrace an increase in mortality that immediately preceded this phenomenon. The descriptive epidemiology of prostate cancer reveals many effects of the introduction of prostate cancer screening. Although the evidence suggests increased prostate cancer testing has yielded public health benefit, this has not yet been shown conclusively.

The key to the problem centres around the adverse effects associated with radical treatment; could a moderate reduction in mortality through early detection be offset by a decreased quality of life in treated men? Suppose that a third of men diagnosed with prostate cancer die from the disease and hence in an unscreened population there are 1000 prostate cancer deaths and 3000 cases. If screening is introduced and decreases the mortality by 30%, then there should be 700 deaths. However, the incidence would double and there would be 6000 prostate cancer cases, most of whom would be early stage and suitable candidates for radical therapy. As noted, in a random sample of Medicare patients the serious adverse effect rate was 28.6% in those treated radically. If 4000 (of 6000) patients were treated radically, then it could be expected that there would be 1114 serious adverse events, i.e. at least 600 ‘extra’. Preventing one death could result in serious adverse events in between one and two men. The importance of having outstanding therapy in place for all men in any community screened is paramount. The need for more large sample, population based data about treatment outcomes is also evident.

It is very unlikely that there will be any deceleration in the continually increasing use of PSA for detecting prostate cancer in the near future. It is possible that it will become as widespread among men as cholesterol measurement, and will share with that mode of screening the notorious distinction of never having had its value (mortality reduction) confirmed in a randomized trial. However, it is an imperative duty, first of all, to ensure that the results of this ‘natural experiment’ can be evaluated, and, second to seek ways to improve the outcome of therapy for prostate cancer. The adverse effects of radical therapy in the community currently present the major hurdle in recommending mass screening for prostate cancer among populations. Systems should be in place now to ensure that men and physicians participating in PSA testing should be involved in a programme in which the effect of the intervention can be evaluated. This much is owed to men in the community.

ACKNOWLEDGEMENTS

This research was conducted within the framework of support from the Associazione Italiana per la Ricerca sul Cancro (AIRC) (Italian Association for Cancer Research) and the Lega Italiana.

Abbreviations

PLCO

Prostate, Lung, Colorectal, and Ovarian Cancer study

ERSSPC

European Randomized Study for Screening for Prostate Cancer

ESS

effective sample size

NHS

National Health Service