Screening for prostate cancer (Review) Ilic D, O’Connor D, Green S, Wilt T
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2006, Issue 3 http://www.thecochranelibrary.com
Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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TABLE OF CONTENTS ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW . . . . . . . . . . . . . . . . . . SEARCH METHODS FOR IDENTIFICATION OF STUDIES . . . . . . . . . . . . . . . . . . . METHODS OF THE REVIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DESCRIPTION OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODOLOGICAL QUALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . POTENTIAL CONFLICT OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characteristics of included studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characteristics of excluded studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Characteristics of ongoing studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 01. Stage of prostate cancer diagnosis in the screening group 1988-1996 (Quebec) . . . . . . . . . . Table 02. Stage of prostate cancer across all groups 1987-1999 (Norrkoping) . . . . . . . . . . . . . . Table 03. Prostate tumour grade across both group 1987-1999 (Norrkoping) . . . . . . . . . . . . . . Table 04. Prostate cancer treatment regime 1987-1999 (Norrkoping) . . . . . . . . . . . . . . . . . ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparison 01. Screening vs control . . . . . . . . . . . . . . . . . . . . . . . . . . . . COVER SHEET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GRAPHS AND OTHER TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 01. Prostate cancer mortality across randomised groups from the Quebec study . . . . . . . . . . . Figure 02. Prostate cancer diagnosis and mortality across randomised groups from the Norrkoping study . . . . . Analysis 01.01. Comparison 01 Screening vs control, Outcome 01 Prostate cancer specific mortality (intention-to-screen) Analysis 01.02. Comparison 01 Screening vs control, Outcome 02 Prostate cancer diagnosis . . . . . . . . .
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Screening for prostate cancer (Review) Ilic D, O’Connor D, Green S, Wilt T
Status: New This record should be cited as: Ilic D, O’Connor D, Green S, Wilt T. Screening for prostate cancer. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004720. DOI: 10.1002/14651858.CD004720.pub2. This version first published online: 19 July 2006 in Issue 3, 2006. Date of most recent substantive amendment: 08 May 2006
ABSTRACT Background Any form of screening aims to reduce mortality and increase a person’s quality of life. Screening for prostate cancer has generated considerable debate within the medical community, as demonstrated by the varying recommendations made by medical organizations and governed by national policies. Much of this debate is due to the limited availability of high quality research and the influence of false-positive or false-negative results generated by use of the diagnostic techniques such as the digital rectal examination (DRE) and prostate specific antigen (PSA) blood test. Objectives To determine whether screening for prostate cancer reduces prostate cancer mortality and has an impact on quality of life. Search strategy Electronic databases (PROSTATE register, CENTRAL the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CANCERLIT and the NHS EED) were searched electronically in addition to hand searching of specific journals and bibliographies in an effort to identify both published and unpublished trials. Selection criteria All randomised controlled trials of screening versus no screening or routine care for prostate cancer were eligible for inclusion in this review. Data collection and analysis The search identified 99 potentially relevant articles that were selected for full text review. From these 99 citations, two randomised controlled trials were identified as meeting the review’s inclusion criteria. Data from the trials were independently extracted by two authors. Main results Two randomised controlled trials with a total of 55,512 participants were included; however, both trials had methodological weaknesses. Re-analysis using intention-to-screen and meta-analysis of results from the two randomised controlled trials indicated no statistically significant difference in prostate cancer mortality between men randomised for prostate cancer screening and controls (RR 1.01, 95% CI: 0.80-1.29). Neither study assessed the effect of prostate cancer screening on quality of life, all-cause mortality or cost effectiveness. Authors’ conclusions Given that only two randomised controlled trials were included, and the high risk of bias of both trials, there is insufficient evidence to either support or refute the routine use of mass, selective or opportunistic screening compared to no screening for reducing prostate cancer mortality. Currently, no robust evidence from randomised controlled trials is available regarding the impact of screening on quality of life, harms of screening, or its economic value. Results from two ongoing large scale multicentre randomised controlled trials that will be available in the next several years are required to make evidence-based decisions regarding prostate cancer screening. Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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PLAIN LANGUAGE SUMMARY Screening for prostate cancer Prostate cancer is one of the most prevalent forms of cancer in men worldwide. Screening for prostate cancer requires diagnostic tests to be performed in the absence of any symptoms or indications of disease. These tests include the digital rectal examination (DRE), the prostate specific antigen (PSA) blood test and the transrectal ultrasound-guided biopsy (TRUS). Screening aims to identify cancers at an early and treatable stage, therefore increasing the chances of successful treatment while also maintaining a patient’s quality of life. This review identified two trials, consisting of 9,026 and 46,486 participants; however, neither was assessed to be of high quality. This review demonstrates that there is not enough high quality evidence to inform whether or not screening for prostate cancer, via either a DRE, PSA or TRUS biopsy, is more effective than no screening in reducing the number of deaths attributable to prostate cancer. The effects of screening upon quality of life and cost have not been researched in randomised controlled trials. The results from two large trials, to be completed in the next few years, will provide greater information on this issue.
BACKGROUND Prostate cancer is the most prevalent cancer in men worldwide and a leading cause of cancer death (Parkin 2001). It is the second leading cause of cancer death in men in the western world, accounting for 15.3% of cancers in men within developed countries and 4.3% in developing countries (Parkin 2001). The prostate specific antigen (PSA) test and the digital rectal examination (DRE) are used as primary screening tools in the early detection of prostate cancer. Transrectal ultrasound-guided needle biopsies (TRUS) are performed to confirm diagnosis following PSA and/or DRE testing. These screening techniques aim to reduce disease-specific morbidity and mortality by identifying prostate cancer more frequently and earlier and thus hopefully leading to early treatment regimes that may be more effective when applied to prostate-confined cancer. Screening for any type of cancer aims to increase the chances of successful treatment through early detection of the disease. Screening may be performed in one of three methods: mass (i.e. large scale screening of an entire population), selective (i.e. screening high-risk populations) or opportunistic (e.g. incorporated as part of a medical consultation). Testing for, or diagnosing, a disease differs from screening. Diagnostic testing attempts to identify the disease in the presence of symptoms; screening is offered to symptom-free individuals. While the intention of screening for prostate cancer is to decrease mortality and increase the patient’s quality of life, the true benefit of screening remains uncertain. Use of the DRE as a screening tool is limited due to the inability to palpate the entire prostate gland, while the PSA test produces high false-negative and false-positive results (Gambert 2001). Additional causes for concern include the cost of follow-up tests, the potentially invasive nature of these tests, the potentially false sense of security following false negative test results, and the use of potentially harmful treatment regimes that may not provide any improvement in health outcomes. Although a man’s risk of prostate cancer diagnosis increases with age, many
men will live with undiagnosed prostate cancer only to die from another disorder, as has been confirmed in unselected autopsies (Holman 1999; Berry 1984). The uncertainty about the value of prostate cancer screening has been further highlighted by the conflicting recommendations made by various medical entities, which reflect the lack of high quality evidence within the medical literature (AUA 2000; Ferrini 1998; USA 2003; Coley 1997; Harris 2002; Smith 2002). Screening for prostate cancer may reduce both morbidity and mortality, yet the best method of screening (if any) is unknown. Equally, screening may promote treatment procedures that are unwarranted or may adversely affect the health outcomes of the patient with no net benefit. The cost-benefits associated with screening and potential follow-up tests and treatment may be justified; however, the economic implication of prostate cancer screening remains unknown. Additionally, treatment trials for early stage prostate cancer have not been conducted in men with predominately screen-detected cancer. A recent report evaluated radical prostatectomy versus watchful waiting in early prostate cancer. After 10 years radical prostatectomy reduced disease-specific mortality, overall mortality, and the risks of metastasis and local progression. The absolute reduction in the risk of death was small (5%) though the reduction in risks of metastasis (10%) and local tumour progression (25%) were large (Bill-Axelson 2005). Survival benefits were limited to men less then 65 years of age. Additionally, the authors noted that in the era of widespread screening the number of patients needed to be treated to achieve a benefit may be high due to the lead time to onset of symptoms and the unnecessary intervention in men with small tumours of no clinical importance.
OBJECTIVES The primary objective of this review is to determine the efficacy of screening asymptomatic men for prostate cancer in reducing all cause and prostate cancer-specific mortality.
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The secondary objectives of this review are to: • determine the impact of prostate cancer screening on quality of life and adverse effect • identify the cost effectiveness, cost utility and cost-benefit of mass screening for prostate cancer
CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW Types of studies All randomised, and quasi-randomised, controlled trials of screening versus no screening for prostate cancer were eligible for this review. To meet the secondary objective, studies including economic evaluation were also eligible for inclusion in the review to identify the economic impact of screening for prostate cancer. No language restrictions were placed on studies considered for inclusion in this review and published or unpublished sources were considered. Types of participants All men enrolled in studies of prostate cancer screening were eligible for this review, with no exclusions based on ethnicity nor age. Men with a previous diagnosis of prostate cancer were excluded. Types of intervention Studies that used any of the following screening procedures, individually or in combination, were included. • digital rectal examination (DRE) • prostate specific antigen (PSA) test (including total, velocity, density and percentage free and complex) • transrectal ultrasound (TRUS) biopsy Types of outcome measures The primary outcome measures for this review were mortality rate (both prostate-cancer specific and all cause) and the number of men diagnosed with prostate cancer (including classification by stage and grade of the cancer). Secondary outcomes included: • Incident prostate cancers by stage and grade at diagnosis • Metastatic disease at follow up • Quality of life • Costs associated with screening programs • Harms of screening (including both adverse outcomes from false positive and/or false negative results and their impact upon resulting treatment procedures)
SEARCH METHODS FOR IDENTIFICATION OF STUDIES See: Prostatic and Urologic Cancers Group methods used in reviews. We performed electronic searches of the PROSTATE register (made available by the Cochrane Prostatic Diseases and Urologic Cancers Group) the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CANCERLIT and the NHS EED. The PROSTATE register was searched in November 2004, with the remaining databases searched for studies published between 1966 and January 2006. Hand searching for reviews and technical reports with regard to prostate cancer screening in specialist journals, as shown below, and grey literature was conducted, as well personal communication in order to identify potential unpublished data. There was no restriction on language. The search strategy is displayed below and was adapted for each electronic database. The following journals were hand searched until March of 2005 BJU International 2000 - 2005 European Urology 2002 - 2005 The Prostate 1998 - 2005 Journal of Urology 1996 - 2005 Urology 2002 - 2005 Cancer 1998 - 2005 The following search strategy was used for MEDLINE, PROSTATE register and CANCERLIT: 1. Prostate-Specific Antigen/ 2. prostate specific antigen.mp 3. psa.mp. 4. digitial rectal examination.mp. 5. dre.mp. 6. transrectal ultrasound$.mp. 7. TRUS.mp. 8. or/1-7 9. Mass Screening/ 10. screening.mp 11. or/9-10 12. Prostatic Neoplasms/pc, di [Prevention & Control, Diagnosis] 13. prostat$ cancer.mp 14. or/12-13 15. clinical trial.pt. 16. random$.mp 17. ((single or double) adj (Blind$ or mask$)).mp 18. placebo$.mp 19. or/14-18 20. 8 and 11 and 14 and 19 The following search strategy was used for EMBASE: 1. Prostate-Specific Antigen/
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2. prostate specific antigen.mp 3. psa.mp. 4. digitial rectal examination.mp. 5. dre.mp. 6. transrectal ultrasound$.mp. 7. TRUS.mp. 8. 1 or 2 or 3 or 4 or 5 or 6 or 7 9. Mass Screening/ 10. screening.mp 11. 9 or 10 12. Prostate Tumor/pc, di [Prevention, Diagnosis] 13. prostat$ cancer.mp 14. 12 or 13 15. clinical trial.pt. 16. random$.mp 17. ((single or double) adj (Blind$ or mask$)).mp 18. placebo$.mp 19. or/14-18 20. 8 and 11 and 14 and 19 The following search strategy was used for the Cochrane Central Register of Controlled Trials and the NHS EED: 1. PROSTATE-SPECIFIC ANTIGEN 2. (prostate next specific next antigen) 3. psa 4. (digital next rectal next examination) 5. dre 6. (transrectal next ultrasound*) 7. trus 8. (#1 or #2 or #3 or #4 or #5 or #6 or #7) 9. MASS SCREENING 10. screening 11. (#9 or #10) 12. PROSTATIC NEOPLASMS 13. (prostat* next cancer) 14. (#12 or #13) 15. (#8 and #11 and #14)
METHODS OF THE REVIEW Selection of Trials Two of the authors (DI, DOC) independently selected trials for possible inclusion against a predetermined checklist of inclusion criteria. Studies were initially categorized into the following groups: • Possibly relevant - studies that met the inclusion criteria and studies from which it was not possible to determine whether they met the criteria either from their title or abstract • Excluded - those clearly not meeting the inclusion criteria If a title, or abstract, appeared to meet the eligibility criteria for inclusion of the review, or we could not tell, a full text version
of the article was obtained and assessed by two authors (DI and DOC) in order to determine whether it met the inclusion criteria. Discrepancies between the authors were resolved via discussion. Assessment of Methodological Quality of Included Trials Two authors (DI and DOC) independently assessed the susceptibility to bias of the selected trials. The risk of bias was assessed by reporting the trial’s conduct against the following key criteria: • Randomisation • Allocation concealment as coded according to the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005). (A) Adequate (B) Unclear (C) Inadequate (D) Not Used • Blinding of participants (graded as yes, no or unclear) • Blinding of outcome assessors (graded as yes, no or unclear) • Completeness of the follow up, i.e. description of any numbers lost to follow up (graded as yes, no or unclear), and • Whether or not an intention-to-screen analysis was performed (graded as yes, no or unclear) Trials were categorized as attributing a ’low’, ’moderate’ or ’high’ risk of bias (Higgins 2005). Data Extraction Two authors (DI and DOC) independently extracted data using a standard data extraction form. Any discrepancies between the authors was resolved by consensus. The data extraction form was pilot tested and modified accordingly before use. In addition to the above mentioned study quality characteristics and the results of the trial, the following study were details recorded: • Participant details, including demographic and inclusion/ exclusion criteria • Types of interventions used and their comparison • Outcomes reported, including the type of measures used to record the outcome Statistical analysis Where data was available and if the trial did not report intention-to-screen analysis results, we performed intention-toscreen analyses using the groups to which the participants were originally randomised to (i.e. screening versus control). Relative risks, with 95% confidence intervals, were reported using both fixed and random effects models to determine the effect of screening on prostate cancer mortality. Heterogeneity was analysed with the I2 statistic.
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DESCRIPTION OF STUDIES Two randomised controlled trials (Quebec and Norrkoping) comparing mass screening for prostate cancer to no screening were identified as meeting the inclusion criteria for this review. Both studies reported data on prostate cancer incidence, disease-specific mortality, stage at diagnosis and treatment follow up. Data on quality of life, all-cause mortality and costs were not reported in any study. A third study (Rotterdam), comparing screening for prostate cancer to no screening, also met the inclusion criteria. This study reported preliminary data from five pilot studies on prostate cancer incidence, disease-specific mortality and treatment follow up. This study has been classified as ongoing. Communication with the authors has confirmed that final follow-up data from the first four pilot studies will be published shortly. Data from the fifth pilot study is part of the final protocol for the European Randomised study of Screening for Prostate Cancer (ERSPC), which will be published in the next few years. The Quebec trial commenced in 1988 and recruited men aged 45 to 80 years registered on the 1985 electoral rolls of metropolitan Quebec City, Canada, and traceable on the health registries. A total of 46,193 men were randomised 2:1 in favour of being invited to screening. Men with a previous diagnosis of prostate cancer, or those who had previously been screened for prostate cancer and referred to the study’s clinic for consultation were excluded from the trial. Participants randomised to receive an invitation to the screening group were invited by letter to receive annual screening for prostate cancer. Participants in the control group were not invited and were assumed to receive usual care. The first round of screening involved a DRE and PSA test. A TRUS biopsy was performed in cases with an abnormal DRE or if the PSA value was greater than 3.0ng/ml. It was noted that the first 1,002 participants received all three tests regardless of result. Follow-up screening was performed by PSA alone. A TRUS biopsy was indicated in follow-up rounds if the PSA value was greater than 3.0ng/ml for the first time or if the PSA value had increased by more than 20% from the last reading. Prostate cancer mortality was the primary outcome measured at 11 years follow up. Clinical stage and the choice of therapy were also selectively reported in men who were randomised to screening. The Norrkoping trial commenced in 1987 and recruited men from Norrkoping, Sweden, aged 50 to 69 years registered on the 1987 national population register. A total of 9,026 men were identified, with every sixth man “randomised” to screening. There was no mention whether men with a previous diagnosis of prostate cancer were excluded from the study. Participants randomised to the screening group were invited by letter to be screened for prostate cancer every three years. Participants in the control group were not invited for screening and were assumed to undergo routine care. The first two rounds of screening (1987 and 1990) involved a DRE alone. The DRE in the first round was performed by both a general practitioner and a urologist, however the DRE was per-
formed by a general practitioner only in the second and subsequent screening rounds. The final two rounds of screening (1993 and 1996) involved both a DRE and PSA test. Only men aged 69 years or younger were invited to the fourth round of screening. A TRUS biopsy was performed in cases with an abnormal DRE or if the PSA value was greater than 4.0ng/ml. Prostate cancer mortality, clinical stage at diagnosis and choice of therapy was reported across both the screening and control groups.
METHODOLOGICAL QUALITY QUEBEC STUDY Randomisation Participants were randomised 2:1 in favour of an invitation for screening and stratified according to age and residential area. Allocation concealment There was no mention of whether any form of allocation concealment was used. Blinding Blinding of outcome assessment was not clearly described in the study. It was reported that information on cause-specific death was obtained from the Death Registry from the Health Department of Quebec. However, it was unclear whether the outcome assessor was blinded to group assignment. Completeness of followup Crossover and contamination were issues for this pragmatic trial. The compliance and contamination rate within both the screening and control groups was described. From a total of 31,133 men randomised to the screening group, only 7,348 (23.6%) were actually screened (i.e. all 31,133 men were invited to be screened but only 23.6% took up the invitation and actually were screened). Similarly, of the 15,353 randomised to the control group, 1,122 (7.3%) were screened for prostate cancer at the study site. There was no report of any other withdrawals or whether participants in the control group were screened somewhere other than the study site; hence it is possible that more than 7.3% of the control group were actually screened. Analysis The data analysis presented was not performed according to the intention-to-screen principle. Rather, mortality from prostate cancer was analysed according to the number of men who underwent screening versus those that actually did not undergo screening regardless of their initial group allocation (i.e. mortality in men who were screened in the screening and control groups was compared to mortality in men who were not screened in the control group plus those randomised to the screening group who did not attend screening). Raw data was presented however to allow intentionto-screen analysis. Risk of bias
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The study was assessed as having a high risk of bias due to unclear allocation, unblinded assessment of outcome, large amount of crossover between groups, and failure to report results according to intention-to-screen analysis. NORRKOPING STUDY Randomisation The study was described as randomised but was quasi-randomised, with every sixth man assigned to the screening group from a list of dates of birth obtained from the national population register. Allocation concealment While assignment to groups may be random, by using this form of randomisation allocation concealment was assessed to be inadequate. Blinding Blinding of outcome assessment was not clearly described in the report. Information on cause-specific death, clinical stage and prostate cancer therapy was obtained from the South-East Region Prostate Cancer Register, a part of the National Cancer Register. The Central Death Register and patient notes were also examined for deaths not registered in the South-East Region Prostate Cancer Register. There was no mention as to whether or not this assessment was performed by an investigator masked to screening allocation. Completeness to followup The compliance of the screening group was described. Withdrawals (due to death, migration or ineligibility - only men aged 69 or younger were invited for screening in the fourth round) in the screening group were described. From a total of 1,494 men assigned to the screening group, 1,161 (77.7%) were actually screened in the first round. From a total of 1,363 men assigned to the second round of screening, 957 (70.2%) were actually screened. From a total of 1,210 men assigned to the third round of screening, 895 (74%) were actually screened. Finally, from a total of 606 men assigned to the fourth round of screening, 446 (73.5%) were actually screened. Data on mortality for the entire screening group, including men that had migrated, were described as complete. However, it was unclear whether these men had migrated to another region or country. There was no description of potential crossover for participants in the control group who may have been screened. Analysis The trial data analysis was reported according to the intention-toscreen principle. Risk of bias The study was assessed as having a high risk of bias due to a quasirandom method of allocation, lack of allocation concealment, potentially unblinded outcome assessment and unknown crossover in the control group.
RESULTS There were 1,965 citations identified by the search of MEDLINE (1966 to October 2006), of which 98 were selected for full-text review. Searches of EMBASE, CANCERLIT, PROSTATE, NHS EED,The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library - Issue 1 2006) and bibliographies of reviewed articles did not reveal any further relevant studies that were not previously identified through the MEDLINE search. Hand searching of identified journals revealed one relevant study not identified through the electronic searches. Of the 99 studies selected for further review, 52 were cohort studies, 19 were narrative reviews or commentaries and five were studies reporting data from pilot studies, or associated data, from the ongoing multicentre European Randomised study of Screening for Prostate Cancer (ERSPC) trial. Sixteen studies reported preliminary data (including randomisation, prostate cancer diagnosis, clinical stage and mortality in the screening groups) from the eight participating countries involved with the ERSPC trial. Since the follow up for primary outcomes of these studies, and that of ERSPC, will not be available until approximately 2008, all of these studies were classified as ongoing. One study reported preliminary data (including randomisation and prostate cancer diagnosis) from the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer-screening trial. Three articles reporting on the Quebec study were selected for inclusion and listed as separate citations of the same study following the full text review along with two articles reporting on the Norrkoping study. One article reporting on the Rotterdam pilot studies was selected for inclusion. This study has been classified as ongoing, with final follow-up data from the first four pilot studies published shortly. Data from the fifth pilot study will be published as part of the ERSPC. PROSTATE CANCER MORTALITY Eleven years after the commencement of the study the authors of the Quebec study reported the relative risk of death from prostate cancer to be 0.39 (95% CI: 0.19-0.65) in men who are screened. However, as stated earlier, this estimate was obtained by comparing prostate cancer mortality in men who had been screened (including those randomised to the control and screening groups) to prostate cancer mortality in men that had not been screened (including those randomised to the control and screening groups). Therefore, this analysis was performed according to the actual intervention received and not to the original group of randomisation, and therefore is likely to be subject to bias as there may be other variables explaining this difference in men who choose to be screened versus those who choose not to be screened. From the data presented in the report of the Quebec study an analysis according to the intention-to-screen principle was conducted (i.e. original group of randomisation, Additional Figure 01). Accordingly, the relative risk of death from prostate cancer was determined to be 1.01 (95% CI: 0.76-1.33). Similarly, from the data presented in
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the Norrkoping paper we were able to determine the relative risk of mortality from prostate cancer (Additional Figure 02). Fifteen years from the commencement of the study we calculated the relative risk of death from prostate cancer to be 1.04 (95% CI: 0.641.68) in the Norrkoping study. A pooled analysis of these two re-analysed studies produced a relative risk of death from prostate cancer of 1.01 (95% CI: 0.80-1.29) (Forest plot 01/01). Adopting random and fixed effects methods did not produce different results. Subgroup analysis of different screening modalities were proposed prior to undertaking the review but there were insufficient studies to perform this. We also aimed to perform a sensitivity analysis based on randomisation and allocation concealment; however both studies in this review had these methodological weaknesses. NUMBER OF CASES OF PROSTATE CANCER DETECTED The eight-year follow-up publication of the Quebec study reported a total of 244 prostate cancer diagnoses from 8,137 first screening round visits, a prevalence of 3.0% (Table 01). The Norrkoping study reported a total of 292 prostate cancer diagnoses in the control group and 85 in the screening group (Table 02). The Norrkoping study demonstrated the rate of diagnosis of prostate cancer in the screening group was 47% higher compared to the control group (RR 1.47; 95% CI: 1.16-1.86) (Forest plot 01/02). CLINICAL STAGE DISTRIBUTION The eight-year follow-up publication of the Quebec study reported stage distribution in the screened cohort at first and follow-up visit (Table 01). The Quebec study reported the stage distribution of prostate cancer cases based on the Jewett Staging system. A total of 244 cancers were reported in the first screening round in comparison to 123 at follow up. A total of 70% of cancers were diagnosed in stage B in the first screening round. This total increased to 86% at follow up. The Norrkoping study also reported stage distribution across both screened and control groups (Table 02 and Table 03).The Norrkoping study reported the stage distribution of prostate cancers cases based on the TNM staging system. A total of 292 cancers were reported in the control group and 85 in the intervention group. Localised tumours were reported in 27% of cases in the control group and 84% in the intervention group. QUALITY OF LIFE Neither study assessed the impact of screening upon quality of life. COSTS Neither study reported a cost assessment (i.e. cost effectiveness, cost utility or cost-benefit) of screening for prostate cancer. HARMS OF SCREENING Neither study reported on the impact of any associated harms of screening (i.e. false negative/positive results, adverse effects of biopsy; and impact upon treatment procedures such as incontinence, erectile dysfunction or mortality). The Norrkoping study reported patients’ prostate cancer treatment regime across both screened and control groups (Table 04).
DISCUSSION Screening for prostate cancer remains a contentious issue, as illustrated by the varying recommendations presented by national groups globally. Much of this difference can be attributed to a lack of high level evidence, i.e. randomised controlled trials (RCTs). This review identified two completed RCTs investigating screening for prostate cancer. A meta-analysis of the data extracted from these studies indicated no statistically significant difference in prostate cancer mortality between men randomised for prostate cancer screening and those randomised to control (RR 1.01, 95% CI: 0.80-1.29). Neither study assessed the effect of prostate cancer screening on quality of life, all-cause mortality or cost effectiveness. Although we were able to perform a meta-analysis on the primary outcome measure, the methodology and results of these studies and the need for reanalysis lead to a need for further examination of this important question in high quality randomised controlled trials. The Quebec study was limited by the lack of adherence to screening from participants randomised to the screening group. Although 31,133 men were randomised to receive screening for prostate cancer, only 23% of participants in this group actually complied with the randomisation and were screened. Similarly approximately 7% of men randomised to the control group were screened for prostate cancer. Therefore, crossover between groups was a genuine issue in this pragmatic trial. Data analysis was also compromised as there was no comparison of socio-demographic data between the intervention and control groups, and mortality data was not analysed according to the intention-to-screen principle. The authors of the trial reported a reduction in prostate cancer-specific mortality by comparing mortality in men who were screened to that of men who were not screened, regardless of their initial randomisation. Conversely, our analysis of the data, according to the intention-to-screen principle, showed no significant difference in mortality between the two groups. Due to these methodological issues, results from this trial do not give a clear indication of any true benefits or harms associated with screening for prostate cancer. Similarly, the Norrkoping study did not provide a comparison of socio-demographic data between the intervention and controls groups. It also reported that information regarding the study was distributed through newspaper, radio and television broadcasting. This raises the potential for contamination and selfselection bias, with participants in the control group choosing to be screened for prostate cancer. Furthermore, the quasi-random method of allocation, lack of allocation concealment and potentially unblinded outcome assessment compromise the quality of the trial. Several fundamental issues must be addressed when considering screening for prostate cancer. Screening for prostate cancer is primarily performed using the DRE and PSA test. However the specificity and sensitivity of both these modalities are not ideal. The consequences of heightened anxiety and further examina-
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tions through biopsies and the considerable side effects associated with various prostate cancer treatments, must be appreciated. This predicament is further compounded by the inability to understand whether identified neoplasms are clinically significant. Some slow growing tumours may never threaten a man’s life, as is represented by the discrepancy between the incidence and death attributed to prostate cancer (Parkin 2001; Quinn 2002). Further evidence is also required to understand the inherent implications when screening across various ethnic groups. Similarly, further evidence is required to evaluate the economic implications of implementing mass screening for prostate cancer.
patient informed shared decision making, regardless of whether they support or reject screening for prostate cancer (Smith 2002; Ferrini 1998; AUA 2000). In the absence of definitive evidence from RCTs, a shared approach to decision making between doctors and patients should be encouraged. Facilitating this process with the aid of appropriate patient education materials will promote informed patient choice with respect to screening for prostate cancer.
In the absence of definitive results from RCTs, case control studies have been conducted in order to identify the effectiveness of screening for prostate cancer (Concato 2006; Friedman 1991; Jacobsen 1998; Kopec 2005). However, conflicting results on the benefit and protective effect of DRE and PSA screening on reducing prostate cancer specific mortality has done little to inform health professionals, policy makers and consumers on the issue. Much of this disagreement can be attributed to the methodological differences, including the selection of populations and outcome assessment, between studies.
Implications for practice
Two large scale RCTs of prostate cancer screening are ongoing. The ERSPC trial was initiated in 1991 with eight European countries (Belgium, Finland, France, Italy, Netherlands, Spain, Sweden and Switzerland) participating. To date over 183,000 men aged 50-75 have been screened for prostate cancer using DRE, PSA and TRUS biopsy modalities. Measured outcomes include cause-specific mortality, cancer incidence, cancer characteristics and quality of life. The PLCO trial is a 23-year trial that was initiated in 1993 across ten screening centres in the USA. In addition to being screened for lung and colorectal cancer, 37,000 men aged 55-74 will also be screened for prostate cancer via DRE and PSA, with 37,000 serving as controls. Measured outcomes include cause-specific mortality, cancer incidence and characteristics. It is anticipated that findings from these two trials will provide the evidence needed to identify whether screening for prostate cancer is warranted or not. A number of principles have been proposed, including the burden of the disease and the effectiveness of diagnostic tests and treatments, to assess whether a screening program is successful (WHO 1968). Prostate cancer is accepted as an important health problem; however uncertainty exists over the effectiveness of diagnostic tests and treatments available. Much debate exists about use of the PSA test and implications of potential false positive/negative results. Similarly, although various treatments for prostate cancer are available (e.g. watchful waiting, radical prostatectomy, hormone and radiotherapy), high quality evidence is lacking. Findings from current RCTs will shed light on the effectiveness of screening and treatment regimes for prostate cancer however, until such data is available, greater emphasis will be placed on patient/doctor communication. Many medical organisations support the concept of
AUTHORS’ CONCLUSIONS
The findings from this review suggest that there is insufficient evidence to either support or refute the routine use of mass, selective, opportunistic or no screening to reduce prostate cancer mortality. The available evidence from two randomised trials was flawed but found that men randomised to screening had prostate cancer more frequently detected but did not have a reduction in prostate cancer specific mortality. No robust evidence exists to determine the impact of screening on quality of life, harms of screening or its economic value. Recommendations cannot be made until data from the ERSPC and PLCO trials are made available to provide the highest level of evidence for practice. In the absence of evidence health professionals, rather than routinely conducting prostate cancer screening, should adopt a shared approach to decision making for men who express an interest in prostate cancer testing and discuss both the potential benefits and harms associated with prostate cancer screening. Furthermore, because of the lack of evidence for benefit and the risk of harms associated with testing and treatment, men who have a life expectancy less then approximately 10-15 years (either due to age or co-morbid conditions) should be informed that testing and treatment is unlikely to be beneficial. Implications for research The lack of high quality evidence supports the need for further studies, of a high methodological quality, to investigate the effectiveness of screening for prostate cancer. These studies should provide data on the impact of prostate cancer screening on quality of life, potential harms, adverse events and an economic evaluation in addition to mortality. Additionally, such studies should be conducted using appropriate, or justified, selection of participants, adequate allocation concealment, adequate blinding of assessors, completeness of follow up and analysis of data according to intention-to-screen principles when possible. The dilemma facing prostate cancer screening is its effectiveness to differentiate between aggressive and slow growing tumours, in which case individuals are faced with one of two scenarios. Individuals may be screened and diagnosed for a cancer that otherwise would never have been clinically significant, in which case the patient is subjected to unnecessary treatment. Conversely, screening in asymp-
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tomatic individuals and detecting the cancer at an early, presymptomatic stage may allow individuals to proceed with treatment that would be beneficial to their health outcome. It is anticipated that results from the current ERSPC and PLCO trials as well as ongoing treatment trials for early stage prostate cancer will further progress our understanding on the effectiveness of prostate cancer screening in potentially reducing prostate specific mortality as well as its impact upon quality of life, harms and the economic impact associated with prostate cancer screening.
POTENTIAL CONFLICT OF INTEREST None known.
ACKNOWLEDGEMENTS We wish to thank Kristine Egberts (Australasian Cochrane Centre) for her help with this review. We would also like to thank the referees and editors of the Prostatic Diseases and Urologic Cancers Group for their comments and valuable assistance.
SOURCES OF SUPPORT External sources of support • No sources of support supplied Internal sources of support • Australasian Cochrane Centre AUSTRALIA
REFERENCES
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prostate specific antigen range of 2.0 to 3.9 ng/ml: value of percent free prostate specific antigen on tumor detection and tumor aggressiveness. Journal of Urology 2004;171(6 Pt 1):2245–2249. Raaijmakers 2004b Raaijmakers R, Wildhagen MF, Ito K, Paez A, de Vries SH, Roobol MJ, Schroder FH. Prostate-specific antigen change in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam. Urology 2004;63(2):316–320. Recker 2001 Recker F, Kwiatkowski MK, Huber A, Stamm B, Lehmann K, Tscholl R. Prospective detection of clinically relevant prostate cancer in the prostate specific antigen range 1 to 3 ng./ml. combined with freeto-total ratio 20% or less: the Aarau experience. Journal of Urology 2001;166(3):851–855. Rietbergen 1997a Rietbergen JB, Kranse R, Kirkels WJ, De Koning HJ, Schroder FH. Evaluation of prostate-specific antigen, digital rectal examination and transrectal ultrasonography in population-based screening for prostate cancer: improving the efficiency of early detection. British Journal of Urology 1997;2:57–63.
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palpation can be organized with consideration to cost effectiveness. Lakartidningen 1989;86(41):3475–3477. Varenhorst 1991 Varenhorst E, Pedersen KV, Carlsson P, Berglund K, Lofman O. Screening for carcinoma of the prostate in a randomly selected population using duplicate digital rectal examination. Acta Oncologica 1991;30(2):273–275. Vis 2001a Vis AN, Hoedemaeker RF, van der Kwast TH, Schroder FH. Defining the window of opportunity in screening for prostate cancer: validation of a predictive tumor classification model. Prostate 2001;46 (2):154–162. Vis 2001b Vis AN, Hoedemaeker RF, Roobol M, van der Kwast TH, Schroder FH. Tumor characteristics in screening for prostate cancer with and without rectal examination as an initial screening test at low PSA (0.0-3.9 ng/ml). Prostate 2001;47(4):252–261. Vis 2002 Vis AN, Kranse R, Roobol M, van der Kwast TH, Schroder FH. Serendipity in detecting disease in low prostate-specific antigen ranges. BJU International 2002;89(4):384–389. Zackrisson 2003 Zackrisson B, Aus G, Lilja H, Lodding P, Pihl CG, Hugosson J. Follow-up of men with elevated prostate-specific antigen and one set of benign biopsies at prostate cancer screening. European Urology 2003;43(4):327–332. Zackrisson 2004 Zackrisson B, Aus G, Bergdahl S, Lilja H, Lodding P, Pihl CG, Hugosson J. The risk of finding focal cancer (less than 3 mm) remains high on re-biopsy of patients with persistently increased prostate specific antigen but the clinical significance is questionable. Journal of Urology 2004;171(4):1500–1503.
References to ongoing studies ERSPC Auvinen A, Maattanen L, Finne P, Stenman U, Aro J, Juusela H, Rannikko S, Tammela T, Hakama M. Test sensitivity of prostatespecific antigen in the Finnish randomised prostate cancer screening trial. International Journal of Cancer 2004;111(6):940–943.
Hugosson J, Aus G, Lilja H, Lodding P, Pihl CG. Results of a randomized, population-based study of biennial screening using serum prostate-specific antigen measurement to detect prostate carcinoma. Cancer 2004;100(7):1397–1405. Hugosson J, Aus G, Lilja H, Lodding P, Pihl CG, Pileblad E. Hugosson J, Aus G, Lilja H, Lodding P, Pihl CG, Pileblad E. Journal of Urology 2003;169(5):1720–1723. Isola J, Auvinen A, Poutiainen M, Kakkola L, Jarvinen TA, Maattanen L, Stenman U, Tammela T, Hakama M, Visakorpi T. Predictors of biological aggressiveness of prostate specific antigen screening detected prostate cancer. Journal of Urology 2001;165(5):1569–1574. Kwiatkowski M, Huber A, Moschopulos M, Lehmann K, Wernli M, Hafeld A, Recker F. Screening for prostate cancer: Results of a prospective trial in Canton Aargu, Switzerland. Swiss Medical Weekly 2004;134:580–585. Kwiatkowski M, Huber A, Stamm B, Lehmann K, Wernli M, Hafeli A, Recker F. Features and preliminary results of prostate cancer screening in Canton Aargau, Switzerland. BJU International 2003;2:44– 47. Makinen T, Tammela TL, Hakama M, Stenman UH, Rannikko S, Aro J, Juusela H, Maattanen L, Auvinen A. Tumor characteristics in a population-based prostate cancer screening trial with prostatespecific antigen. Clinical Cancer Research 2003;9(7):2435–2439. Nelen V, Thys G, Neels H, Neetens I, Coebergh JW, Dourcy-BelleRose B, Denis L. ERSPC: features and preliminary results from the Antwerp study centre. BJU International 2003;2:17–21. Roobol MJ, Kirkels WJ, Schroder FH. Features and preliminary results of the Dutch centre of the ERSPC (Rotterdam, the Netherlands). BJU International 2003;2:48–54. Schroder FH, Denis LJ, Roobol M, all participants of the ERSPC. The story of the European Randomized Study of Screening for Prostate Cancer. BJU International 2003;2:1–13. van der Cruijsen-Koeter IW, van der Kwast TH, Schroder FH. Interval carcinomas in the European Randomized Study of Screening for Prostate Cancer (ERSPC)-Rotterdam. Journal of the National Cancer Institute 2003;95(19):1462–1466.
Berenguer A, Lujan M, Paez A, Santonja C, Pascual T. The Spanish contribution to the European Randomized Study of Screening for Prostate Cancer. BJU International 2003;2:33–38.
Villers A, Malavaud B, Rebillard X, Bataille V, Iborra F. ERSPC: features and preliminary results of France. BJU International 2003; 2:27–29.
Ciatto S, Gervasi G, Frullini P, Zendron P, Zappa M. Specific features of the Italian section of the ERSPC. BJU International 2003;2:30– 32.
PLCO Andriole G, Levin D, Crawford D, Gelmann E, Pinsky P, Chia D, Kramer B, Reding D, Church T, Grubb R, Izmirlian G, Ragard L, Clapp J, Prorok P, Gohagan J. Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer screening trial: Findings from the initial screening round of a randomized controlled trial. Journal of the National Cancer Institute 2005;97:433– 438.
Finne P, Stenman UH, Maattanen L, Makinen T, Tammela TL, Martikainen P, Ruutu M, Ala-Opas M, Aro J, Karhunen PJ, Lahtela J, Rissanen P, Juusela H, Hakama M, Auvinen A. The Finnish trial of prostate cancer screening: where are we now?. BJU International 2003;2:22–26. Hugosson J, Aus G, Bergdahl S, Fernlund P, Frosing R, Lodding P, Pihl C, Lilja H. Population-based screening for prostate cancer by measuring free and total serum prostate-specific antigen in Sweden. BJU International 2003;2:39–43.
Rotterdam Schroder F, Roobol M, Damhuis R, de Koning H, Blijenberg B, van der Kwast T, Kirkels W, Bangma C. Rotterdam randomized pilot studies of screening for prostate cancer - an overview after 10 years. Journal of the National Cancer Institute 2005;97:696.
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Additional references AIHW 2002 Australian Institute of Health and Welfare (AIHW) and Australasian Association of Cancer Registries (AACR). Cancer in Australia 1999 2002. AUA 2000 American Urological Association. Prostate-Specific Antigen (PSA) Best practice policy. Oncology 2000;14:277–278. Berry 1984 Berry S, Coffey D, Walsh P, Ewing L. The development of human benign prostatic hyperplasia with age. Journal of Urology 1984;132: 474–479. Bill-Axelson 2005 Bill-Axelson A. Holmberg L. Ruutu M. Haggman M. Andersson SO. Bratell S. Spangberg A. Busch C. Nordling S. Garmo H. Palmgren J. Adami HO. Norlen BJ. Johansson JE. Radical prostatectomy versus watchful waiting in early prostate cancer. New England Journal of Medicine 2005;352(19):1977–84. [MedLine: 15888698]. Coley 1997 Coley C, Barry M, Mulley A. Clinical Guideline. Part III: Screening for Prostate Cancer. Annals of Internal Medicine 1997;126:480–484. Concato 2006 Concato J, Wells C, Horowitz R, Penson D, Fincke G, Berlowitz D, Froehlich G, Blake D, Vickers M, Gehr G, Raheb N, Sullivan G, Peduzzi P. The effectiveness of screening for prostate cancer. A nested case-control study. Archives of Internal Medicine 2006;166:38–43. Cruijsen-Koeter 2001 van dan Cruijsen-Koeter I, Wildhagen M, De Koning H, Schroder F. The value of current diagnostic tests in prostate cancer screening. BJU International 2001;88:458–466. Ferrini 1998 Ferrini R, Woolf S. American College of Preventive Medicine Practice Policy. Screening for prostate cancer in American men. American Journal of Preventive Medicine 1998;15:18–84. Friedman 1991 Friedman G, Hiatt R, Quesenberry C, Selby J. Case-control study of screening for prostatic cancer by digital rectal examinations. Lancet 1991;337:1526–1529. Gambert 2001 Gambert S. Screening for prostate cancer. International Urology and Nephrology 2001;33:249–257. Harris 2002 Harris R, Lohr K. Screening for prostate cancer: An update of the evidence for the US preventive services task force. Annals of Internal Medicine 2002;137:917–929. Higgins 2005 Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5. In: The Cochrane Library, Issue 2, 2005. Chichester, UK: John Wiley & Sons, Ltd, updated May 2005.
Holman 1999 Holman C, Wisniewski Z, Semmens J, Rouse I, Bass A. Mortality and prostate cancer risk in 19598 men after surgery for benign prostatic hyperplasia. BJU International 1999;84:37–42. Jacobsen 1998 Jacobsen S, Bergstralh E, Katusic S, Guess H, Darby C, silverstein M, Oesterling J, Lieber M. Screening digital rectal examination and prostate cancer mortality: a population based case-control study. Urology 1998;52:173–179. Kopec 2005 Kopec J, Goel V, Bunting P, Neuman J, Sayre E, Warde P, Levers P, Fleshner N. Screening with prostate specific antigen and metastatic prostate cancer risk: a population based case-control study. The Journal of Urology 2005;174:495–499. Labrie 1999 Labrie F, Candas B, Dupont A, Cusan L, Gomez JL, Suburu RE, Diamond P, Levesque J, Belanger A. Screening decreases prostate cancer death: first analysis of te 1988 Quebec prospective randomized controlled trial. The Prostate 1999;38:83–91. Parkin 2001 Parkin D, Bray F, Devesa S. Cancer burden in the year 2000. The global picture. European Journal of Cancer 2001;37:S4–S66. Partin 2002 Partin M, Wilt T. Informing patients about prostate cancer screening: identifying and meeting the challenges while the evidence remains uncertain. American Journal of Medicine 2002;113:691–693. Potosky 1995 Potosky A, Miller B, Albertsen P, Kramer B. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995;273: 548–552. Quinn 2002 Quinn M, Babb P. Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part I: international comparisons. BJU International 2002;90:162–173. Smith 2002 Smith RA, Cokkinides V, von Eschenbach AC, Levin B, Cohen C, Runowicz CD, Sener S, Saslow D, Eyre HJ, American Cancer Society. American Cancer Society guidelines for the early detection of cancer. CA: A Cancer Journal for Clinicians 2002;52:8–22. USA 2003 USA 2003. Urological Soceity of Australasia (USA). PSA Screening for prostate cancer. Available at; http://www.urosoc.org.au Accessed 12/3/2005. WHO 1968 Wilson J, Jungner G. Principles and practice of screening for disease. World Health Organisation, 1968. ∗
Indicates the major publication for the study
Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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TABLES
Characteristics of included studies Study
Norrkoping
Methods
Every sixth man randomly allocated to the screening group from a list of date of births obtained from the national population register to screening. The remaining men served as controls. Data analysis was performed according to intention-to-screen. It was stated that mortality data for the entire cohort, including men who had migrated, was available. Prostate cancer diagnosis and death across both groups was identified through the South-East Region Prostate Cancer Register, Central Death Register and patient notes. There was no further report on the method of this outcome assessment. Male inhabitants of Norrkoping aged 50-69. Only men 69 or younger were invited to the 4th screening round in 1996. There was no mention on any other specific exclusion criteria (e.g. previous diagnosis of prostate cancer or with symptoms) Screening group - 1,494 Control group - 7,532
Participants
Interventions
Screening every 3 years versus control (not invited for screening). 1st and 2nd rounds of screening included only a DRE. The 1st screening round DREs were performed by a general practitioner and a urologist. In the 2nd and subsequent rounds the DRE was performed by a general practitioner only. The 3rd and 4th rounds of screening included a DRE and a PSA test. TRUS biopsy was performed if the DRE was deemed abnormal or if PSA was greater than 4.0 ng/ml.
Outcomes
Prostate cancer mortality at 15 years follow-up. Prostate cancer death incidence rates in screened versus unscreened cohorts. Clinical stage and choice of therapy in men diagnosed with prostate cancer across both screened and control groups.
Notes
There was no socio-demographic comparison between the screening and control groups. It is unclear as to how men were randomised from the list of dates of birth. Participants and researchers were not blind to the intervention. It is unclear whether there were any co-interventions. It is unclear whether there was a blinded assessment of outcomes. Withdrawals were cited, but it is unclear how the data for those men who migrated was available. All participants were accounted for in the analysis.
Allocation concealment
C – Inadequate
Study
Quebec
Methods
Random allocation of men identified from electoral roles 2:1 in favour of screening. Data analysis was performed according to intervention and not intention-to-screen. No reported loss to follow up. No report on the method of outcome assessment.
Participants
Male inhabitants of Quebec city aged 45-80. Men with a previous diagnosis of prostate cancer or previously screened and referred to the study clinic for consultation were not eligible. Screening group - 31,133 Control group - 15,353
Interventions
Annual screening versus control (not invited for screening). 1st screening round included a PSA test and a DRE. TRUS biopsy was performed in cases with PSA > 3.0ng/ml and/or abnormal DRE (except for first 1,002 men who had all three procedures performed).
Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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Characteristics of included studies (Continued ) Follow up screening included a PSA test. TRUS biopsy was only performed if PSA was above 3.0 ng/ml for the first time or increased by more than 20% from last measurement. Outcomes
Prostate cancer mortality at 11 years follow-up. Prostate cancer death incidence rates in screened versus unscreened cohorts. Clinical stage and choice of therapy in men diagnosed with prostate cancer.
Notes
There was no socio-demographic comparison between the screening and control groups. Authors concluded that screening resulted in a 67 reduction in death rate incidence from prostate cancer in the 1999 study and a 62% reduction in death rate incidence from prostate cancer in the 2004 (11 year follow up) study, but these results were not supported by intention-to-screen analysis. It is unclear how men were randomised from the electoral roles. Participants and researchers were not blind to the intervention. It is unclear whether there were any co-interventions. It is unclear whether was a blinded assessment of outcomes. Withdrawals from both the screening and control groups were cited. All participants were accounted for in the analysis however the analysis was not performed according to the intention-to-screen principle.
Allocation concealment
B – Unclear
Characteristics of excluded studies Anonymous 2000
Descriptive study - report on a screening program in the USA
Aus 2001
Cohort study - cancer detection rate via biopsy in men with an elevated PSA level in the screening group of the Swedish arm of the ERSPC Cohort study - explored the cumulative risk of cancer detection in a cohort of men from the screening group of Swedish arm of the ERSPC Cohort study - reported the cumulative prostate cancer risk in men with different PSA levels within the Swedish arm of the ERSPC Finnish pilot study for the ERSPC, with a 2 year follow-up and no results report for the control group
Aus 2004 Aus 2005 Auvinen 1996 Bangma 1995a
Cohort study - evaluation of the diagnostic value of volume adjusted PSA values in a screening population of the Dutch feasibility study for the ERSPC
Bangma 1995b
Cohort study - explored the value of the f/t PSA ratio for cancer detection in the screening group of the Dutch arm of the ERSPC Cohort study - explored the value of the f/t PSA ratio, PSAD and PSA age references for cancer detection in the screening group of the Dutch arm of the ERSPC
Bangma 1995c Bangma 1997
Descriptive study - report on the design and features of the Dutch arm of the ERSPC
Beemsterboer 1999
Cohort study - explored the incidence of prostate cancer in the screening group of the Dutch arm of the ERSPC
Beemsterboer 2000
Survey - identifed the rate of PSA testing before and during the Dutch arm of the ERSPC
Candas 2000
Cohort study - incidence of prostate cancer in screening cohort of the Quebec trial along with a cost assessment
Ciatto 1993
Cohort study - Italian pilot feasibility study for the ERSPC with preliminary results
Ciatto 1994
Cohort study - Italian pilot feasibility study for the ERSPC with preliminary results
Ciatto 2002 Ciatto 2003b
Cohort study - analysis of PSA velocity in ’healthy’ participants in the screening cohort within the Italian arm of the ERSPC Descriptive study - report on the issue of screening within the control group of the Italian arm of the ERSPC
Cusan 1994
Descriptive study - report on the preliminary results of the Quebec trial
Essink-Bot 1998
Cohort study - explored the health status of men randomised to screening in the Dutch arm of the ERSPC
Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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Characteristics of excluded studies (Continued ) Finne 2002
Cohort study - explored the diagnostic value of PSA properties in diagnosing prostate cancer in the screening group of the Finnish arm of the ERSPC
Ford 2003 Gohagan 1994a
Descriptive study - described the demographic details of the AAMEN project, which attempts to recruit African American men to the PLCO Descriptive study - report on the design of the PLCO
Gohagan 1994b
Editorial on the issue of screening for prostate cancer
Gohagan 1995
Descriptive study - report on the design of the PLCO
Gohagan 2000
Descriptive study - report on the design of the PLCO
Gustafsson 1992
Cohort study - explored the correlation between PSA measurement to prostate cancer in a randomly selected cohort of men screened for prostate cancer in Sweden
Gustafsson 1995
Cohort study - explored the cost effectiveness of prostate cancer screening in a randomly selected cohort of men in Sweden Cohort study - explored the effectiveness of prostate cancer screening in a randomly selected cohort of men in Sweden Cohort study - explored the prostate cancer charcterisitcs in a cohort of the screening group of the Dutch arm of the ERSPC Cohort study - explored the frequency of PIN in prostate biopsies within the Dutch arm of the ERSPC
Gustafsson 1998 Hoedemaeker 1999 Hoedemaeker 2001 Labrie 1992
Cohort study - explored the effectiveness of prostate cancer screening in a randomly selected cohort of men in Quebec, Canada
Labrie 1996
Cohort study - explored the stage and grade of prostate cancer in men within the screening arm of the Quebec study
Lodding 1998
Cohort study - explored the biopsy characterisitcs in a cohort of the screening group from the Swedish arm of the ERSPC Cohort study - explored the detection rates and clinical characterisitcs of cancers in a cohort of the screening group from the Spanish arm of the ERSPC
Lujan 2004 Maattanen 1999
Cohort study - explored the detection rate in a cohort of the screening group from the Finnish arm of the ERSPC
Maattanen 2001
Descriptive study - report on the preliminary results of the Finnish arm of the ERSPC
Makinen 2001
Cohort study - explored the detection rate in a cohort of the screening group from the Finnish arm of the ERSPC
Makinen 2002
Cohort study - explored the association between family history and diagnosis of prostate cancer in the screening group from the Finnish arm of the ERSPC
Makinen 2004
Cohort study - reported intermediate screening efficacy indicators within the Finnish arm of th ERSPC
Norming 1991
Cohort study - explored the effectiveness of prostate cancer screening in a randomly selected cohort of men in Sweden ERSPC - explored the extent of opportunistic screening in the Dutch arm of the ERSPC
Otto 2003 Pedersen 1990 Postma 2004
Cohort study - explored the effectiveness of prostate cancer screening in a randomly selected cohort of men in Sweden Cohort study - explored the incidence and circumstances of advanced prostate cancer in a cohort of the screening group from the Dutch arm of the ERSPC
Prorok 1994
Descriptive study - report on the design of the PLCO
Prorok 2000
Descriptive study - report on the design of the PLCO
Raaijmakers 2002
Cohort study - explored the risk factors associated with performing a biopsy in a cohort of the screening group from the Dutch arm of the ERSPC Cohort study - explored the cancer detection rate of men in a cohort from the screening group from the Dutch arm of the ERSPC Cohort study - explored the indicators of prostate cancer from changes in PSA characterisitcs in a cohort from the screening group from the Dutch arm of the ERSPC
Raaijmakers 2004a Raaijmakers 2004b
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Characteristics of excluded studies (Continued ) Recker 2001
Cohort study - explored the cancer detection rate of men in a cohort from the screening group from the Swiss arm of the ERSPC
Rietbergen 1997a
Cohort study - explored the cancer detection rates and characterisitcs within the screening group from the Dutch arm of the ERSPC Cohort study - explored the risk factors associated with performing a biopsy in a cohort of the screening group from the Dutch arm of the ERSPC
Rietbergen 1997b Rietbergen 1998a
Cohort study - explored the discriminating potential of the PSA test in a cohort of the screening group from the Dutch arm of the ERSPC
Rietbergen 1998b
Cohort study - explored the yield of serial screening in a cohort of the screening group from the Dutch arm of the ERSPC Preliminary results of the ERSPC exploring the cancer detection rate and clinical features of men in the screening group from the Dutch arm of the ERSPC to the incidental cases in a region where no screening was performed
Rietbergen 1999 Roobol 2004 Schroder 1995
Cohort study - explored possible predictors of prostate cancer in the screening group from the Dutch arm of the ERSPC Descriptive study - report on the pilot studies of the ERSPC
Schroder 1997
Descriptive study - report on the design and features of the ERSPC
Schroder 1998
Cohort study - explored the value of the DRE as a stand alone test in the screening group from the Dutch arm of the ERSPC Descriptive study - report on the design and features of the ERSPC
Schroder 1999 Schroder 2000
Schroder 2001b
Cohort study - explored the dignostic value of tests in a cohort of the screening group from the Dutch arm of the ERSPC Cohort study - explored the dignostic value of tests in a cohort of the screening group from the Dutch arm of the ERSPC Descriptive study - commentary on the issue of screening for prostate cancer
Schroder 2005
Cohort study - explored the PSA progression within a specified period of screened men
Shroder 1996
Dutch pilot studies to establish the feasibility of the ERSPC
Standaert 1997
Descriptive study - report on the progress of the ERSPC
Taha 2005
Cohort study - explored the effectiveness of prostate cancer screening in a randomly selected cohort of men in Saudi Arabia
Tornblom 2001
Cohort study - explored the correlation between PSA measurement to prostate cancer in a randomly selected cohort of men screened for prostate cancer in Sweden
Tornblom 2004
Cohort study - explored the lead time for prostate cancer detection in Sweden
Varenhorst 1989
Cohort study - explored the effectiveness of prostate cancer screening in a randomly selected cohort of men in Sweden. Pilot results for the Norrkoping study. No data is given on the controls.
Varenhorst 1991
Cohort study - explored the effectiveness of prostate cancer screening in a randomly selected cohort of men in Sweden. Pilot results for the Norrkoping study. No data is given on the controls.
Vis 2001a
Cohort study - explored the categorization of cancer in a select cohort of men from the screening group of the Dutch arm of the ERSPC
Vis 2001b
Cohort study - explored the value of differing screening protocols within the ERSPC
Vis 2002
Cohort study - explored the magnitude of prostate cancer detection by serendipity within the Dutch arm of the ERSPC Cohort study - explored the value of serial screening in a cohort of the screening group from the Swedish arm of the ERSPC
Schroder 2001a
Zackrisson 2003 Zackrisson 2004
Cohort study - explored the clinical and pathalogical cancer characterisitcs within the Swedish arm of the ERSPC
de Koning 2002
Descriptive study - report on the preliminary results of the ERSPC and PLCO trials
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Characteristics of excluded studies (Continued ) Characteristics of ongoing studies Study
ERSPC
Trial name or title European Randomised study of Screening for Prostate Cancer Participants
Male inhabitants across the eight participating study sites including; Belgium, Finland, France, Italy, Netherlands, Spain, Sweden and Switzerland aged 50-75. Screening group - 83,645 Control group - 99,393
Interventions
Screening group - DRE, PSA and/or TRUS biopsy Control group - usual care/no screening offered
Outcomes
Prostate cancer mortality, detection rates, stage of cancer, quality of life
Starting date
1991
Contact information Notes Study
PLCO
Trial name or title Prostate, Lung, Colorectal and Ovarian cancer screening trial Participants
For Prostate: Male inhabitants across 10 screening centres in the USA aged 55-74. Screening group - 37,000 Control group - 37,000
Interventions
Screening group - DRE, PSA (men are also screened for lung and colorectal cancer) Control group - usual care/no screening offered
Outcomes
Prostate cancer mortality, cancer detection rates, stage of cancer
Starting date
1993
Contact information Notes Study
Rotterdam
Trial name or title Pilot studies of the European Randomised study of Screening for Prostate Cancer Participants
Male inhabitants aged 55-74 from Rotterdam (The Netherlands). Screening group - 1163 Control group - 1204
Interventions
Screening group - DRE, PSA and/or TRUS biopsy Control group - usual care
Outcomes
Prostate cancer mortality, cancer detection rates, treatment regime
Starting date
1991 to 1994
Contact information Notes Pilot study 1 - PSA performed on all participants as a pre-screen. Pilot studies 2 to 5 - DRE, PSA, TRUS biopsy only offered to screening group. Data from pilot studies 1 to 4 reported. Data from pilot study 5 is incorporated within the final protocol of the ERSPC.
Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
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ADDITIONAL TABLES
Table 01. Stage of prostate cancer diagnosis in the screening group 1988-1996 (Quebec) Clinical stage
# (%) at 1st vist
# (%) at follow up
A2
1 (0.4)
0
A3
2 (0.8)
0
B0
15 (6.4)
21 (17.9)
B1
86 (36.4)
63 (53.9)
B2
69 (29.2)
22 (18.8)
C1
28 (11.9)
10 (8.5)
C2
20 (8.5)
1 (0.8)
D1
3 (1.3)
0
D2
12 (5.1)
0
N/A
8
6
Total
244
123
Table 02. Stage of prostate cancer across all groups 1987-1999 (Norrkoping) Category
# (%) in control
# (%) in screened
T1 (a/b/c not registered)
9 (3.1)
19 (22.4)
T1a
13 (4.5)
5 (5.9)
T1b
27 (9.2)
8 (9.4)
T1c
15 (5.1)
8 (9.4)
T2
92 (31.5)
21 (24.7)
T3
89 (30.5)
13 (15.3)
T4
43 (14.7)
11 (12.9)
TX/T (category not registered)
4 (1.4)
0 (0)
N0
42 (14.4)
21 (24.7)
N1-4
13 (4.5)
3 (3.5)
NX/N (category not registered)
237 (81.2)
61 (71.8)
M0
129 (44.2)
56 (65.9)
M1
63 (21.6)
14 (16.5)
MX/M (category not registered)
100 (34.2)
15 (17.6)
Total diagnosed
292
85
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Table 03. Prostate tumour grade across both group 1987-1999 (Norrkoping) Tumour Grade
# (%) in control
# (%) in screened
G1
94 (32.2)
43 (50.6)
G2
149 (51.0)
31 (36.5)
G3
43 (14.7)
11 (12.9)
GX/tumour grade not recorded
6 (2.1)
0 (0)
Total
292
85
Table 04. Prostate cancer treatment regime 1987-1999 (Norrkoping) Treatment
# (%) in control
# (%) in screened
Hormonal
147 (50.3)
27 (31.8)
Expectancy/watchful waiting
101 (34.6)
37 (43.5)
Radical prostatectomy
23 (7.9)
16 (18.8)
External radiotherapy
15 (5.1)
4 (4.7)
Brachytherapy
3 (1.0)
1 (1.2)
Treatment not registered
3 (1.0)
0 (0)
Total
292
85
ANALYSES
Comparison 01. Screening vs control Outcome title 01 Prostate cancer specific mortality (intention-to-screen) 02 Prostate cancer diagnosis
No. of studies 2
No. of participants 55512
Relative Risk (Fixed) 95% CI
1.01 [0.80, 1.29]
1
9026
Relative Risk (Fixed) 95% CI
1.47 [1.16, 1.86]
Statistical method
Effect size
COVER SHEET Title
Screening for prostate cancer
Authors
Ilic D, O’Connor D, Green S, Wilt T
Contribution of author(s)
Dragan Ilic initiated the review and wrote the protocol. He also conducted the literature search, reviewed abstracts and full text studies for inclusion, performed quality assessment, data extraction, analysis and writing of the review. Denise O’Connor assisted with the protocol development. She also reviewed abstracts and full text studies for inclusion, performed quality assessment, data extraction, and assisted with the analysis and writing of the review. Sally Green assisted with the protocol development. She also assisted with the inclusion of studies, quality assessment and provided input with the writing. Tim Wilt assisted with the protocol development. He also assisted with the inclusion of studies, quality assessment and helped with the writing.
Issue protocol first published
2004/2
Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
21
Review first published
/
Date of most recent amendment
19 May 2006
Date of most recent SUBSTANTIVE amendment
08 May 2006
What’s New
Information not supplied by author
Date new studies sought but none found
Information not supplied by author
Date new studies found but not yet included/excluded
Information not supplied by author
Date new studies found and included/excluded
Information not supplied by author
Date authors’ conclusions section amended
Information not supplied by author
Contact address
Mstr Dragan Ilic PhD Candidate Australasian Cochrane Centre Monash University Australasian Cochrane Centre, Monash Institute of Health Services Research Locked Bag 29, Monash Medical Centre Clayton Victoria 3168 AUSTRALIA E-mail:
[email protected] Tel: +61 3 9594 7523 Fax: +61 3 9594 7554
DOI
10.1002/14651858.CD004720.pub2
Cochrane Library number
CD004720
Editorial group
Cochrane Prostatic and Urologic Cancers Group
Editorial group code
HM-PROSTATE
Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
22
GRAPHS AND OTHER TABLES Figure 01.
Prostate cancer mortality across randomised groups from the Quebec study
Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
23
Figure 02.
Prostate cancer diagnosis and mortality across randomised groups from the Norrkoping study
Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
24
Analysis 01.01. Review:
Comparison 01 Screening vs control, Outcome 01 Prostate cancer specific mortality (intention-to-screen)
Screening for prostate cancer
Comparison: 01 Screening vs control Outcome: 01 Prostate cancer specific mortality (intention-to-screen) Study
Screening
Control
Relative Risk (Fixed)
Weight
n/N
n/N
95% CI
(%)
Relative Risk (Fixed) 95% CI
Norrkoping
20/1494
97/7532
24.2
1.04 [ 0.64, 1.68 ]
Quebec
153/31133
75/15353
75.8
1.01 [ 0.76, 1.33 ]
32627
22885
100.0
1.01 [ 0.80, 1.29 ]
Total (95% CI)
Total events: 173 (Screening), 172 (Control) Test for heterogeneity chi-square=0.01 df=1 p=0.91 I?? =0.0% Test for overall effect z=0.12
p=0.9
0.1 0.2
0.5
1
Favours screening
Analysis 01.02. Review:
2
5
10
Favours control
Comparison 01 Screening vs control, Outcome 02 Prostate cancer diagnosis
Screening for prostate cancer
Comparison: 01 Screening vs control Outcome: 02 Prostate cancer diagnosis Study
Norrkoping Total (95% CI)
Screening
Control
Relative Risk (Fixed)
Weight
Relative Risk (Fixed)
n/N
n/N
95% CI
(%)
95% CI
85/1494
292/7532
100.0
1.47 [ 1.16, 1.86 ]
1494
7532
100.0
1.47 [ 1.16, 1.86 ]
Total events: 85 (Screening), 292 (Control) Test for heterogeneity: not applicable Test for overall effect z=3.20
p=0.001
0.1 0.2
0.5
Favours control
1
2
5
10
Favours screening
Screening for prostate cancer (Review) Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd
25
