Prostate Cancer Screening Clinical Practice Guidelines

Transcription

1 NATIONAL CLINICAL PRACTICE GUIDELINES Prostate Cancer Screening Clinical Practice Guidelines Reviewed/Approved by the National Guideline Directors November 2017 Next Review/Approval: November 2019 Developed by the National Prostate Cancer Screening Guideline Development Team Disclaimer These guidelines are informational only. They are not intended or designed as a substitute for the reasonable exercise of independent clinical judgment by practitioners, considering each patient s ne eds on an individual basis. Guideline recommendations apply to populations of patients. Clinical judgment is necessary to design treatment plans for individual patients.

2 Table of Contents National Prostate Cancer Screening Clinical Practice Guidelines... 3 Topic: Prostate cancer screening in average-risk men... 4 Topic: Prostate cancer screening in high-risk men... 4 Topic: Shared decision-making... 4 Topic: Age to discontinue screening... 4 Topic: Frequency of prostate cancer screening... 4 Topic: Referral to urology... 4 Appendix A: National Prostate Cancer Screening Guideline Development Team... 5 Appendix B. Summary of Recommendation Decisions ( )... 6 Appendix C. GRADE Assessment Appendix D. Evidence Review Topic: Prostate cancer screening Topic: Harms of prostate cancer screening Topic: Age to initiate and discontinue screening Topic: Frequency of prostate cancer screening Topic: Referral to urology References

3 Purpose National Prostate Cancer Screening Clinical Practice Guidelines This guideline was developed by the KP National Prostate Cancer Screening Guideline Development Team (GDT) (Appendix A) to assist primary care physicians and other health care professionals in screening for prostate cancer in adult men. Background The 2015 National Prostate Cancer Screening Guideline was reviewed by two board-certified clinicians in November 2017, and deemed current. No updates to the recommendations, rationales and supporting documentation were made. Methods KP National Guideline Program follows a methodology 1 that incorporates well-established scientific frameworks to critically appraise evidence and evaluate external guidelines. In developing these recommendations, the GDT considered the 2014 KP recommendations, USPSTF 2016 recommendations, and supplementary evidence reviews on selected, high priority topics. The GDT s decisions and justification are outlined in Appendix B1. The KP National Guideline methodology, updated in its entirety in 2012, categorizes recommendation strength as strong, conditional, or no recommendation for or against. In December 2017, the methodology was revised to change the strength of recommendation label from weak to conditional. The intent of the recommendation remains the same. Clinicians should consider the strength of the recommendation when determining the appropriate course of action based on patient s individual situation. GDTs develop guideline recommendations using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria, which considers the balance between desirable and undesirable effects, quality of evidence, patient values and preferences, and resource use. When the GDT changes an existing KP guideline, adapts an external guideline with modifications, or reviews new evidence to inform its updated recommendation, the GRADE framework provides transparency into those decisions. Appendix C summarizes GDT deliberations from the GRADE process. KP recommendations that were unchanged and external guidelines that were adopted verbatim are not subject to GRADE assessment. Additional evidence review work that informed the development of these recommendations is documented in Appendix D. This may include assessment of the quality of external guidelines for KP adoption using the AGREE II criteria; review of the methodological rigor of systematic reviews using the AMSTAR criteria; descriptions of original systematic reviews conducted by KP; and summaries and excerpts from individual studies or systematic reviews used to inform the recommendations. 3

4 Recommendations Topic: Prostate cancer screening in average-risk men For average-risk men ages who have at least a 10-year life expectancy, consider offering PSA-based a prostate cancer screening. (Conditional recommendation) Topic: Prostate cancer screening in high-risk men For higher- risk men (Black/African American descent or family history b of prostate cancer in at least one first-degree relative) ages who have at least a 10-year life expectancy, consider offering PSA-based prostate cancer screening. (Conditional recommendation) Topic: Shared decision-making If PSA-based screening is offered, it should be done in the context of shared decision-making. (Strong recommendation) Topic: Age to discontinue screening For men age 70 years and older, do not offer prostate cancer screening. (Strong recommendation) Topic: Frequency of prostate cancer screening For men who elect to have PSA-based prostate cancer screening, consider a screening interval of every 2 years. (Conditional recommendation) Topic: Referral to urology When PSA values exceed the age-specific thresholds in Table 1, consider repeating the PSA test within one month c. If the repeat PSA value still exceeds the age-specific thresholds, consider referral to Urology. (Conditional recommendation) Table 1. PSA Threshold by age Age range(years) PSA threshold >2.5 ng/ml >3.5 ng/ml >4.5 ng/ml (if tested) >6.5 ng/ml a While there is evidence that DRE may detect some cancers that are not detected by PSA alone, the randomized trials demonstrating a potential benefit of screening are based on PSA testing alone. b Elements associated with higher risk from family history of prostate cancer include: multiple first degree family members, family member(s) diagnosed at advanced stages, age <65 years at diagnosis c Normal variation of PSA values of ~20% have been demonstrated in some studies 4

5 Appendix A: National Prostate Cancer Screening Guideline Development Team Lead Team Joseph Presti, MD, Clinical Lead, Urology, KP Northern California Craig Robbins, MD, Clinical Lead, Family Medicine, Medical Director Center for Clinical Information Services, KP Program Office Elizabeth Liles, MD, Methodologist, Internal Medicine, KP Northwest Deborah Regidor, PhD, Principal Consultant, CMI Evidence Services, KP Program Office Guideline Development Team Michele Aspera, MD, Urology, KP Hawaii Catherine Bender, MD, Internal Medicine, KP Hawaii Michael Chen, MD, Urology, KP Colorado Joseph Dall era, MD, Urology, KP Colorado Louis Edelson, MD, Internal Medicine, KP Northern California Matthew Forsyth, MD, Urology, KP Northwest Daniel Grizzle, MD, Family Medicine, KP Georgia Robert Jefferson, MD, Urology, KP Georgia Marguerite Koster, Practice Leader, EBM, KP Southern California Eric Reid, MD, Urology, KP Northwest Steven Steinberg, MD, Family Medicine, KP Southern California Matthew Wagner, MD, Urology, KP Northwest Jeffrey Wheat, MD, Urology, KP Northwest Conflicts of Interest The NGP manages conflicts of interest in accordance with the Guidelines International Network Principles for Disclosure of Interests and Management of Conflicts in Guidelines (Schünemann HJ, Al-Ansary LA, Forland F, Kersten S, Komulainen J, Kopp IB, et al. Guidelines International Network: Principles for Disclosure of Interests and Management of Conflicts in Guidelines. Ann Intern Med. 2015; 163: ). GDT members have the following disclosures: Dr. Robbins is a Board of Trustee member for the Guidelines International Network. 5

6 Appendix B. Summary of Recommendation Decisions ( ) 2017 KP Recommendation 2015 KP Recommendation Topic: Prostate cancer screening in average-risk men KP GDT Decision Justification For average-risk men ages who have at least a 10-year life expectancy, consider offering PSA-based a prostate cancer screening. (Conditional recommendation) Offering PSA-based b prostate cancer screening is an option for average-risk men ages who have at least a 10-year life expectancy. (Weak recommendation) Updated language/ strength to align with current NGP methodology GL reviewed by 2 board-certified MDs in November 2017 and deemed current Topic: Prostate cancer screening in high-risk men For higher- risk men (Black/African American descent or family history c of prostate cancer in at least one first-degree relative) ages who have at least a 10-year life expectancy, consider offering PSA-based prostate cancer screening. (Conditional recommendation) Offering PSA-based prostate cancer screening is an option for higher- risk men (Black/African American descent or family history d of prostate cancer in at least one first-degree relative) ages who have at least a 10-year life expectancy. (Weak recommendation) Updated language/ strength to align with current NGP methodology GL reviewed by 2 board-certified MDs in November 2017 and deemed current Topic: Shared decision-making a While there is evidence that DRE may detect some cancers that are not detected by PSA alone, the randomized trials demonstrating a potential benefit of screening are based on PSA testing alone. b While there is evidence that DRE may detect some cancers that are not detected by PSA alone, the randomized trials demonstrating a potential benefit of screening are based on PSA testing alone. c Elements associated with higher risk from family history of prostate cancer include: multiple first-degree family members, family member(s) diagnosed at advanced stages, age <65 years at diagnosis d Elements associated with higher risk from family history of prostate cancer include: multiple first-degree family members, family member(s) diagnosed at advanced stages, age <65 years at diagnosis 6

7 2017 KP Recommendation 2015 KP Recommendation KP GDT Decision Justification If PSA-based screening is offered, it should be done in the context of shared decision-making. (Strong recommendation) If PSA-based screening is offered, it should be done in the context of shared decision-making. (Strong recommendation) No changes from 2015 GL reviewed by 2 board-certified MDs in November 2017 and deemed current Topic: Age to discontinue screening For men age 70 years and older, do not offer prostate cancer screening. (Strong recommendation) Prostate cancer screening is not recommended for men age 70 and older. (Strong recommendation) Updated language to align with current NGP methodology GL reviewed by 2 board-certified MDs in November 2017 and deemed current Topic: Frequency of prostate cancer screening For men who elect to have PSA-based prostate cancer screening, consider a screening interval of every 2 years. (Conditional recommendation) For men who elect to have PSA-based prostate cancer screening, a screening interval of every 2 years is an option. (Weak recommendation) Updated language/ strength to align with current NGP methodology GL reviewed by 2 board-certified MDs in November 2017 and deemed current Topic: Referral to urology When PSA values exceed the age-specific thresholds in Table 1, consider repeating the PSA test within one month a. If the repeat PSA value still exceeds the agespecific thresholds, consider referral to Urology. (Conditional recommendation) When PSA values exceed the age-specific thresholds in Table 1, consider repeating the PSA test within one month b. If the repeat PSA value still exceeds the age-specific thresholds, Updated strength to align with current NGP methodology GL reviewed by 2 board-certified MDs in November 2017 and deemed current a Normal variation of PSA values of ~20% have been demonstrated in some studies b Normal variation of PSA values of ~20% have been demonstrated in some studies 7

8 2017 KP Recommendation 2015 KP Recommendation KP GDT Decision Justification Table 1 Age PSA range(years) threshold >2.5 ng/ml >3.5 ng/ml >4.5 ng/ml (if tested) >6.5 ng/ml referral to Urology is recommended (Weak recommendation) Table 1 Age range(years) PSA threshold >2.5 ng/ml >3.5 ng/ml >4.5 ng/ml (if tested) >6.5 ng/ml 8

9 Appendix C. GRADE Assessment Topic: Prostate cancer screening Recommendation Basis of recommendation A. For average-risk men ages who have at least a 10-year life expectancy, consider offering PSA-based a prostate cancer screening. (Conditional recommendation) B. For higher- risk men (Black/African American descent or family history b of prostate cancer in at least one first-degree relative) ages who have at least a 10-year life expectancy, consider offering PSA-based prostate cancer screening. (Conditional recommendation) C. If PSA-based screening is offered, it should be done in the context of shared decision-making. (Strong recommendation) Prostate cancer is the most common non-skin cancer in men. Despite conflicting evidence regarding the balance of potential benefits vs. harms, epidemiological data and cultural expectations since the PSA test was introduced make consideration of screening for this cancer reasonable. The 5-year relative survival rate for prostate cancer for those with localized and regionally spread prostate cancer approaches 100%. Prostate cancer specific symptoms do not typically arise until distant metastases are present, and the 5-year survival rate for those with distant metastases is low, approximately 28%. Because some men may wish to screen in spite of potential risks, it is appropriate to offer screening in the context of a shared decision-making discussion. Shared decision-making is appropriate when the balance of benefits and harms is unclear or controversial. The shared decision-making approach for prostate cancer screening is supported by multiple guidelines, including those published by the American Urological Association (AUA), the American Cancer Society (ACS), the National Comprehensive Cancer Network (NCCN) and the American College of Physicians (ACP). While the USPSTF generally recommends against prostate cancer screening, it suggests that if screening is considered, it should be done in the context of shared decision-making. The recommendation of age 50 as the lower end of the range for a screening discussion in average-risk men is based primarily on evidence from the European Randomized Study of Screening for Prostate Cancer (ERSPC). The study showed a 17% relative reduction (0.1% absolute reduction) in prostate cancerspecific mortality in the entire cohort (50-74 years) and a 21% relative reduction (0.08% absolute reduction) in the core group (55-69 years). As well, a single randomized trial in men ages years from ERSPC s Swedish site (Goteborg), the only site of ERSPC that included men under the age of 55, demonstrated a 44% relative reduction (0.4% absolute reduction) in prostate a While there is evidence that DRE may detect some cancers that are not detected by PSA alone, the randomized trials demonstrating a potential benefit of screening are based on PSA testing alone. b Elements associated with higher risk from family history of prostate cancer include: multiple first-degree family members, family member(s) diagnosed at advanced stages, age <65 years at diagnosis 21

10 cancer-specific mortality. The recommendation of age 45 as the lower end of the range for higher-risk men was based in part on observational studies indicating that higher risk men have the same prevalence of prostate cancer mortality as average-risk men beginning about 5 years earlier than average-risk men. As well, SEER data shows that mortality from prostate cancer in men younger than 45 is exceedingly low regardless of risk factors. GRADE criteria GRADE assessment Current evidence for effectiveness of prostate cancer screening is limited. After a follow-up of years, absolute prostate cancer-specific mortality reduction from screening in randomized studies has ranged from 0 to 0.4%, and relative risk ranged from a 21% decrease to a 9% increase. ERSPC, which showed a prostate cancer-specific mortality reduction, also demonstrated a reduction in metastatic disease in the screening arm compared to the control arm (absolute risk of metastatic disease was 0.67% per 1000 men in the screening arm vs. 0.86% per 1000 men in the control arm (ARR=0.31%; HR = 0.70 ( )). All-cause mortality was reported from the ERSPC and Stockholm trials. Compared with no screening, PSA-based screening resulted in no difference in all-cause mortality in either of these trials (pooled RR (95%CI) = 0.99( ). Balance of desirable and undesirable effects The results of two good quality RCTs of treatment for localized prostate cancer suggest that prostatectomy does not result in reduction in all-cause mortality compared with observation, but may provide protection against distant metastasis. The impact on prostate cancer-specific mortality is unclear but may suggest a benefit in younger men with intermediate or high-risk disease. Harms of the screening exam and biopsy include pain, fever, bleeding, and transient urinary difficulties associated with prostate biopsy. Observed rates for transient urinary difficulties, severe urinary retention and infection leading to hospitalization are 22-50%, 0.4% and 0.5%, respectively. Unnecessary biopsy is also associated with psychological harm from false-positive test results, overdiagnosis and over-treatment. In men with localized prostate cancer treated with prostatectomy, results from the 2 treatment RCTs reported absolute increases in erectile dysfunction of ~ 28.0% and in urinary incontinence of 10.8%-27.5% (compared to watchful waiting or active surveillance). Serious perioperative events included mortality (~0.5%) and cardiovascular events (3%). On a population basis, some may argue that the known harms of screening and subsequent treatment of localized prostate cancer outweigh the potential mortality benefit. Nonetheless, prostate cancer is the second leading cause of cancer death in American men, and PSA-based screening is the only means available for early detection. Individual men are likely to weigh the potential 22

11 benefits and risks differently and to make different personal decisions whether to participate in prostate cancer screening. SCREENING (vs. no screening) Category (overall assessment) Outcome Importance #/study design Benefit (low quality) Harms (low quality) Prostatecancer mortality All-cause mortality False-positive rates Assessment Explanation Critical 5 RCTs Low quality High risk of bias, In directness Critical 2 RCTs Moderate Indirectness quality Important 2 RCTs Moderate Indirectness quality Hospitalizations Important 1 RCT Low quality Imprecision, Indirectness Urinary retention Important 1 RCT Low quality Imprecision, Indirectness TREATMENT (vs. watchful waiting/active surveillance) Quality of evidence Category (overall assessment) Benefit (moderate quality) Harms (high quality) Benefit (very low quality) Harms (very low quality) Outcome Prostatecancer mortality All-cause mortality Urinary incontinence Erectile dysfunction Prostatecancer mortality All-cause mortality Urinary incontinence Erectile dysfunction Bowel dysfunction Importance #/study design Assessment Prostatectomy Critical 2 RCTs Moderate quality Critical 2 RCTs High quality Critical 2 RCTs High quality Critical 2 RCTs High quality Radiation Therapy Critical 4 cohort Critical 5 cohort Very low quality Very low quality Explanation Imprecision Study design, Risk of bias Study design, Risk of bias Critical 1 RCT Low quality Risk of bias, Imprecision Critical 6 Very Study design, cohort low Risk of bias quality Critical 2 cohort Very low quality Study design, Risk of bias Values and preferences This recommendation places a high value on individual patient choice. Variability of values and preferences with regard to the balance of benefits and harms of 23

12 screening for asymptomatic prostate cancer is likely to be high. Uncertainty regarding these values and preferences is estimated to be high. Resource implications Although the cost of an individual PSA test is low, the burden of screening all eligible men is high. Considerable clinician time is needed for shared decisionmaking discussions and considerable resources are required for biopsy and treatment of localized prostate cancers. 24

13 Topic: Age to discontinue screening Recommendation For men age 70 years and older, do not offer prostate cancer screening. (Strong recommendation) The KP National Prostate Cancer Guideline Development team endorses the following statement from the AUA 2013 Guidelines for Early Detection of Prostate Cancer as the basis for this KP recommendation: Basis of recommendation The rationale for this recommendation is based on the absence of evidence of a screening benefit in this population with clear evidence of harms. In the ERSPC randomized trial of screening, there was no reduction in mortality among men age 70 years or older. Although men in this age group have a higher prevalence of prostate cancer and a higher incidence of fatal tumors, they also have increased competing mortality compared to younger men, and no compelling evidence of a treatment benefit, especially in men with a limited life expectancy below 10 to 15 years. Therefore, given the lack of direct evidence for benefit of screening beyond age 70 years, and especially beyond age 74 years, as well as higher quality data regarding harms, the Panel discourages routine screening in this age group. GRADE criteria GRADE assessment Post-hoc sub-group analyses of prior randomized trials of prostate cancer screening (ERSPC and PLCO) and treatment (SPCG-4 and PIVOT) were used to weigh the balance of potential benefit versus harm of prostate cancer screening in men ages 70 and older. Balance of desirable and undesirable effects In a sub-group analysis from the ERSPC randomized trial of screening, there was no reduction in either all-cause or prostate cancer-specific mortality among PSA-screened men age 70 years or older (all-cause: RR=1.03( ); prostate cancer-specific: RR=1.18( ). In a sub-group analysis from the PLCO randomized trial of screening, there was no reduction in prostate cancer-specific mortality among all PSA-screened men, and when stratified by younger (55-64 years; RR=1.19( )) and older (65-74 years; RR=1.02( )) men. A sub-group analysis of the SPCG-4 trial of radical prostatectomy vs. watchful waiting for the treatment of localized prostate cancer showed no difference between groups in either all-cause or prostate cancer-specific mortality in men ages 65 years and older (all-cause: RR=1.04( ); prostate cancer specific: 0.87( ). Post-hoc subgroup analyses of the PIVOT trial of radical prostatectomy vs. watchful waiting or active surveillance in the treatment of localized prostate cancer showed no difference between groups in either all-cause or prostate cancer-specific mortality for men ages 65 years or older (allcause: RR=0.89 ( ); prostate cancer-specific: RR=0.63(

14 1.32). More than 90% of the study population was older than 65 years of age. There is a lack of evidence for mortality reduction from screening for or treating localized prostate cancer in men ages 70 and over. Given the known harms of screening, which are no less common in men of this age range, screening men ages 70 and over is not recommended. The evidence for benefit in men >70 years consists of post-hoc analyses of two RCTs of screening and two RCTs of treatment. The quality of evidence for harms of screening and treatment is described in the rationale for prostate cancer screening. Benefits of screening in men >70 years: Quality of evidence Category (overall assessment) Benefit (very low quality) Benefit (low quality) Outcome Importance #/study design Prostate cancer mortality All-cause mortality Critical Critical 2 RCTs (subgroup analysis) 1 RCT (subgroup analysis) Assessment Very low quality Low quality Explanation High risk of bias, indirectness imprecision High risk of bias, indirectness Benefits of treatment in men >70 years: Category (overall assessment) Benefit (low quality) Benefit (low quality) Outcome Importance #/study design Prostate cancer mortality All-cause mortality Critical Critical 2 RCTs (subgroup analysis) 2 RCTs (subgroup analysis) Assessment Very low quality Very low quality Explanation High risk of bias, imprecision High risk of bias, imprecision Values and preferences Resource implications This recommendation places a high value on avoiding the harms of screening and treatment over very low likelihood of prostate cancer mortality benefit in men screened for asymptomatic prostate cancer at age 70 years or older. Variability of values and preferences is estimated to be low. Uncertainty regarding values and preferences is estimated to be high as values as preferences were derived by guideline development team members. Although the cost of an individual PSA test is low, the resource burden of screening men age 70 years or older would be high. Considerable clinician time is needed for shared decision- making discussions and considerable resources are required for biopsy and treatment of localized prostate cancers. 26

15 Topic: Frequency of prostate cancer screening Recommendation For men who elect to have PSA-based prostate cancer screening, consider a screening interval of every 2 years. (Conditional recommendation) Basis of recommendation GRADE criteria Balance of desirable and undesirable effects Quality of evidence As opposed to annual screening, the 2-year screening interval option is based on the natural history of prostate cancer, on very low quality observational evidence, and on the recommendations of external guidelines. These different resources indicate that moving from annual to biennial screening intervals results in a similar benefit-to-risk profile, measured by risk of prostate cancer death vs. risk of harm due to unnecessary treatment in patients with indolent cancers. Key external guidelines recommend a 2-year or 4-year screening interval for similar reasons. The decision to recommend biennial screening over 4-year screening is based upon a study comparing two randomized trials with 2- and 4-year screening intervals, with the biennial screening site showing a more significant reduction in prostate cancer-related deaths, albeit with a concomitant slightly increased risk of over-diagnosis. GRADE assessment Evidence to inform appropriate screening intervals is limited and based on indirect comparisons, observational data and predictive modeling. Nonetheless, these studies consistently predict a small reduction in overdiagnosis (~0.5% reduction in predicted risk over a lifetime) with very little increased risk of prostate cancer death (~0.1% increase in predicted risk over a lifetime) for biennial screening, as compared to annual screening. Overall quality=very low (study design, imprecision) No direct RCT evidence exists. 1 vs. 2-year interval: very low quality [observational study, imprecision] Advanced cancer at diagnosis: low [observational study] Prostate cancer mortality: very low [observational study, imprecision] 2 vs. 4-year interval: very low quality Advanced cancer at diagnosis: very low [observational, high risk of bias, indirect] Values and preferences Resource implications This recommendation attempts to balance the importance to patients of reducing prostate cancer death while minimizing over-diagnosis. As no patient-specific information is available, uncertainty in values and preferences is high and variability in acceptance of a biennial screening interval is unknown. Extending screening intervals to two years reduces cost with minimal impact on risk of prostate cancer death. 27

16 Appendix D. Evidence Review Executive Summary Uncertain evidence In 2012, the United States Preventive Services Task Force (USPSTF) recommended against systematically screening all men for prostate cancer, due to the lack of definitive evidence of screening benefit, combined with a moderate level of evidence for potential harm from the treatments. In the clinical considerations, the USPSTF laid out talking points for explaining the balance of benefit and harm to ageappropriate men. The American Academy of Family Practitioners (AAFP) has endorsed the USPSTF recommendations. The American Cancer Society (ACS), American College of Physicians (ACP), American Urological Association (AUA), and National Comprehensive Cancer Network (NCCN), recommend an informed discussion describing potential benefits and risks of screening. These organizations interpret the implications of the evidence differently, resulting in moderately disparate recommendations. Prostate cancer screening and incidence Prostate cancer is the most commonly diagnosed cancer, and the second most common cause of cancerrelated death for men in the United States. 2 Randomized trials demonstrate that screening increases the detection of prostate cancer by 4-12%. Epidemiologic studies reflect the increased cancer detection resulting from PSA screening programs. Incidence rates rose rapidly in the early 1990s in the United States, Australia, Canada and the Nordic countries soon after the introduction of PSA testing, followed by a sharp decline, presumably due to a smaller pool of prevalent cases. The relationship between screening, treatment, and prostate cancer-related mortality is less clear. Death rates for prostate cancer have been declining in the last 20 years in many developed countries, including Australia, Canada, the United Kingdom, the United States, Italy, and Norway. It is unclear how much of this decline is due to screening, and how much is due to improved treatment techniques. Brachytherapy and hormonal treatment of localized prostate cancer have become more common during the past two decades and higher doses are being used in external beam radiotherapy. 3 In contrast to the trends in Western countries, mortality rates appear to be rising in some Eastern European countries, such as Slovenia and Croatia. 4 It is unclear whether this is due to increased life expectancy or to biologic or cultural factors that are increasing the incidence of prostate cancer in these countries. Natural history The high survival rate from prostate cancer partly reflects a slow growth rate of most prostate tumors. Evidence from observational studies suggests most men with PSA- detected, localized untreated prostate cancer have excellent health outcomes for up to ten years after diagnosis. 5 The 5-year relative survival rate for prostate cancer for those with localized and regionally spread prostate cancer approaches 100%, whereas the 5-year survival for those with distant metastases is approximately 28%. 6 Screening effectiveness An ideal screening program would identify those men with disease most likely to result in prostate cancerrelated morbidity and/or mortality. Three fair-quality randomized trials of prostate cancer screening with low risk of bias have reported mortality outcomes (PLCO, ERSPC, and the Swedish [Goteborg] site of ERSPC). Absolute prostate cancer- specific mortality reduction (ARR) from screening in these studies ranged from 0 to 0.4% after a follow-up of years (RR(95%CI) =0.87( )). 7 It is unclear whether these results reflect contamination or bias in the studies, inadequate length of follow-up or rather 28

17 that PSA (leading to current standard treatments) is ineffective in distinguishing prostate cancer that is likely to cause premature death. ERSPC also demonstrated a lower rate of metastatic disease in the screening arm compared to the control arm (0.67% vs.0.86% per 1000 men; ARR=0.31%; HR = 0.70 ( )). Future directions in prostate cancer screening refinement There are no new or ongoing trials of prostate cancer screening, aside from those that have recently reported results. Given that PSA-based screening is the standard of care for patients who wish to be screened, designing a trial without any utilization of screening in the control group would not likely be feasible. Unless a new test for prostate cancer screening emerges, the refinement of prostate cancer screening may depend on better identification of those men with PSA-detected prostate cancer who are most likely to benefit from treatment. The informed discussion A less controversial element of informed discussion relates to the harms of screening and biopsy procedures needed to identify prostate cancer. The screening tests themselves are associated with rare bleeding or pain from the DRE (0.03%) and bruising or fainting due to venipuncture (0.26%). 7 After 4 screening sessions, the chance of having a false positive PSA test approaches 13%. 8 A false positive test result has been associated with increased worry about prostate cancer and perceived increased risk for prostate cancer in observational studies. 5 In large trials, a prostate biopsy was relatively safe, leading to urinary retention or infection in less than 1% of patients, with about 0.5% of men developing a complication requiring hospitalization (e.g., sepsis). Deciding whether to screen for prostate cancer must also take into account whether the patient would want to receive treatment for localized prostate cancer, if it were detected. Treatments are effective but also have a risk of harm. The most common excess risks associated with treatment of localized prostate cancer with prostatectomy are erectile dysfunction (absolute risk increase (ARI) = 35.6%-37.0%) and urinary incontinence (ARI= 10.8%-27.5%). 9,10 In the 30-day perioperative period, PIVOT reported cardiovascular events (0.2%), deep venous thrombosis (0.7%) and death (<0.1%). Watchful waiting or active surveillance of prostate cancer may also be recommended options for localized prostate cancer, which would involve additional PSA tests and/or prostate biopsies at intervals. There is a paucity of current evidence to guide treatment decisions about prostate cancer. Patients currently decide to treat or monitor screen-detected localized prostate cancer based primarily on their individual judgment and the recommendations of their urologist. Only consensus-based recommendations about treatment thresholds exist currently. Under current practices in the United States, 77-80% of those diagnosed with screen-detected prostate cancer receive treatment. 7 Given the uncertainties about effectiveness of PSA-based screening, it is important for men to understand that a positive screening result would more likely lead to treatment than to active surveillance or watchful waiting. Screening discussion age range: average-risk men ages years, high-risk men ages years There is no strong, comparative evidence to inform the age range for offering prostate cancer screening to average-risk or higher-risk men. Recommending a screening discussion starting at age 50 in averagerisk men is based largely on the positive findings of the Swedish site of the ERSPC trial (Goteborg), which is the only site in the multi-site study that included men years old. The randomized trial at this site demonstrated a 44% relative reduction and 0.40% absolute reduction in prostate cancer-specific mortality among those in the screening group. 29

18 Recommending a screening discussion to start specifically at age 45 in higher risk men is based primarily on observational data. SEER data indicate that starting screening at age 45 would miss few aggressive prostate cancers. The mortality from prostate cancer in men aged is low (0.0006% for black men, who have the highest incidence and mortality by race). 11 As well, observational studies using comprehensive disease registries in Sweden indicate that prostate cancer incidence and mortality for men with a family history of prostate cancer (whether one affected relative or more) reach comparable levels to those of average-risk men beginning about 5 years earlier than average-risk men. External recommendations make a distinction between a high-risk family history (a single first-degree relative affected) and a very high risk family history (multiple family members affected). There is no existing evidence to support a screening discussion at age 40 in men with a very high risk family history of prostate cancer. Because of this, and to improve ease of implementation, we collapsed the definition of family history into one higher risk family history category. Similarly, the selection of a cut-point for age of the affected relative by external guidelines is consensusbased, and no evidence exists to inform that decision. Because of concern about discouraging screening for those with a family history that may not meet an arbitrary definition of age 65 or less (e.g., a patient with a father who was found to have metastatic prostate cancer at age 66), we elected to not specifically define an age cut-point in the body of the recommendation. The variability in the current recommendations of professional societies regarding prostate cancer screening age ranges by risk status illustrates the existing low level of evidence available: Professional Association Average-risk High-risk (by family Very high-risk family history or Black race) history USPSTF AAFP Do not recommend screening Do not recommend screening Do not recommend screening Do not recommend screening ACS Informed discussion > 50 years, >10-year life expectancy ACP Informed discussion 50-69, >10-15-year life expectancy AUA Informed discussion years, >10-15-year life expectancy Informed discussion > 45 years Do not recommend screening Do not recommend screening Informed discussion > 40 years Informed discussion 45- Informed discussion years Decisions should be individualized. Decisions should be individualized. PSA-based screening The decision to offer screening primarily with PSA, without the addition of digital rectal exam, is based largely on the fact that randomized trials demonstrating a potential benefit of screening are based on PSA testing alone. As well, PSA as a standalone screening strategy is intended to reduce barriers to screening. This recommendation emphasizes patient choice to screen, based upon a face-to-face, relatively complex discussion between healthcare provider and patient about screening pros and cons. If the embarrassment or anticipated discomfort associated with the digital rectal examination appears to be a factor in the patient s decision about screening, it should be kept in mind that DRE contribute proportionally little additional sensitivity to the screening sensitivity of PSA alone. 30

19 PSA threshold for biopsy The currently recommended PSA thresholds for biopsy represent PSA levels that are greater than the 95 th percentile for the respective ages: Age range (years) PSA threshold >2.5 µg/l >3.5 µg/l >4.5 µg/l (if tested) >6.5 µg/l This recommendation was developed for the 2011 national prostate cancer guideline and remains current. PSA-based screening interval The new optional recommendation to screen all men biennially, regardless of PSA level, is based on two retrospective cohort studies and a modeling study. Two of these studies suggest that there is no significant increase in prostate cancer-specific mortality from screening biennially instead of annually; screening biennially in both studies was found to mitigate overdiagnosis as well. An additional low-quality observational study suggested that screening every 4 years instead of every 2 years may result in an unacceptable increase in prostate cancer specific mortality. Based on these three studies, the current recommendation is to offer biennial screening to all men, and to refer to urology if the PSA reaches the age-specific threshold (as above). Recommendations from major professional societies regarding PSA threshold for biopsy and screening interval are below. Professional Association Recommended PSA threshold for biopsy Screening Interval ACS No specific recommendation Every year if PSA >2.5 ng/ml Every 2 years if PSA <2.5 ng/ml ACP No specific recommendation Every year if PSA >2.5 ng/ml Every 4 years if PSA <2.5 AUA PSA of 3-4 ng/ml, taking into account other Every 2 years if PSA >1.0 ng/ml factors Longer interval if PSA<1.0 ng/ml Summary and conclusion Prostate cancer is relatively common, and screening detects more prostate cancer cases than usual care. Men who wish to be screened for prostate cancer should understand that if they do screen positive, watchful waiting or active surveillance is often an appropriate decision. Through a comprehensive shared decision-making discussion with his healthcare provider, the patient should understand the benefits and risks of screening as well as the benefits and risks of treatment when deciding whether to be screened. 31

20 Key Questions This evidence update uses the analytic framework and search strategy from AHRQ s Evidence Review AHRQ Publication No EF-1 October 2011 Prostate-Specific Antigen-Based Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force 12 and AHRQ Publication No EF-1 October 2011 Treatments for Localized Prostate Cancer: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation. 13 In the analytic framework below, the overarching clinical question addresses the effect of screening for prostate cancer on reduction in morbidity and mortality, through screening s effect on identification of prostate cancer at an early, treatable stage. To address this, the Evidence Practice Centers (EPCs) examined both the direct effect of screening and the effect of treatment in men with screen-detected or early-stage prostate cancer. Of note, they limited examined outcomes to mortality only, in spite of the mention of morbidity in the main clinical question. Analytic framework a Screening 1. What is the direct evidence that screening for prostate cancer with prostate-specific antigen (PSA), as a single-threshold test or as a function of multiple tests over time, decreases morbidity and/or mortality? 2. What are the harms of PSA-based screening for prostate cancer? Treatment 1. What are the benefits of treatment of early-stage or screen-detected prostate cancer? 2. What are the harms of treatment of early-stage or screen-detected prostate cancer? a Adapted from: AHRQ Publication No EF-1 October 2011 Treatments for Localized Prostate Cancer: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation. 32

21 Topic: Prostate cancer screening Benefits of prostate cancer screening Clinical Question: Population: Intervention: Does PSA-Based Screening Decrease Prostate Cancer-Specific or Allcause Mortality? Men without a prior diagnosis of prostate cancer and without bone pain or constitutional symptoms a PSA-based screening b Comparison No prostate cancer screening Critical Health Outcomes Prostate cancer mortality All-cause mortality The literature search conducted by the EPC examined studies published up to July, Because updates to the two major screening trials (PLCO 8, ERSPC 14 ) as well as a major treatment study (PIVOT 9 ) were published subsequent to the EPC review, a bridge search was done in November 2012 to identify all relevant studies published subsequent to July In addition, a literature search to inform the definition of family history of prostate cancer was performed. Methodology The search strategy and other methodological details from the EPC s evidence synthesis may be found here, with details of search strategy found here. Study design was limited to RCTs, systematic reviews and meta-analyses. PSA-based screening is defined by the EPC as a screening program for prostate cancer in asymptomatic men that incorporates one or more PSA measurements, with or without additional modalities such as digital rectal examination or trans-rectal ultrasonography. Asymptomatic is defined as without symptoms that are highly suspicious for prostate cancer. We consider both prostate-specific mortality and all-cause mortality to be critical outcomes and are equally important for different reasons. While all-cause mortality may be the most germane outcome, it generally is not as robust due to inadequate sample size. Search Results A QUOROM figure describing the EPC s search results may be found here. Among 379 unique articles retrieved, 7 publications met inclusion criteria and are included in the review: Andriole 2009 (PLCO); Schroder 2009 (ERSPC); Hugosson 2010 (ERSPC-Goteborg center); Kjellman 2009 (Stockhom South Hospital); Sandblom 2011 (Norrkoping); Djulbegovic 2010 (BMJ meta-analysis); and Ilic 2010 (Cochrane Review). a Lower urinary tract symptoms and erectile dysfunction are not indications for ordering a PSA test. b PSA-based screening is defined as a screening program for prostate cancer in asymptomatic men that incorporates one or more PSA measurements, with or without additional modalities such as digital rectal examination or trans-rectal ultrasonography. 33

22 Literature search update A bridge search was conducted to update the EPC evidence. The search strategies are consistent with that of the EPC. Search results are shown in Table 1, and study selection in Figure 1. Among 102 unique articles retrieved, 5 studies met inclusion criteria and are included in this review: 4 ERSPC updates and 1 PLCO update for screening studies. In addition, 2 relevant treatment studies were identified. 9,15 Table 1: Screening for prostate cancer: search strategy and results Dates of search: 7/1/ /1/2012 Database: PubMed Search Name Search String Query translation Database: PubMed outcomeprostate cancer Prostatic Neoplasms[Mesh] prostatic neoplasms[mesh Terms] Number of hits intervention- PSA screening Screening OR prostatespecific antigen[mesh] ("diagnosis"[subheading] OR "diagnosis"[all Fields] OR "screening"[all Fields] OR "mass screening"[mesh Terms] OR ("mass"[all Fields] AND "screening"[all Fields]) OR "mass screening"[all Fields] OR "screening"[all Fields] OR "early detection of cancer"[mesh Terms] OR ("early"[all Fields] AND "detection"[all Fields] AND "cancer"[all Fields]) OR "early detection of cancer"[all Fields]) OR "prostate-specific antigen"[mesh Terms] outcome qualifier 3. Early diagnosis[mesh] early diagnosis[mesh Terms] PSA qualifier 4. PSA velocity[all Fields] PSA velocity[all Fields] Prostate specific antigen Prostate specific antigen velocity[title/abstract] PSA qualifier velocity[title/abstract] PSA doubling PSA doubling time[title/abstract] PSA qualifier 420 time[title/abstract] 7. Prostate specific antigen Prostate specific antigen doubling[title/abstract] PSA qualifier doubling[title/abstract] #2 OR #3 OR #4 OR Combination #2 OR #3 OR #4 OR #5 OR #6 #5 OR #6 searches OR # OR #7 Combination searches 9. #1 AND #8 #1 AND # Limits 10. Limit 9 to English[lang] AND Randomized Controlled Trial[ptyp] AND Publication Date from 2011/07/01 to 2012/11/01 (#1 AND #8) AND (("2011/07/01"[PDAT] : "2012/11/01"[PDAT]) AND Randomized Controlled Trial[ptyp] AND English[lang]) Total Number of Hits

23 Figure 1: Selection of studies from bridge search of screening for prostate cancer PubMed search (n=102) Rejected (n=85): Population: 31 Intervention: 40 Comparator: 2 Outcome: 6 Study design: 6 Full-text review (n=17) Rejected (n=10) Intervention: 2 Comparator: 5 Outcome: 1 Study design: 2 Accepted(n=7) Screening: 5 Treatment: 2 A literature search to inform the definition of family history of prostate cancer was performed on 6/8/2013 (see Table 2). From the 1594 studies retrieved, 44 studies were selected for further review; of these, 4 studies provided relevant information (see Figure 2)

24 Table 2: Literature search: definition of family history Search Query Items found #12 Search Prostatic neoplasms [MeSH] #13 Search Prostate cancer [tiab] #14 Search Prostatic cancer [tiab] 6379 #15 Search Prostate neoplasm [tiab] 29 #16 Search Prostatic neoplasm [tiab] 58 #17 Search Prostate adenocarcinoma [tiab] 1636 #18 Search Prostatic adenocarcinoma [tiab] 2224 #19 Search (#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR 18) #20 Search Family Health [MeSH] #21 Search Genetic predisposition to disease [MeSH] #22 Search Family history [tiab] #23 Search First-degree relative [tiab] 1595 #24 Search First-degree relatives [tiab] 7418 #25 Search (#20 OR #21 OR #22 OR #23 OR #24) #26 Search Death [tiab] #27 Search Deaths [tiab] #28 Search Survival [tiab] #29 Search Mortality [tiab] #30 Search Mortality [MeSH] #31 Search Survival Rate [MeSH] #32 Search Survival Analysis [MeSH] #33 Search (#26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32) #34 Search (#19 AND #25 AND #33)

25 Figure 2: Selection of studies: definition of family history PubMed search (n=1594) rejection (n=1550) Full-text review (n=44) Reject (n=35) P=14 I=8 C=0 Accepted references (n=9) Study design=2 Duplicate=1 Evidence Synthesis Key Study Characteristics Five RCTs examining the effect of prostate cancer screening on mortality are included in the EPC review (Quebec, Norrkoping, Stockholm, ERSPC, PLCO), and are synthesized in a meta-analysis by The Cochrane Collaboration. 20 Studies were published between Subsequent to the EPC review, updated results from the PLCO and ERSPC trials were published in Study sizes ranged from 9, ,387; median follow-up time ranged from years. Studies differed in screening protocol, screening interval and biopsy threshold. The EPC report rated PLCO and ERSPC as fair quality evidence; the remaining 3 RCTs were considered poor quality. Key study characteristics of individual studies are found here; narrative of study characteristics and results are found here. Although 5 trials were included in the analysis, special attention was given to the PLCO and ERSPC trials, as they were significantly larger and of higher quality than the other screening RCTs. These two RCTs differed in several important characteristics, including setting, screening protocol, screening interval and biopsy threshold. Table 3 compares characteristics of the PLCO and ERSPC trials. 37

26 Table 3: Comparison of ERSPC and PLCO Characteristic ERSPC Sample size 162,388 (core group ages 55-69) 181,999 (entire group ages 50-74) Trigger for biopsy PSA 3 ng/ml, with some variation among individual sites Study 76,693 >4 ng/ml PLCO Screening interval Q 4 years for 87%; Q 2 years for Q yearly 13%) Median follow up 11 years 13 years Screening protocol PSA Years 1-4: PSA+DRE; Years 5-6: PSA only Primary endpoint Prostate cancer-specific mortality Cause-specific mortality for each of the PLCO cancers Age Base population Range: (core group) (entire group) Population registries in 8 EU countries Range: centers in US Inclusion/Exclusion Not well defined. Exclusion: History of a PLCO cancer Current cancer treatment Having had more than one PSA blood test in the previous 3 years (starting in 1995). Compliance (Screened at least once) Mean (range) = 83% ( ) PSA: 85% DRE: 86% Contamination It has been estimated that in the control group, ~20% of men per year underwent PSA screening. In the control group, the rate of PSA testing was 40% in the first year and increased to 52% in the sixth year. The rate of screening by digital rectal examination in the control group ranged from 41 to 46%. 38

27 Results Results of the key prostate cancer screening trials are organized by data reported prior to 2012 (and therefore included in the Cochrane meta-analysis and EPC review for the USPSTF), and additional trial updates (for ERSPC and PLCO) reported in We performed an original meta-analysis, incorporating the more recent publications, below. Updated ERSPC and PLCO results Table 4 shows detailed results of these trial updates published in ERSPC results showed a 21% relative decrease (RR [95% CI] = 0.79[ ]) and a 0.1% absolute decrease in prostate cancerspecific mortality for a pre-specified subgroup of men, aged Results for the entire study population were similar, with a 17% relative decrease (RR [95% CI] = 0.83 [ ]) and a 0.08% absolute decrease in prostate cancer-specific mortality. The most recent PLCO results failed to show any statistically significant difference in prostate cancer mortality between the screening and control groups (RR[95%CI] =1.09[ ]) meta-analysis results We acknowledged the existence of clinical heterogeneity, as the design of some RCTs differed from each other with respect to screening frequency and biopsy threshold. It was decided that a meta-analysis was still appropriate, and chose to acknowledge clinical heterogeneity in our GRADE assessment of quality of evidence by downgrading for indirectness. We chose to include all 5 RCTs (using the updated results from the ERSPC and PLCO studies) in our primary meta-analysis since this was reflective of the most current body of evidence and used a random-effects model to account for heterogeneity between studies. A sensitivity analysis was conducted comparing a fixed effect to a random effects model. Further sensitivity analyses were done on the basis of evidence quality, performing separate analyses for low vs. high risk of bias studies. With the exception of using a fixed effects model with the updated results of the two studies with the lowest risk of bias, the sensitivity analyses consistently showed an absence of a statistically significant reduction in prostate cancer-specific mortality. Table 5 compares meta-analyses of the 5 screening studies reported in the EPC 7 and Cochrane 20 reviews to those incorporating 2012 ERSPC and PLCO updates (for the endpoint of prostate cancerspecific mortality). We report results separately by fixed vs. random effects modeling techniques, and also report the different results for pooling only the two most high-quality trials (ERSPC and PLCO), as opposed to pooling all 5 trials. A meta-analysis of the 2012 ERSPC and PLCO results alone (using fixed effects) showed a 13% relative decrease in prostate cancer mortality and 0.07% absolute decrease; however, no statistically significant effect was seen when using a random effects analyses. There was considerable statistical heterogeneity, which may be partially explained by the study differences highlighted in Table 3 (above). As both the PLCO and ERSPC studies suffered from contamination (40% and 20% of those in the controlled group received screening, respectively), it is possible these results underestimate the true effect of screening on prostate cancer mortality. No statistically significant reduction in prostate cancer mortality was seen when all 5 (most recent) studies were included in a metaanalysis. Figures 3 and 4 provide individual and pooled results in the meta-analyses, including Forest plots. An updated (2012) meta-analysis of the 2 studies reporting all-cause mortality is shown in Figure 5. No effect of screening on all-cause mortality was seen (RR (95%CI) =0.99( )). 39

28 Pre-2012 results The Cochrane review also reported the effect of screening on Prostate cancer mortality stratified by risk of bias and age, as well as all-cause mortality and Prostate cancer diagnosis. A summary of these analyses are found here. To summarize, there were no differences in Prostate cancer mortality when stratified by risk of bias or age, and no effect on all-cause mortality. An updated analysis of all-cause mortality including 2012 ERSPC data showed similar results as the Cochrane analysis (see metaanalysis below). The Cochrane review considered the ERSPC and PLCO trials to be low risk of bias, with the remaining trials, high risk of bias. Details of the risk of bias assessment are found here. 40

29 Table 4: Recent ERSPC and PLCO results (2012) Study (Follow-up) Outcome Screen Control Relative risk (95% CI) ERSPC core group- Prostate CI= 0.39/1000 CI= 0.50/1000 MR= ages years cancer person- years person- years 0.79(0.68- (excludes France) Mortality 0.91) (11 yr F/U) Schroder (unadjusted) Screen (n= 72,891) Control (n=89,352) MR= 0.71 ( ) (adjusted for compliance) Absolute risk (95% CI) ARR= 1.07 /1000 men RD= (-0.17, ) per 1000 person-years NNI= 936 to prevent 1 death over 11 years ERSPC entire groupages years (excludes France) (11 yr F/U) Screen (n=82,816) Prostate cancer Mortality CI = 0.42/1000 person- years CI = 0.50/1000 person- years MR = 0.83 ( ) NND = 33 to prevent 1 death over 11 years ARR = 0.8/1000 men RD = (-0.14, -0.02) per 1000 person years Control (n=99,183) ERSPC Sweden 21 (Goteborg)- ages years Median 14 years of F/U Screen: (n=10,000 randomized, 9952 evaluated) Control: (n=10,000 randomized, 9952 evaluated) PLCO (13 yr F/U) Andriole Screen (n=38,340) Control (n=38,345) Prostate cancer Mortality Prostate cancer Mortality CI = 0.53/1000 person- years CI = 0.37/1000 person- years CI = 0.95/1000 person- years CI = 0.34/1000 person- years MR = 0.56( ) MR=1.09 ( ) NNI=1,250 to prevent 1 death over 11 years ARR = 4.2/1000 men RD = per 1000 person-years NNI=293( ) to prevent 1 death over 14 years ARI = 0.3/1000 men RD = per 1000 person-years Prostate cancer incidence CI= 108.4/ 10,000 person- years CI= 97.1/10,000 person- years RR=1.12 ( ) Key: ARR: Absolute risk reduction ARI: Absolute risk increase CI: Cumulative incidence MR: Mortality ratio NND: number of cancers needed to detect NNI: number needed to invite to Prostate cancer screening RD = Risk difference 41

30 Table 5: Meta-analyses: Comparison of prostate cancer-specific mortality meta-analyses previously reported in 2011 with subsequently calculated meta-analyses incorporating 2012 ERSPC and PLCO trial results Evidence N Fixed effects-mh weighting Existing evidence (pre-2012) Random effects-iv weighting (Not published) ERSPC+PLCO 258, ( ) 0.93 ( ) (low RoB) Norrkoping + Quebec + Stockholm 82, ( ) 1.05 ( ) (high RoB) All existing evidence (5 studies) 341, ( ) 0.95 ( ) Updated evidence (2012 ERSPC, PLCO updates) ERSPC a +PLCO 238, ( ) 0.92 ( ) All 5 studies including updated results 321, ( ) 0.97 ( ) a Includes core ages for ERSPC (55-69 yrs) 42

31 Figure 3: Meta-analysis of 2012 ERSPC+PLCO results only: (a) random effects; (b) fixed effects (a) ERSPC+PLCO Prostate cancer mortality Random effects IV weighting 43

32 (b) ERSPC+PLCO Prostate cancer mortality Fixed effects MH weighting 44

33 Figure 4: All studies of Prostate cancer screening, incorporating updated ERSPC & PLCO results: (a) random effects; (b) fixed effects (a) Random effects IV weighting 45

34 (b) Fixed effects MH weighting 46

35 Figure 5: All-cause mortality with updated ERSPC results 47