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Keywords:

  • prostate cancer;
  • radical prostatectomy;
  • antiandrogens;
  • LHRH analogues;
  • PSA screening;
  • secular trends;
  • mortality

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

OBJECTIVE

To aid the interpretation of the trends in prostate cancer mortality, which declined in the UK in the early 1990s for unknown reasons, by investigating prostate cancer death rates, incidence and treatments in England and Wales in 1975–2004.

METHODS

Join-point regression was used to assess secular trends in mortality and incidence (source: Office of National Statistics), radical prostatectomy and orchidectomy (source: Hospital Episode Statistics database) and androgen-suppression drugs (source: Intercontinental Medical Statistics).

RESULTS

Prostate cancer mortality declined from 1992 (95% confidence interval, CI, 1990–94). The relative decline in mortality to 2004 was greater and more sustained amongst men aged 55–74 years (annual percentage mortality reduction 2.75%; 95% CI 2.33–3.18%) than amongst those aged ≥75 years (0.71%, 0.26–1.15%). The use of radical prostatectomy increased between 1991 (89 operations) and 2004 (2788) amongst men aged 55–74 years. The prescribing of androgen suppression increased between 1987 (33 000 prescriptions) and 2004 (470 000).

CONCLUSIONS

The decrease in prostate cancer mortality was greater amongst men aged 55–74 years than in those aged ≥75 years, but pre-dated the substantial use of prostate-specific antigen screening and radical prostatectomy in the UK. An increase in radical therapy amongst younger groups with localized cancers and screen-detected low-volume locally advanced disease as a result of stage migration, as well as prolonged survival from increased medical androgen suppression therapy, might partly explain recent trends.


Abbreviations
RP

radical prostatectomy

HES

Hospital Episodes Statistics

OPCS

Office of Population Censuses and Surveys

ONS

Office of National Statistics

ICD

International Classification of Diseases

IMS

Intercontinental Medical Statistics

INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

In Europe and North America prostate cancer is the second commonest cause of male cancer deaths [1]. Prostate cancer incidence and mortality increased steadily in several countries during the 1980s [2], but while mortality rates continued to increase in most areas in the 1990s, there were sizeable declines in seven countries (Canada, USA, Austria, France, Germany, Italy, UK) beginning in 1988–91 [3]. Some authors have attributed declining death rates to the introduction of screening based on PSA testing, either through an empirical demonstration of inverse ecological associations between PSA screening intensity and prostate cancer mortality [4], or by indicating that screening has resulted in the earlier diagnosis [5] and increased radical treatment [6] of localized, well-differentiated prostate cancer.

Whether screening explains these favourable mortality trends is controversial for several reasons [7–9]. First, the effectiveness of PSA screening has not been shown in well-conducted randomized controlled trials. Second, there is uncertainty over the effectiveness of treatments for screen-detected disease [9], which might have a limited effect at a population level [10] because of considerable potential for over-diagnosis and over-treatment of clinically insignificant prostate cancer [11,12]. Third, the mean lead time (the time by which diagnosis is advanced by screening) for prostate cancer is >10 years [12], whereas mean lead times of ≤3 years would be required to explain the reductions in mortality reported within 3–4 years of the introduction of widespread PSA screening in 1988 in the USA [13]. Finally, several comparisons of mortality patterns between regions, both within and outside the USA, where PSA screening intensity levels are markedly different, reveal no [3,14–17] or a very weak [18] relationship between prostate cancer death rates and the intensity of screening or increased levels of radical treatment.

Trials of PSA testing are ongoing in the UK [19], USA [20] and the European mainland [21], but are not due to report their results for several years. In the absence of trial data, considerable interest remains in determining whether PSA testing has had any effect on mortality at a population level. As well as the issues of interpretation outlined above, previous ecological studies have been hampered by a lack of data beyond the first few years after the introduction of PSA testing, and because other factors, e.g. changes in treatment patterns, were often not considered. We examined age-specific trends in prostate cancer mortality between 1975 and 2004 in England and Wales, in the context of age-specific trends in prostate cancer incidence, use of radical prostatectomy (RP) and hormone therapy.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

DATA SOURCES

The age-specific prostate cancer incidence between 1975 and 2004 was obtained from the MB1 series published by the Office of Population Censuses and Surveys (OPCS) until 1996 and the Office of National Statistics (ONS) thereafter. These volumes cover cancer registrations for both England and Wales until 1994, and England only from 1995 onwards. The validity of these data has been established for comparisons of cancer risk over time [22].

Age-specific prostate cancer mortality in England and Wales between 1975 and 2004 was obtained from the ONS Series DH2, Mortality statistics: Cause. The process of collecting and coding death registrations changed over the study period. These changes included: updates of International Classification of Diseases (ICD) codes from ICD-8 to ICD-9 in 1979 and from ICD-9 to ICD-10 in 2001 [23,24], introduction of automated cause of death coding in 1993 [25] and changes to the interpretation of WHO Rule 3 for selecting underlying cause of death in 1984, 1993 [26,27] and 2001 [26]. Rule 3 allows a condition reported in either Part I or Part II of the death certificate to take precedence over a condition selected using other coding rules if the latter is obviously a direct consequence of that condition. Between 1984 and 1992, a revised interpretation of WHO Rule 3 was introduced by the OPCS. Consequently, deaths from causes such as pneumonia declined steeply in 1984, whereas deaths from causes often mentioned in part II of the certificate increased [27]. This change resulted in an increase in the death rate from prostate cancer in 1984, which was most marked in the elderly. The change in 1993 was a move back to the internationally accepted interpretation of Rule 3 operating in England and Wales before 1984. Under ICD-10 adopted in January 2001, the interpretation of Rule 3 is similar to that adopted by the OPCS for deaths in 1984–92. A bridge-coding exercise showed that for cancers coded by ICD-9 Rule 3 between 1993 and 2000, the application of ICD-10 Rule 3 would have selected prostate cancer more often as the underlying cause of death [23,24], the ratio of the number of deaths coded to prostate cancer using ICD-10 compared with applying ICD-9 rules being 1.008, 1.031 and 1.358 at ages <75, 75–84 and ≥85 years, respectively [23]. The influence of these procedural changes on the mortality data is investigated by applying the multipliers 1.008 (for deaths in men aged <75 years) and 1.031 (for deaths >75 years) to the data between 1993 and 2000, to give an expected number of deaths that would have been coded to prostate cancer in ICD-10.

The Hospital Episode Statistics (HES) database for England holds information on the care provided to those admitted to NHS hospitals and for NHS hospital patients treated elsewhere. This includes details of surgical procedures carried out, coded using OPCS-4 codes. HES records were extracted from the database held by the Department of Social Medicine, Bristol using the OPCS procedure codes M 61 (RP) and N051, N052, N061, N063 (orchidectomy) when the underlying diagnosis was prostate cancer (ICD9, 185; and ICD10, C61). This information was available from 1991 to 2004.

Data on overall prescribing in England and Wales (1975–2004) of hormonal therapy for prostate cancer (i.e. oestrogens, LHRH analogues and antiandrogens) were obtained from Intercontinental Medical Statistics (IMS) Health Medical Data Index [28]. Age-specific prescribing data were not available. Since 1967, IMS Health has collected quarterly data on drug prescribing in the UK. A prescription is defined as every drug item on a prescription form given as a result of a consultation. Since 1994, anonymized prescribing data have been collected electronically every day from a stratified sample of 500 GPs, giving a total of 26 000 doctor-weeks per year. Sample data are projected to the whole of the UK, weighted by a regional factor, and the figures adjusted to reflect the total number of prescriptions dispensed in the UK as indicated by data published by the UK Prescription Pricing Authority.

Age-specific rates for prostate cancer incidence and mortality, and RP, were estimated for the age groups <55, 55–74 and ≥75 years using the year-by-year information on the mid-year resident population of England and/or Wales, as appropriate, from 1975 to 2004 as provided by the Population Estimates Unit of the ONS. The mid-year population of men resident in England only was used for calculating age-specific incidence rates from 1995 to 2004, and age-specific rates for orchidectomy and RP from 1991 to 2004. The population of men aged ≥55 years in England in 2004 was 6.26 million, compared to 0.40 million in Wales, so if trends differ in the two countries this would only have a minor impact on the results. Unless otherwise noted, all rates are expressed per 100 000 population per year.

Analysis of prostate cancer incidence and mortality trends was conducted by join-point regression, in which trend data are described by a number of contiguous linear segments and ‘join points’ (points at which trends change). Join-point regression was used to estimate the annual change in incidence and mortality rates and the number and location of join points [29]. Models were based on linear regression, with incidence and mortality rates as the dependent variables and year as the independent variable. To identify the best-fitting combination of line segments and join points, a series of permutation tests was used, first testing the null hypothesis (Ho= no join points) vs the alternative hypothesis (Ha= three join points). Hypothesis testing proceeded sequentially, increasing the number of join points under Ho by one if the null hypothesis was rejected and decreasing the number of join points under the alternative hypothesis if Ho was accepted. The maximum number of join points tested was three in each analysis. For each model, the locations (i.e. years and 95% CI) of the best-fitting join points were identified using a grid search algorithm [30]. A Bonferonni correction was applied by conducting each test at the α/3 level, ensuring that the probability of a type I error (i.e. concluding that there are one or more join points when there are in fact none) was at most 0.05. Analyses were conducted using Joinpoint software (version 3 April 2005) made available by the National Cancer Institute (srab.cancer.gov/joinpoint).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

Figure 1 summarizes the secular trends in age-specific prostate cancer incidence. Overall, the annual number of new cases of prostate cancer increased from 7168 in 1975 (England and Wales) to 29 406 in 2004 (England). Incidence rates amongst men aged <55 years were low but increased six-fold between 1975 (3.07 per 100 000) and 2004 (18.30 per 100 000).

image

Figure 1. Annual age-specific prostate cancer incidence rates per 100 000 men in England and Wales, 1975–2004. Source: MB1 series, ONS (formerly OPCS).

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Amongst men aged 55–74 years, the incidence of prostate cancer increased four-fold between 1975 and 2004. The increase in incidence began in 1985 (95% CI for year of change 1982–89; P for slope change <0.001). The estimated mean increase in incidence between 1985 and 1998 was 10.35 additional new cases per 100 000 per year (95% CI 8.76–11.94; P < 0.001 for the test of the null hypothesis that the annual change was zero). From 1998 (95% CI 1995–2000) until 2004, there was an acceleration in the incidence amongst this age group (P for slope change <0.001), the incidence increasing to a mean of 21.83 additional new cases per 100 000 per year (95% CI 17.28–26.38; P < 0.001). Table 1 summarizes the annual change and join points for trends in the age-specific incidence (and mortality) rates.

Table 1.  A summary of the annual change and join points for trends in age-specific incidence and mortality rates, England and Wales, 1975–2004
Age group, yearsAnnual change (95% CI) for period
1 (1975 to JP1)2 (JP1 to JP2)3 (JP2 to 2004)
Absolute*/100 000Relative%JP1 (95% CI)Absolute*/100 000Relative%JP2 (95% CI)Absolute*/100 000Relative%
  1. JP, join point; *Absolute annual rate change, based on the linear model option in Joinpoint. †Annual percentage rate change, based on the log-linear model option in Joinpoint. ‡Based on the linear model option, but join points based on the log-linear model option were little different. **Annual percentage change is for JP1 to 2004, as only 1 JP in 1984 was estimated from the log-linear model.

Incidence
55–740.380.52198510.35 7.06**199821.83
(−1.72; 2.48) (−0.93; 1.99)(1982, 1989)(8.76; 11.94)(6.59; 7.52)(1995, 2000)(17.28; 26.38) 
≥755.461.10198637.936.1919942.740.27
(1.42; 9.50)(0.32; 1.89)(1983, 1988)(29.93; 45.93)(5.05; 7.35)(1992, 1995) (−1.92; 7.40) (−0.51; 1.04)
Mortality
55−740.150.6619791.723.081992−1.61−2.75
(−1.05; 1.35) (−1.67; 3.05)(1977, 1983)(1.50; 1.94)(2.63; 3.54)(1990, 1993) (−1.83; −1.39) (−3.18; −2.33)
≥750.020.10198114.844.431992−3.81−0.71
(−5.25; 5.28) (−1.34; 1.57)(1979, 1984)(12.41; 17.27)(3.61; 5.25)(1990, 1994) (−5.65; −1.97) (−1.15; −0.26)

Amongst men aged ≥75 years the incidence of prostate cancer increased slowly between 1975 and 1986, with a mean annual increase of 5.46 per 100 000 (95% CI 1.42–9.50). The rise in incidence increased steadily after 1986 (95% CI 1983–88; P for slope change <0.001), peaking in 1994 (95% CI 1992 to 1995). From 1994, new registrations of prostate cancer amongst men aged ≥75 years reached a plateau (P for slope change <0.001) with little evidence of any annual change in incidence up to 2004 (P = 0.3).

Figure 2 summarizes the age-specific prostate cancer mortality rates. The numbers of deaths from prostate cancer in England and Wales doubled from 4421 in 1975 to 9169 in 2004. Death rates amongst men aged <55 years were low in 1975 (0.31 per 100 000) and 2004 (0.45 per 100 000). Death rates amongst men aged 55–74 years started to increase in 1979 (95% CI 1977–83), from 46.33 per 100 000 to a peak of 67.33 per 100 000 in 1992 (95% CI 1990–93). The estimated mean increase in mortality between 1979 and 1992 was 1.72 additional deaths per 100 000 per year (95% CI 1.50–1.94; P < 0.001). There was strong evidence that mortality amongst men aged 55–74 years started to decline steadily after 1992 (P for slope change <0.001); the estimated mean decrease in deaths between 1992 and 2004 was 1.61 per 100 000 per year (95% CI 1.39–1.83; P < 0.001), from 67.33 to 49.64 deaths per 100 000. In relative terms, the annual percentage reduction in mortality was 2.75% (95% CI 2.33–3.18%) in this age group between 1992 and 2004 (an overall 26% decrease in mortality rates). The observed and fitted values for the mortality trend in men aged 55–74 years are shown in more detail in Fig. 3, with a shorter ordinate scale from 0 to 80 per 100 000.

image

Figure 2. Annual age-specific prostate cancer mortality rates per 100 000 men in England and Wales, 1975–2004. Shaded area, revised interpretation of WHO Rule 3 was introduced by the OPCS.

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image

Figure 3. Observed and fitted prostate cancer mortality rates amongst men aged 55–74 years, per 100 000 men in England and Wales, 1975–2004. Source: DH2, Mortality statistics: Cause. ONS.

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Amongst men aged ≥75 years death rates started to increase in 1981 (95% CI 1979–84), from 296.23 per 100 000 to a peak of 456.97 per 100 000 in 1992 (95% CI 1990–94; Fig. 2). The estimated mean increase in mortality between 1981 and 1992 was 14.84 additional deaths per 100 000 per year (95% CI 12.41–17.27; P < 0.001). There was strong evidence that mortality amongst those aged ≥75 years started to decline after 1992 (P for slope change <0.001), the estimated mean slope between 1992 and 2004 indicating 3.81 fewer deaths per 100 000 per year (95% CI 1.97–5.65; P < 0.001). In relative terms, the annual percentage reduction in mortality was 0.71% (95% CI 0.26–1.15%) in this age group between 1992 and 2004 (an overall 7% decrease in mortality). There was little effect of adjusting for the return between 1993 and 2000 to the internationally accepted interpretation of Rule 3 operating in England and Wales before 1984 (which particularly affected those aged ≥75 years); using adjusted estimates suggested that the decline in mortality started after 1993 (95% CI 1991–94) and might have been slightly greater than estimated using the original data (−5.42 deaths per 100 000 per year; 95% CI −3.60 to −7.24). Amongst men aged ≥75 years, there was borderline statistical evidence that the data fitted a three join-point model (P = 0.05). In this model, death rates increased in 1981 (95% CI 1979–83) and declined in 1993 (95% CI 1991–95), in line with the two join-point model, but there was a suggestion visually and in the three join-point model that mortality rates might have reached a plateau in 1999 (95% CI 1996–2002).

Figure 4 shows the annual age-specific RP and orchidectomy rates per 100 000 men in England, 1991–2004. The number of RPs in patients with prostate cancer increased 19-fold from 164 in 1991 to 3070 in 2004. The increased use of RP was mainly amongst men aged 55–74 years (a 31-fold increase from 89 in 1991 to 2788 in 2004). In this age group there appeared to be an acceleration in the annual increase in operation rates after 1997 (95% CI 1995–99; P for slope change <0.001). Amongst those aged 55–74 years orchidectomy rates for prostate cancer decreased each year, from 28.07 per 100 000 in 1991 to 2.45 per 100 000 in 2004; the corresponding decrease amongst men aged ≥75 years was from 106.58 to 15.17.

image

Figure 4. Annual age-specific RP and orchidectomy rates per 100 000 men in England, 1991–2004. Source: HES Database, England. Rates for men aged <55 years are not shown because there were very few.

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Figure 5 shows the rates per 100 000 men of prescriptions for LHRH analogues, antiandrogens and oestrogens for treating prostate cancer in the UK between 1975 and 2004. The number of prescriptions for LHRH analogues steadily increased from 1987 (95% CI: 1985–89) to 2004, from 4000 (14.5 per 100 000) to 319 000 (1089.8 per 100 000) per annum over this time (an estimated annual increase of 17 810 prescriptions; 95% CI: 16 338–19 282). Prescriptions for antiandrogens also increased from 0 in 1982 to 151 000 (515.9 per 100 000) in 2004 (an estimated annual increase of 7508 prescriptions; 95% CI 6950–8066). Prescriptions of oestrogens for treating prostate cancer decreased from 139 000 (508.0 per 100 000) in 1975 to a nadir of 14 000 (49.5 per 100 000) in 1996, thereafter increasing steadily to 34 000 (116.2 per 100 000) in 2004.

image

Figure 5. Rates per 100 000 men of prescribing for hormone treatment for prostate cancer UK, 1975–2004. Source: IMS Health Medical Data Index.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

We found strong evidence that prostate cancer death rates in England and Wales began to increase steadily in the late 1970s/early 1980s, reached a plateau about 1992 and then started to decline. This decline was steady amongst men aged 55–74 years until the end of data collection in 2004, decreasing by 26%. In the older men, aged ≥75 years, prostate cancer mortality declined by 7% between 1992 and 2004, although there was some evidence that death rates reached a plateau in 1999. Changes to the interpretation of WHO coding Rule 3 in 1993–2000 did not explain the mortality declines, as was suggested by others.

To distinguish possible explanations for these mortality trends we placed them in the context of concomitant changes in disease incidence and advances in treatments for prostate cancer. In interpreting the findings, it is important to recognize the main limitations of the study, which are the lack of data on secular changes in radiotherapy management of prostate cancer and systematically obtained data on PSA testing rates. There are no long-term national sources of these data, although we are aware that steps are being taken to rectify this. We also lacked data on age-specific prescribing of medical antiandrogen therapy, although we did have indication-specific data.

SCREENING AND RADICAL THERAPY

Annual PSA testing rates in NHS general practice in England and Wales, amongst men who were initially free from prostate cancer, increased from 1.4% overall in 1994 [31] to 4.2% (aged 55–69 years) and 5.3% (≥70 years) in 1999 [32] and to 8.8% (55–74 years) and 14.0% (≥75 years) in 2002 [33]. Our data suggest that the secular increase in prostate cancer incidence accelerated from 1998 amongst men aged 55–74 years, possibly reflecting an increase in PSA testing. The mortality reduction, which started about 1992 in both those aged 55–74 and ≥75 years, pre-dates even the modest use of PSA testing in the UK in the late 1990s [33], and the wider use of RP for clinically localized disease observed since 1991 [34]. Prostate cancer death rates in the first decade after the diagnosis of localized disease are relatively low in both screen-detected prostate cancer (because of the >10-year mean lead-time [12]) and clinically identified disease [35–37]. The above considerations suggest that factors other than increased detection and radical treatment of early-stage disease contributed to the beginning of the decline in mortality starting in 1992. The start of this decline in about the same year in both the 55–74 and ≥75 year age groups suggests a period effect operating at that time (e.g. some aspect of prostate cancer management, if real, or cause of death assignment, if artefactual) rather than a cohort effect (which tends to implicate an environmental cause).

The cause(s) of the start of the decline in prostate cancer mortality in the early 1990s in many countries has been very difficult to determine because of inconsistent international mortality patterns reported soon after the introduction of PSA testing [3,14–16,18,38]. However, with longer-term monitoring of trends, our age-specific data might provide some clues. Of particular interest is that between 1992 and 2004 relative reductions in death rates were greater and sustained in those aged 55–74 years than in those aged ≥75 years. Although probably not a factor in the start of the decline in mortality, it is possible that the rapidly increasing use of RP in the younger group (Fig. 4) might be having some mortality benefit on the long-term trends at a population level. Between 1992 and 2004, prostate cancer deaths in those aged 55–74 years decreased by a total of 529, from 3071 to 2542 (≈44 fewer deaths per year) while the use of RP increased from 89 in 1991 to 2788 in 2004 (≈208 extra RPs per year). These extra RPs might be having a detectable effect on mortality trends to 2004 on the 50% of men with lead times of <10 years [12]. The observed trends would be consistent with an improved prognosis amongst younger men with clinically significant aggressive prostate cancer, and relatively short lead times [13], some of whom are being diagnosed by PSA testing and undergoing radical treatment before the disease has metastasized. Such a scenario would be expected to affect mortality more in the younger than the older group, amongst whom RP rates were low and stable, but an age-related divergence in mortality rates should only be detectable at 5–10 years after the increased use of radical therapy [35], which is what we found. An improved prognosis through the earlier detection of prostate cancer is consistent with declines in the mortality rate of disease diagnosed at an advanced stage in the PSA era in the USA [38]. However, it is likely that such benefits are restricted to a relatively small proportion of screen-detected men, most of whom have indolent disease and might be receiving unnecessary treatment [39].

HORMONES

Androgen suppression using oestrogens and surgical castration by bilateral orchidectomy was used for palliation in advanced prostate cancer, declining markedly in favour of LHRH analogues during the period of this study, perhaps because of concerns about adverse effects in the case of oestrogens, and the acceptability of orchidectomy. Starting in the mid-1980s, there were rapid increases in the prescribing of alternative forms of hormonal therapy, i.e. LHRH analogues and antiandrogens, in the UK. In the USA rapid increases in use of these androgen-deprivation therapies commenced in the late 1980s [40–42]. We are unable to determine whether earlier or more aggressive use of androgen-deprivation therapies (such as occurred in the USA [40–42]) explain their increase in the UK, but such changes in management would be in line with increased interest in their use in early disease [43–45]. Even though hormonal therapy is not curative, trial data suggest that increased uptake earlier in the course of the disease [46,47] or as maximum androgen blockade in advanced disease [43,48–50], could have contributed to the recent declines in mortality by delaying death from prostate cancer long enough for the man to die from other causes [40,51]. Such a possibility is supported by an ecological relationship between the intensity of early hormone ablation therapy and declines in mortality [18]. This hypothesis would be consistent with declines in mortality starting before any plausible effects of the increased use of radical treatment for localized disease became apparent. The combined effect of stage migration through screening and the detection of asymptomatic early extracapsular cancers treated aggressively with radiotherapy and androgen suppression might explain the early mortality effect reported in a study from Austria, where ≈5 years after the introduction of mass screening, there was a lower mortality from prostate cancer in the Tyrol region [4]. Radiotherapy alone with dose escalation might also have played a role in delaying death from prostate cancer [52], but we have no data on this issue.

ARTEFACT

If it is accepted that the increase in disease incidence was largely an artefact of greater surveillance, because of increased use of TURP [53] and PSA testing [14] (see below), then the increase in mortality between 1979 and 1992 might also have been an artefact. It is unlikely that increased diagnosis adversely affected prostate cancer-specific survival during this time, by increasing iatrogenic deaths, as RP was limited before 1992 and the operative mortality is low [54], although concerns were recently raised about fatal myocardial infarction associated with androgen-suppression therapy [55]. Perhaps a more plausible explanation is increased attribution of deaths, that would have previously been labelled as death from other causes, as being from prostate cancer, merely as a result of the cancer being detected [38,56,57]. The ICD-9/10 coding rules might select prostate cancer as the underlying cause of death despite clinical uncertainty, if a diagnosed prostate cancer is entered at some point on the death certificate [58]. It is possible that the changes to the interpretation of WHO coding Rule 3 in 1984, which increased deaths from causes often mentioned in part II of the certificate [27], explains the sharp increase in prostate cancer mortality between 1983 and 1984, but not the continued increase in mortality trends until 1992. Incidence rates have not declined, but the recent mortality declines could have been artefactual, if the bias in cause of death attribution was reduced once physicians recognized the relatively good prognosis of localized prostate cancer, and therefore might have been less likely to record prostate cancer on the death certificate [38]. One report suggests biased under-attribution of prostate cancer as the underlying cause of death amongst men who had radical treatment [59]; this might partly explain the decline in mortality amongst men aged 55–74 years. However, in those aged 55–74 years the mortality has declined to below the levels apparent before the increase in incidence rates in 1985, indicating that reduced misattribution bias probably does not explain all the decline in mortality. The continued rising incidence rate in this age group is more likely to be masking larger mortality declines.

PROSTATE CANCER INCIDENCE

The incidence of prostate cancer increased steadily from the mid-1980s. A cohort analysis indicates that there might have been a real increase in risk in the Netherlands [60]. In Japan, large increases in childhood height [61], a marker for early childhood nutrition and levels of the dietary regulated, anti-apoptotic peptide IGF-I [62], have been followed by steady increases in the rate of prostate cancer [63]. However, as most prostate cancers that can be potentially detected have an indolent natural history, a large proportion of the increasing incidence is likely to reflect improvements in the detection of cancers that formerly were undiagnosed [53,64,65]. This hypothesis is supported by strong positive ecological correlations between the rates of use of techniques that increase the diagnosis and incidence of prostate cancer [53,64–66], and by the similarity in mortality patterns between areas with markedly divergent incidence rates [3,15,16,64]. During the 1980s, the increased use of TURP for BPH probably explains the increased incidence observed during the 5 years before the introduction of PSA testing in the UK in 1990 [53,64,67].

In conclusion, prostate cancer mortality has been decreasing steadily in England and Wales since 1992, after a period of increasing artefactual incidence and mortality in the 1980s. The availability of PSA screening is unlikely to explain the initial decline in mortality, as the decrease coincides with the period during which PSA testing and aggressive treatment in England was limited, and is inconsistent with the long lead-time involved in the progression of prostate cancer. RP, which was largely restricted to men aged 55–74 years, might have been a factor in the continued steady mortality decline in men aged 55–74 years compared with those aged ≥75 years. Increasing use of medical androgen-deprivation therapy might be responsible for at least part of the mortality decline, by improving survival long enough for competing causes of death to feature. Even if early detection and radical treatment of localized prostate cancer explains some of the continued decline in mortality in middle-aged men in England, the dilemma remains that current screening tests cannot differentiate between cancers that have a low biological likelihood of progression from those with aggressive potential [68], for which early radical treatment might be justified [39]. There is thus the potential for a population-based screening programme to result in substantial over-diagnosis (estimated at 18–84%) and over-treatment of clinically insignificant prostate cancer [11,69], and the prospect of substantial morbidity as a result of treatment [70]. The relative effectiveness of the major forms of treatment for localized disease (RP, radical radiotherapy and active monitoring, i.e. regular PSA testing with radical intervention for tumours that progress) remain the subject of a large ongoing trial [71]. The debate about the effectiveness of screening and subsequent treatment will continue until the results of randomized controlled trials are known [9].

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES

The HES data were made available by the Department of Health. HES analyses conducted within the Department of Social Medicine are supported by the South West Public Health Observatory.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. CONFLICT OF INTEREST
  9. REFERENCES