ࡱ>   | } ~  5@ l~ bjbj22 O XX- OMBBB L LLLPXXXPAfP jp ~y|~~~~~~$R۹LD4 DP"XXj,KCCCHX8C|CCD$MX"4|m X r(0hn&a0jٺ|ٺL|mPPXXXXٺL|m ~ v C, 6 ~ ~ ~PPyd23lPPSystematic Evidence Review Number 16 Screening for Prostate Cancer Agency for Healthcare Research and Quality www.ahrq.gov  SEQ CHAPTER \h \r 1This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.  SEQ CHAPTER \h \r 1AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakerspatients and clinicians, health system leaders, and policymakersmake more informed decisions and improve the quality of health care services. Systematic Evidence Review Number 16 Screening for Prostate Cancer Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 2101 East Jefferson Street Rockville, MD 20852  HYPERLINK "http://www.ahrq.gov" http://www.ahrq.gov Contract No. 290-97-0011 Task No. 3 Technical Support of the U.S. Preventive Services Task Force Prepared by: Research Triangle Institute/University of North Carolina 3040 Cornwallis Road PO Box 12194 Research Triangle Park, NC 27709 Russell Harris, MD, MPH Kathleen N. Lohr, PhD Rainer Beck, MD Kenneth Fink, MD Paul Godley, MD, MPH Audrina J. Bunton, BA October 2002 Preface The Agency for Healthcare Research and Quality (AHRQ) sponsors the development of Systematic Evidence Reviews (SERs) through its Evidence-based Practice Program. With guidance from the third U.S. Preventive Services Task Force( (USPSTF) and input from Federal partners and primary care specialty societies, two Evidence-based Practice Centersone at the Oregon Health Sciences University and the other at Research Triangle Institute-University of North Carolinasystematically review the evidence of the effectiveness of a wide range of clinical preventive services, including screening, counseling, immunizations, and chemoprevention, in the primary care setting. The SERscomprehensive reviews of the scientific evidence on the effectiveness of particular clinical preventive servicesserve as the foundation for the recommendations of the third USPSTF, which provide age- and risk-factor-specific recommendations for the delivery of these services in the primary care setting. Details of the process of identifying and evaluating relevant scientific evidence are described in the Methods section of each SER. The SERs document the evidence regarding the benefits, limitations, and cost-effectiveness of a broad range of clinical preventive services and will help to further awareness, delivery, and coverage of preventive care as an integral part of quality primary health care. AHRQ also disseminates the SERs on the AHRQ Web site ( HYPERLINK http://www.ahrq.gov/uspstfix.htm http://www.ahrq.gov/uspstfix.htm) and disseminates summaries of the evidence (summaries of the SERs) and recommendations of the third USPSTF in print and on the Web. These are available through the AHRQ Web site ( HYPERLINK http://www.ahrgq.gov/uspstfix.htm) http://www.ahrgq.gov/uspstfix.htm), through the National Guideline Clearinghouse ( HYPERLINK http://www.ncg.gov) http://www.ncg.gov), and in print through the AHRQ Publications Clearinghouse (1-800-358-9295). We welcome written comments on this SER. Comments may be sent to: Director, Center for Practice and Technology Assessment, Agency for Healthcare Research and Quality, 6010 Executive Blvd., Suite 300, Rockville, MD 20852. Carolyn Clancy, M.D. Robert Graham, M.D. Acting Director Director, Center for Practice and Agency for Healthcare Reseach and Quality Technology Assessment Agency for Healthcare Research and Quality The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service. Structured Abstract Context More than 31,000 men were expected to die from prostate cancer in 2001. Researchers and the public have given most attention for controlling prostate cancer to screening. No well-conducted randomized controlled trial (RCT) of screening has been completed. We are thus left with examining indirect evidence to determine the efficacy of screening for reducing prostate cancer mortality. Objective To examine the evidence of the benefits and harms of screening and earlier treatment in reducing prostate cancer mortality and to assist the US Preventive Services Task Force in making recommendations on this topic. Data Sources We first developed an analytic framework and 9 key questions that represent the logical chain between screening and reduced mortality. We then systematically searched MEDLINE from January 1994 to September 15, 2002, using the Medical Subject Heading prostate neoplasms and combining this term with predefined strategies to identify English language studies concerning the 9 key questions. We also searched the Cochrane Library, contacted experts, and scanned review bibliographies. Study Selection We examined abstracts and full articles of all identified studies to determine whether they met preset inclusion and exclusion criteria for each key question. We selected studies that met the following inclusion criteria: (1) randomized controlled trials (RCTs), case-control studies, and ecologic studies that examined links between screening and reduced mortality, (2) studies that addressed the accuracy, reliability, and yield of screening tests by applying the test and a reference standard uniformly to a defined population; (3) RCTs with clinical outcomes for treatment questions; (4) studies of patient reports about their experience with screening or various treatments; and (5) studies that examined or modeled the costs and benefits of screening. For key questions about treatment, we required RCTs with clinical outcomes. We graded the quality of all included articles according to criteria established by the USPSTF. Data Extraction Members of the study team abstracted relevant information from included studies and entered it into established abstraction forms. The first author checked all abstractions against the original papers. Data Synthesis No conclusive direct evidence shows that screening reduces mortality from prostate cancer. Although we could not precisely determine the sensitivity and specificity of screening with prostate-specific antigen (PSA) and digital rectal examination (DRE), research is clear that these tests can detect prostate cancer at an earlier stage than clinical detection. Because of the heterogeneity in the natural history of prostate cancer, we could not determine how many screen-detected cancers would eventually become clinically important. The efficacy of treatment for clinically localized prostate cancer detected by screening with any of the currently used approaches is unknown. Each treatment is associated with several well-documented potential harms. The cost of a national screening program is potentially large. Modeling studies show that men ages 50 to 69 years could receive benefit at reasonable cost from screening under favorable assumptions about the efficacy of earlier treatment. These studies do not adjust for the potential harms of screening. Given the current strategy for screening, men with a life expectancy of less than 10 years are unlikely to benefit even under favorable assumptions. Conclusions We are unable to determine the net benefit of screening because we cannot establish the presence and, if present, the magnitude of benefit from screening. We can establish the presence of potential harms. Table of Contents Structured Abstract vi List of Figures and Tables xi I. Introduction 1 Background 1 Burden of Suffering 2 Epidemiology 4 Difference Between Incidence and Mortality 4 Risk Factors 4 Screening Tools 5 Treatment Modalities 6 Staging and Histologic Grading 6 Focus of this Review 8 II. Methods 10 Analytic Framework and Key Questions 10 Eligibility Criteria for Admissible Evidence 11 Literature Search Strategy and Synthesis 12 Development of the Final Systematic Evidence Review 13 III. Results 18 Key Question 1: Efficacy of Screening in Reducing Mortality from Prostate Cancer 18 Randomized Controlled Trial 19 Case-Control Studies 20 Ecologic Data 22 Summary of Results on Efficacy of Screening 26 Key Question 2: Yield of Screening for Prostate Cancer 26 Methodologic Issues 27 Reference Standard 30 Accuracy of Screening 31 Screening with PSA 32 Screening with Variations on the PSA 34 Screening with DRE 36 Studies of the Yield of Large Screening Programs 37 Variation in Yield with Different Screening Intervals 42 Summary: Yield of Screening 43 Key Question 3: Harms of Screening 45 Psychological Effects of Screening 45 Physical Effects of Screening 46 Summary: Harms of Screening 47 Key Question 4 to 7: Efficacy of Treatment 47 General Approach 47 Key Question 4: Efficacy of Treatment with Radical Prostatectomy 48 Randomized Controlled Trials 48 Observational Studies 50 Summary of Efficacy of Treatment with Radical Prostatectomy 51 Key Question 5: Efficacy of Treatment with Radiation 52 External Beam Radiation Therapy 53 Randomized Controlled Trials 53 Observational Studies 53 Summary of Efficacy of External Beam Radiation Therapy 54 Brachytherapy 55 Summary of Efficacy of Brachytherapy 55 Key Question 6: Efficacy of Treatment with Androgen Deprivation 56 Randomized Controlled Trials 56 Summary of ADT Efficacy 58 Key Question 7: Efficacy of Treatment with Watchful Waiting 58 Randomized Controlled Trials 59 Observational Studies 59 Summary: Efficacy of Treatment with Watchful Waiting 62 Summary: Efficacy of Treatment 63 Key Question 8: Harms of Treatment 64 Radical Prostatectomy 66 Erectile Dysfunction 66 Summary: Erectile Dysfunction after Radical Prostatectomy 68 Urinary Incontinence 68 Summary: Urinary Dysfunction after Radical Prostatectomy 70 Harms of External Beam Radiation Therapy 70 Erectile dysfunction 70 Summary of Erectile Dysfunction from External Beam Radiation Therapy 71 Urinary Incontinence 71 Summary of Urinary Dysfunction from External Beam Radiation Therapy 72 Bowel Dysfunction 72 Summary of Bowel Dysfunction from External Beam Radiation Therapy 73 Harms of Brachytherapy 73 Summary of Harms from Brachytherapy 75 Harms of Androgen Deprivation Therapy 76 Summary of Harms from Androgen Deprivation Therapy 77 Summary for Key Question 8: Harms of Therapy 78 Key Question 9: Costs and Cost-Effectiveness of Screening 78 IV. Discussion 81 Context 81 Major Findings and Limitations of the Literature 81 Benefits and Harms 82 Future Research Needs 84 References 86  TOC \h \z \c "Appendix"  HYPERLINK \l "_Toc515190790" Appendix A. Acknowledgements  PAGEREF _Toc515190790 \h 106  HYPERLINK \l "_Toc515190791" Appendix B. Evidence Tables  PAGEREF _Toc515190791 \h 109  List of Figures and Tables  TOC \h \z \c "Figure"  HYPERLINK \l "_Toc515189932" Figure 1. Analytic Framework for Screening for Prostate Cancer  PAGEREF _Toc515189932 \h 15  HYPERLINK \l "_Toc515189933" Figure 2. Ages 50-59 estimated yield of screening with PSA (or PSA and DRE) 38 PAGEREF _Toc515189933 \h Error! Bookmark not defined. Figure 3. Ages 60-69 - estimated yield of screening with PSA (or PSA and DRE) 39 Figure 4. Ages 70-79 estimated yield of screening with PSA (or PSA and DRE)....40  TOC \h \z \c "Table"  HYPERLINK \l "_Toc515190917" Table 1. Staging Systems for Prostate Cancer  PAGEREF _Toc515190917 \h 9 Table 2. Inclusion Criteria, Search Strategy, and Results of Searches 16 Table 3. Harms of treatment 65 I. Introduction Background Prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer death in US men. Although several studies are exploring the potential of primary prevention of this disease, primary care clinical practice is currently dealing with great public interest in screening. Screening for prostate cancer is a controversial topic. Those in favor of screening point to the lack of symptoms in early stage disease, the higher 5-year relative survival for localized (greater than 99%) compared with distant (less than 40%) cancer, and the fact that screening increases the proportion of cancers detected at an early stage. QUOTE "1"  ADDIN PROCITE \11\05\19\02\00\00\00\011\01\01\00\01\00\00\01\00\00\00\1BM_\01\00\00\00,\00p\03\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\07\00\00 5% resected tissue. Moderately or poorly differentiated grade with < 5% resected tissue from TURP.B0T1cCancer detected by needle biopsy (e.g., following elevated PSA).2. Palpable cancers apparently confined within prostate capsuleB1T2aInvolves one-half of one lobe of the prostate or less.B1T2bInvolves more than one-half of one lobe, but not both lobes.B2T2cInvolves both lobes of gland but apparently confined (B2, but not T2c cancers can be greater than 1.5 cm but still involve only one lobe.3. Local extra-capsular penetrationC1T3a-3bPenetration of the prostate capsule palpable without evidence of invasion of the seminal vesicles outside the prostate.C2T3c aT4a-4bPalpable invasion of seminal vesicle. Invasion of the bladder neck, external sphincter, rectum, or pelvic muscles.4. Metastatic DiseaseD1NxCannot assess; no apparent nodal involvementN1 N2 N3Metastasis in a single lymph node 2 cm, metastasis single nodes 2-5 cm, or multiple nodes (all e" 5 cm), metastasis in node e" 5 cm.D2M1Distant metastasis.M1aLymph nodes outside the region of the prostateM1bBone.M1cOther site(s). * In the TNM system,  T refers to characteristics of the tumor,  N refers to the extent cancerous cells are found in lymph nodes, and M refers to the extent of metastasis (spread of the cancer). PSA indicates prostate-specific antigen blood test; TURP, Transurethral resection of the prostate, a procedure for treating benign prostatic hypertrophy (BPH), a noncancerous enlargement of the prostate, by surgically removing parts of the gland. SOURCE: Office of Technology Assessment, 1995. Based on information presented in M.J. Barry, C.M. Coley, C. Fleming, et.al, The Safety, Effectiveness, and Cost of Early Detection and Treatment of Prostate Cancer Among Older Men: A Report to the Congressional Office of Technology Assessment. QUOTE "13"  ADDIN PROCITE \11\05 \19\02\00\00\00\0213\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\1D\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\07\00\00x\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\05\00\00x\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\02\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt!Catalona, Ramos, et al. 2000 #370\00!\00 69,72 QUOTE ""  ADDIN PROCITE \11\05\19\02\00\00\00\00\01\00\00\0D\04\00\00x\00\01\00\00\00\01\00\00\00\00\00\00\00hI_<\00\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt%Beemsterboer, Kranse, et al. 1999 #20\00%\00 79 the PSAD test has fallen out of favor as a primary screening test. Percent free PSA (%fPSA). In the serum, PSA circulates in 2 forms: free and complexed with such molecules as alpha-1 antichymotrysin. Men with prostate cancer tend to have a lower percentage of their PSA in the free form compared with men without prostate cancer. QUOTE "80,81"  ADDIN PROCITE \11\05 \19\02\00\00\00\0580,81\01\01\00\05\00\00\01\00\00\00\1BM_\01\00\00\00L"!\00\00=x\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\06\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt"Stenman, Hakama, et al. 1994 #7550\00"\00 80,81 QUOTE ""  ADDIN PROCITE \11\05\19\02\00\00\00\00\01\00\00\07\00\00x\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\04\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt#Mettlin, Chesley, et al. 1999 #2020\00#\00 82 to 30%. QUOTE "83"  ADDIN PROCITE \11\05 \19\02\00\00\00\0283\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00=x\00\01\00\00\00\01\00\00\00\00\00\00\00hI_~\05\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt#Catalona, Beiser, et al. 1997 #3840\00#\00 83 Several studies have examined the %fPSA test. Its major use in research has been to increase the specificity of screening by distinguishing between men with PSA between 4.0 ng/ml and 9.9 ng/ml who should be biopsied and those who should not. Using various cutpoints, from 20% to 40% of biopsies could potentially be avoided, although 2% to 15% of cancers would then be missed. QUOTE "82,84-88"  ADDIN PROCITE \11\05 \19\02\00\00\00\0882,84-88\01\01\00\08\00\00\01\00\00\00\1BM_\01\00\00\00\11"!\00 ;x\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\04\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt#Mettlin, Chesley, et al. 1999 #2020\00#\00 82,84-88 QUOTE ""  ADDIN PROCITE \11\05\19\02\00\00\00\00\01\00\00<\05\00\00\03\00\00\03\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt!Beard, Propert, et al. 1997 #4870\00!\00 178 Two other studies used a single questionnaire after EBRT to assess sexual function. Each found that about 50% of men had erections inadequate for intercourse. QUOTE "166,167"  ADDIN PROCITE \11\05\19\02\00\00\00\07166,167\01\01\00\07\00\00\01\00\00\00\1BM_\01\00\00\00"\00\00'\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\19\03\00\00\03\00\00\03\00\00\03\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt!Beard, Propert, et al. 1997 #4870\00!\00 178 Two studies surveyed men about bowel function at least 1 year after having EBRT.  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Widmark A, Fransson P, Tavelin B. Self-assessment questionnaire for evaluating urinary and intestinal late side effects after pelvic radiotherapy in patients with prostate cancer compared with an age-matched control population. Cancer. 1994;74:2520-2532. 181. Nguyen LN, Pollack A, Zagars GK. Late effects after radiotherapy for prostate cancer in a randomized dose-response study: results of a self-assessment questionnaire. Urology. 1998;51:991-997. 182. Dearnaley DP, Khoo VS, Norman AR, et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet. 1999;353:267-272. 183. Lee WR, McQuellon RP, Harris-Henderson K, Case LD, McCullough DL. A preliminary analysis of health-related quality of life in the first year after permanent source interstitial brachytherapy (PIB) for clinically localized prostate cancer. Intl J Rad Oncol Biol Phys. 2000;46:77-81. 184. Stock RG, Kao J, Stone NN. 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Sexuality after treatment for early prostate cancer: exploring the meanings of "erectile dysfunction". J Gen Intern Med. 2001;16:649-655. 199. Barry MJ, Fleming C, Coley CM, Wasson JH, Fahs MC, Oesterling JE. Should Medicare provide reimbursement for prostate-specific antigen testing for early detection of prostate cancer? Part IV: Estimating the risks and benefits of an early detection program. Urology. 1995;46:445-61. 200. Lubke W.L., Optenberg S.A., Thompson I.M. Analysis of the First-Year Cost of a Prostate Cancer Screening and Treatment Program in the United States. J Natl Cancer Inst. 1994;86:1790-1792. 201. Fleming C, Wasson JH, Albertsen PC, Barry MJ, Wennberg JE. A decision analysis of alternative treatment strategies for clinically localized prostate cancer. Prostate Patient Outcomes Research Team. JAMA. 1993;269:2650-2658. 202. Krahn MD, Mahoney JE, Eckman MH, Trachtenberg J, Pauker SG, Detsky AS. Screening for prostate cancer. A decision analytic view. JAMA. 1994;272:773-780. 203. Kattan MW, Cowen ME, Miles BJ. A decision analysis for treatment of clinically localized prostate cancer. J Gen Intern Med. 1997;12:299-305. 204. Coley CM, Barry MJ, Fleming C, Fahs MC, Mulley AG. Early detection of prostate cancer. Part II: Estimating the risks, benefits, and costs. American College of Physicians. Ann Int Med. 1997;126:468-479. 205. Oliver SE, May MT, Gunnell D. International trends in prostate-cancer mortality in the "PSA ERA". Int J Cancer. 2001;92:893-898. 206. Furuya Y, Akakura K, Akimoto S, Ichikawa T, Ito H. Radiotherapy for local progression in patients with hormone-refractory prostate cancer. Intl J Urol. 1999;6:187-191. 207. Schmidt JD, Gibbons RP, Murphy GP, Bartolucci A. Adjuvant therapy for clinical localized prostate cancer treated with surgery or irradiation. Eur Urol. 1996;29:425-433. 208. Bratt O, Elfving P, Flodgren P, Lundgren R. Morbidity of pelvic lymphadenectomy, radical retropubic prostatectomy and external radiotherapy in patients with localised prostatic cancer. Scand J Urol Nephrol. 1994;28:265-271. 209. Badalament RA, Bahn DK, Kim H, Kumar A, Bahn JM, Lee F. Patient-reported complications after cryoablation therapy for prostate cancer. Urology. 1999;54:295-300. 210. Barry MJ, Fleming C, Coley CM, Wasson JH, Fahs MC, Oesterling JE. Should Medicare provide reimbursement for prostate-specific antigen testing for early detection of prostate cancer? Part III: Management strategies and outcomes. Urology. 1995;46:277-289. 211. Kattan MW, Stapleton AM, Wheeler TM, Scardino PT. Evaluation of a nomogram used to predict the pathologic stage of clinically localized prostate carcinoma. Cancer. 1997;79:528-537. Appendix A Acknowledgements Acknowledgements This study was supported by Contract 290-97-0011 from the Agency of Healthcare Research and Quality (Task No. 3). We acknowledge at AHRQ the continuing support of Jacqueline Besteman, J.D., M.A., Director of the AHRQ Evidence-based Practice Center Program and David Atkins, M.D., M.P.H., Director of the Clinical Prevention Program for the US Preventive Services Task Force. We especially want to thank our USPSTF liaisons: Cynthia D. Mulrow, M.D., M.P.H., University of Texas at San Antonio, San Antonio, TX; Paul S. Frame, M.D., Tri-County Family Medicine, Cohocton, New York, and Albert Siu, M.D., M.S.P.H., The Mount Sinai Medical Center, New York, NY. The investigators deeply appreciate the considerable support and contributions of staff of Research Triangle Institute, including Linda Lux, M.P.A., and Sonya Sutton, B.S.P.H., for substantive and editorial work on this systematic review, and Loraine Monroe, for superior secretarial assistance. In addition, we are indebted to staff from the University of North Carolina at Chapel Hill and the Cecil G. Sheps Center for Health Services Research, including Timothy S. Carey, M.D., M.P.H., Director of the Sheps Center and Co-Director of the RTI-UNC Evidence-based Practice Center; Anne Jackman, M.S.W., Lynn Whitener, M.S.L.S., Dr.P.H., and Carol Krasnov. We also owe our thanks to our external peer reviewers, who provided constructive feedback and insightful suggestions for improvement of this systematic evidence review: Michael Barry, M.D., Massachusetts General Hospital, Boston, MA; Barry Kramer, Journal of the National Cancer Institute, Baltimore, MD; Richard Hoffman, M.D., M.P.H., Albuquerque VA Medical Center, Albuquerque, NM; Curtis Mettlin, M.D., Roswell Park Cancer Institute, Buffalo, NY; Marc B. Garnick, M.D., Beth Israel Deaconess Medical Center, Boston, MA; David Lush, M.D., Medical College of Pennsylvania Hospital, Philadelphia, PA; Theodore Geniats, M.D., University of California, San Diego, La Jolla, CA; Ian M. Thompson, M.D., University of Texas Health Sciences Center at San Antonio, San Antonio, TX; and John W. Freightner, M.D., M.Sc., F.C.F.P, Canadian Task Force on Preventive Health Care, London, Ontario, Canada. Appendix B. Evidence Tables Appendix B. Evidence table glossary Abbr.Definition+PositiveADTApparent diffusion tensorAggAggressiveAPCAnnual percent changeAUCArea under ROC curveAvAverageBPHBenign prostatic hyperplasiaBxBiopsyCaCancerCIConfidence IntervalCTComputerized tomographyDESDiethylstilbestrolDiffDifferenceDREDigital rectal examinationDxedDiagnosedEBRTExternal beam radiation therapyEndptsEndpointsERSPCEuropean Randomized Study of Screening for Prostate CancerF/UFollow-upFxnFunctionGyGrayHRQolHealth-related quality of lifeIVPIntravenous pyelogramLHRHLuteinizing hormone-releasing hormoneLRLikelihood ratioLUTSLower urinary tract symptomsm-yMonths-yearsMRIMagnetic resonance imagingMosMonthsNCHSNational Center for Health StatisticsNonaggNon-aggressiveNsNot statistically significantOROdds RatioPCProstate CancerPFSProgression free survivalQALYQuality adjusted life yearOROdds ratioQolQuality of lifePProbabilityPCProstate cancerPPVPositive predictive valuePSAProstate specific antigenRadRadiationRandRandomizationRCTRandomized controlled trialROCReceiver operator characteristicRPRadical prostatectomySEERSurveillance, Epidemiology, and End Results ProgramStdStandardTRUSTransrectal ultrasoundTURPTransurethral resection of the prostateTxTreatmentUCLAUniversity of California at Los AngelesUSUnited StatesWWWatchful WaitingXRTRadiation therapyYrsYears Evidence Table 1A: Health outcomes of screening in reducing mortality RCTs (Key Question 1) CitationStudy Population SelectionStudy Population DescriptionInterventionResultsCommentsDesignLabrie F et al., 1999 QUOTE "20"  ADDIN PROCITE \11\05 \19\02\00\00\00\0220\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@Zx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_@\00\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt\1FLabrie, Candas, et al. 1999 #60\00\1F\00 20Men registered in the 1985 electoral rolls of Quebec City were randomized to screening or no screening Study conducted from 1/1/89 through 12/31/9646,173 men aged 45-80 years 30,956 invited to be screened; 7,155 (23%) screened; Av age 60+/-7 Of 15,237 controls, 14,255 (93.6%) were not screened; Av age 58+/-9Screening by PSA and DRE PSA cutpoint >3.0 ng/ml Screen test positive had TRUS and biopsyPrimary outcome was death from prostate cancer as recorded in the death registry of the province health dept. In the screened group, (including all screened men from both groups) the death rate was 13.7/105 m-y. In the unscreened group, the death rate was 41.6/10105 m-y The authors conclude that screening resulted in a 67% reduction in death rate incidence No sociodemographic comparison of the two groups was presented Men in the screened group were followed an av 3.8 years; whereas men in the control group were followed an av 7.4 years The death rates from other causes for the two groups were not presented or compared No intention to treat analysis Quality: poor Evidence Table 1B: Health outcomes of screening, case-control studies (Key Question 1) CitationCasesControlsMeasurements (exposure, confounders)ResultsCommentsJacobsen SJ et al., 1998 QUOTE "23"  ADDIN PROCITE \11\05 \19\02\00\00\00\0223\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\00Zx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_ \07\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt'Jacobsen, Bergstralh, et al. 1998 #9910\00'\00 23 Population-based case-control Study of DRE and PC mortality Olmstead County, MN StudyN=173 Men with PC on death certificate between 1976 and 1991, verified by chart review (116 had PC listed as immediate or underlying cause of death)N=346 2 men with registration numbers closest to each case, matched to date of birth and duration of medical record (all cases and controls in Olmsted County database) Reviewed medical records for 10 years before index (diagnosis) date for evidence of DRE and findings from DRE Also abstracted obstructive urologic symptoms and comorbidity score (reliability high) Controls more likely to have had DRE in years 2-10 before index year than cases: OR=0.51 (0.31-0.84) OR=0.53 (0.32-1.06) if cases restricted to those with PC as immediate or underlying cause of death OR=0.31 in men without urologic symptoms Results not changed by comorbidity score adjustment For only DRE in years 1-3, OR=0.76 If had DRE in years 4-6, no association for DRE in years 1-3 (OR=1.11)Alternative explanation: healthy screenee bias, men being screened may have had lower probability of dying of PC Could have missed DREs not recorded in medical record Study occurred before widespread PSA screening Disagreement about excluding DREs in the year before diagnosis Quality: goodRichert-Boe KE et al., 1998 QUOTE "22"  ADDIN PROCITE \11\05\19\02\00\00\00\0222\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00Yx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_" \07\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt(Richert-Boe, Humphrey, et al. 1998 #9900\00(\00 22 Matched case-control study among patients at Kaiser NorthwestN=150 Men who died from PC between 1981-1990, age 40-84 when PC diagnosed, members of plan for at least 2 years, verified by chart review Excluded men whose death not due to PC N=299 2 controls randomly selected from Kaiser members, matched according to age and entry into health plan Medical record review of all DREs between enrollment in plan and index date (date of diagnosis of case) Findings of DRE and urologic symptoms also recorded Blinded reviewer categorized each DRE as screening or due to any of several symptoms Analyzed only screening DREs Reliability highAbout half of fatal PCs were poorly differentiated, and half were stage D at diagnosis 77% of cases and 80% of controls had had a screening DRE during the 10yrs ending just before index date (OR=0.84; 0.48-1.46)Study done before widespread PSA screening Could not adjust for family history No analysis reported for all DRE Only 58% of case subjects and 12% of controls with suspicious findings on DRE went on to have a biopsy Quality: good Evidence Table 1C: Health outcomes for screening, ecologic studies (Key Question 1) CitationStudy PopulationMeasurementsResultsCommentsDesignSelectionDescriptionEtzioni R et al.. 1999 QUOTE "33"  ADDIN PROCITE \11\05\19\02\00\00\00\0233\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 Yx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\07\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt"Etzioni, Legler, et al. 1999 #9930\00"\00 33 7 year population-based cohort (computer simulation model)US lifetables SEER dataMedicare population from 1988-1994 QUOTE "34"  ADDIN PROCITE \11\05 \19\02\00\00\00\0234\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@Yx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\04\00\0080% of men with abnormal test had biopsy Treatments primarily RP or EBRT No mass screening program in rest of Austria Dramatic increase in incidence of PC in Tyrol, 1988-92 No information on incidence in rest of country PC mortality decreased in Tyrol (1993-1999) more than rest of country (p=0.0004)Because we have no information about screening in rest of country, and because we have no comparison of treatment Quality: fairOliver, SE et al. 2001 QUOTE "205"  ADDIN PROCITE \11\05\19\02\00\00\00\03205\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00Wx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\07\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt\1DOliver, May, et al. 2001 #202\00\1D\00 205 Ecologic StudyPopulation dataMale residents of England, Wales, and USA PSA screening is less common and even discouraged in UKPC incidence and mortality from 1970-97 More screening in USA than UKMuch larger increase in incidence in USA compared to UK from 1989-92, then a larger decline in USA Mortality was higher in USA until 1985, when mortality was same in the 2 countries Since 1993, mortality higher in UK Decline in mortality in USA 1993-97 was 3.8% compared with 1.7% in UK (statistically significant)Because mortality declined in both countries after 1993, authors suggest cause may be disease management Quality: good Evidence Table 2A: Yield of screening (Key Question 2) CitationParticipantsScreening Test and Gold StandardResultsCommentsGann PH et al., 1995 QUOTE "35"  ADDIN PROCITE \11\05\19\02\00\00\00\0235\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 Wx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\06\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt"Gann, Hennekens, et al. 1995 #7360\00"\00 35Nested case-control study 22,071 physicians between ages 40 and 84 in 1982 520 cases of PC were reported by 1992 366 of the cases of PC and supplied a blood sample For each PC case, selected 3 controlsPSA (e"4.0) Gold std: follow-up x10 yrs.Follow-up 1 yr. 2-3 yrs. 3-4 yrs. Agg.-nonagg Agg.-nonaggSensitivity 100%-56% 92%-67% 73%-33% Specificity 83% 86% 98%Aggressive Cancers = stage C or D (i.e., extracapsular) + Gleason 7 or higher Of 366 total PCs, 183 (50%) classified as aggressive Quality: goodOverall detected in 0-5 yrs. 73% 50% 88% Area under ROC curve for cancers diagnosed in 5 yrs: 0.85 Av lead time: 5.5 yrs.Meigs, JB, Barry MJ et al., 1996 QUOTE "60"  ADDIN PROCITE \11\05 \19\02\00\00\00\0260\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@Wx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\0A\06\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt\1FMeigs, Barry, et al. 1996 #5240\00\1F\00 60 Men with organ-confined PC (N=276) Unselected men from the community who were not found to have PC by screening and biopsy of positive screens (N=305) Men with LUTS and BPH coming to prostatectomy (and were found not to have PC) (N=173) Men with BPH enrolled in the North American finasteride trial (N=770)PSA test Biopsy is gold standardOverall LR+ for men with PSA 4.1-6.0 = 3.4 for unselected men and 1.4 for men with BPH Men with LUTS had lower LR+ than men without LUTS In cancer group, 39.2% of men with organ-confined PC and PSA < 4.0Quality: good Evidence Table 2B: Yield of screening, studies of screening programs (Key Question 2) CitationPopulationTest Abnormals (% of Screened)Biopsies % ScreenedCancers % Screened % BiopsiesStaging, GradingScreened, Participation Rate, AgeMartin E et al., 1999 QUOTE "105"  ADDIN PROCITE \11\05 \19\02\00\00\00\03105\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\00Wx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\04\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt Martin, Lujan, et al. 1999 #1940\00 \00 105 N=2,576 screened 18% participation Men ages 50+ City in Spain DRE: (3.6%) PSA>4: (6.5%) One or other: (8.7%) % abnormal screens: Ages 50-55 (3.3%) Ages 66-70 (17.0%)225 (8.7%) Ages 50-54: 3.3% Ages 66-70: 17.0%Overall 33: Screened: 1.3% Biopsies: 14.7% Ages 50-54: Screened: 0-2% Biopsies: 6.1% Ages 66-70: Screened: 2.4% Biopsies: 14.3%Clinically: 60.6% organ confined 12.1% Metastatic Histologically: 67% Well differentiated 27% Moderate 6% Poor Quality: goodHorninger W et al., 2000 QUOTE "104"  ADDIN PROCITE \11\05 \19\02\00\00\00\03104\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00Vx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\02\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt&Horninger, Reissigl, et al. 2000 #9160\00&\00 104N=21,078 screened 32% participation Men 45-75 Living in TyrolPSA, age referenced standard: 1618 abnormal (7.7%) PSA>4: 8.9%778 (48.1% of positive test) (3.7% of screened) Biopsies/screened: Ages 50-59: 1.5% Ages 70-75: 11%197 Screened: 1.2% Biopsies: 25.3% Ages 50-59: Screened: 0.3% Biopsies: 19.7% Ages 70-75: Screened: 3.0% Biopsies: 27.5%135 (68.5%) of all cancers had RP 95 (70.4%) path organ confined Quality: good Evidence Table 2B: Yield of screening, studies of screening programs (Key Question 2) (continued) CitationPopulationTest Abnormals (% of Screened)Biopsies (% Screened)Cancers (% Screened) (% Biopsies)Staging, GradingScreened, Participation Rate, AgeMaattanen L et al., 1999 QUOTE "102"  ADDIN PROCITE \11\05 \19\02\00\00\00\03102\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 Vx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_?\00\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt#Maattanen, Auvinen, et al. 1999 #50\00#\00 102N=15,685 screened (69% participation) Ages 55-67PSA e"4.0: 1342 (8.6%) PSA 3-3.9: ~15% had +DRE (DRE only given to men with PSA 3-3.9) PSA 3-3.9: 801 (5.1%) of all men1,236 biopsies (7.9% screened) from abnormal PSAPSA e"4.0: 386 cancers Screened: (2.5%) Biopsies: (29%) 22 additional cancers from DRE in men with PSA 3-3.9: Screened: (2.7%) Biopsies: (~18%)84% of cancers Gleason 2-6 16% Gleason 7-10 No staging data given Quality: goodSchroder, F et al., 2000 QUOTE "43"  ADDIN PROCITE \11\05 \19\02\00\00\00\0243\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@Vx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\5C\04\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt3Schroder, van der Cruijsen-Koeter, et al. 2000 #910\003\00 43N=10,523 screened (uncertain participation) Ages 55-74 Living in Rotterdam PSA e"4.0: 1312 (12.5%) PSA e"4.0 +DRE+TRUS: biopsied any abnormality2,499 total biopsies (23.7%) PSA e" 4.0: 1,184 (47%) PSA< 4.0: 1,315 (52.6%) due to DRE or TRUS 478 total cancers found: Screened: (4.5%) Biopsies: (19%) 351 due to PSA e" 4.0 Screened: (3.3%) Biopsies: (29.6%) PSA<4.0: 127 due to DRE/TRUS: Screened with PSA<4.0: (1.4%) Biopsies: (9.7%)166 (34.7%) patients with cancers had RP PSA e" 4.0: 116 cancers 44% Gleason 4-6 51.7% Gleason 7 4.3% Gleason 8-10 68% organ confined 9.7% overall pathologically metastatic Quality: good Evidence Table 2B: Yield of screening, studies of screening programs (Key Question 2) (continued) CitationPopulationTest Abnormals (% of Screened)Biopsies (% Screened)Cancers (% Screened) (% Biopsies)Staging, GradingScreened, Age, Participation RateLabrie F et al., 1992 QUOTE "67"  ADDIN PROCITE \11\05\19\02\00\00\00\0267\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\00Vx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\05\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt'Labrie F., DuPont A., et al. 1992 #9320\00'\00 67 Labrie F et al., 1993 QUOTE "106"  ADDIN PROCITE \11\05 \19\02\00\00\00\03106\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00Ux\00\01\00\00\00\01\00\00\00\00\00\00\00hI_:\07\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt%Labrie F, Dupont A, et al. 1993 #8280\00%\00 106 Labrie F et al., 1999 QUOTE "20"  ADDIN PROCITE \11\05 \19\02\00\00\00\0220\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 Ux\00\01\00\00\00\01\00\00\00\00\00\00\00hI_@\00\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt\1FLabrie, Candas, et al. 1999 #60\00\1F\00 20 Labrie F et al., 1996 QUOTE "103"  ADDIN PROCITE \11\05 \19\02\00\00\00\03103\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@Ux\00\01\00\00\00\01\00\00\00\00\00\00\00hI_K\00\00\003.0) and DRE 1451 PSA >3.0 19.7% of screened761 biopsies (10.4% of screened)252 Cancers 222 (88%)found by PSA >3.0 and 119 (47%) by DRE Screened: 3.4% Biopsies: 33% (17.4% of abnormal tests) Of 222 cancers found by PSA > 3.0 Screened: 3.0% (2.5% age 55-60; 6.9% age 65-70) Of 119 found by DRE Screened: 1.6% 196 cancers found in men with PSA >4.0 Screened: 2.7%Of 228 cancers clinically staged, 70% organ confined; 10.5% metastatic Quality: goodCatalona, WJ et al., 1994 QUOTE "44"  ADDIN PROCITE \11\05\19\02\00\00\00\0244\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\00Ux\00\01\00\00\00\01\00\00\00\00\00\00\00hI_(\07\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt#Catalona, Richie, et al. 1994 #8100\00#\00 44 Richie JP et al., 1993 QUOTE "45"  ADDIN PROCITE \11\05 \19\02\00\00\00\0245\01\01\00\02\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00Tx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_~\06\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt-Richie J.P., Catalona W.J., et al. 1993 #9380\00-\00 45N= 6,630 men Ages 50+ from advertisements in 6 communitiesPSA>4.0: 983 Screened: 14.8% +DRE: 982 Screened: 14.8% Positive on at least one test: 1,710 (25.8%)1,167 biopsies: Screened: (17.6%) Abnormal: (68.2%) 686 biopsies due to PSA and 683 due to DRE264 cancers: Screened: (4.0%) Biopsies: (2.3%) Screened for PSA > 4.0: (3.3%) Screened for +DRE: (2.2%) Clinically, 99% cancers were organ confined 162 (61%) cancer patients had RP 71% pathologically organ confined No distant metastases beyond pelvic lymph nodes PSA>4.0 found 75% of organ confined cancers DRE found 56% of organ confined cancers Quality: good Evidence Table 3: Harms of screening (Key Question 3) CitationParticipantsMeasurementsResultsCommentsEssink-Bot, ML et al., 1998 QUOTE "116"  ADDIN PROCITE \11\05 \19\02\00\00\00\03116\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 Tx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\02\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt(Essink-Bot, de Koning, et al. 1998 #3060\00(\00 116Men ages 55-74 Initially: 600 participants in Rotterdam ERSPC, group invited to be screened Attrition to 541 after screening 235 of 500 non-participantsSF-36 EQ-5D, European quality of life instrument STAI to measure state and trait anxiety Visual analogue scale for overall health Pain and physical discomfort of screening DRE, TRUS, biopsy Limitations in week after biopsyNegative screening test group (pre to post test): Small improvement in mental health on SF-36 Decrease in anxiety False positive screening test group (pretest to post biopsy) Small improvements in bodily pain and general health perceptions Small decrease in anxiety Entire group Anxiety increased mostly in those with high trait anxiety DRE: 52% some discomfort/pain TRUS 39% some discomfort/pain Biopsy: 98% some discomfort/pain 4% used pain killers 4-6% interfered with functionHigh response rate from participant group Quality: good Evidence Table 4: Efficacy of treatment with radical prostatectomy (Key Question 4) CitationParticipantsMeasurementsInterventionResultsCommentsNumber/DescriptionAkakura et al., 1999123100 of 243 eligible men aged less than 75 years without obvious enlargement of pelvic nodes by CT or MR with newly diagnosed Stage B or C prostate cancer enrolled Between 1989 and 1993, eligible men recruited from 6 Japanese hospitals 5 of 100 excluded before randomization for other reasonsOutcomes were progression (local growth of tumor and/or appearance of distal metastasis) and cause-specific survival (death after progression was considered as cancer death)All participants received endocrine therapy for 8 weeks before RP or EBRT and were continued on it 46 men were randomized to receive RP with pelvic lymph node dissection; 49 men received EBRT4 (9%) in RP group and 12 (25%) in EBRT group developed disease progression. 5-year progression free survival was 91% in the RP group and 81% in the EBRT group (p=0.044); at 5 years, cause-specific survival was 97% in the surgery group and 85% in the XRT group (p=0.024) 5-year overall survival rate was 86% in the RP group and 76% in the EBRT group (p=Ns)Only 41% of those eligible enrolled Rising PSA not included as disease progression Patients were only followed for approximately 5 years Quality: good but smallIversen P et al., 1995 QUOTE "122"  ADDIN PROCITE \11\05 \19\02\00\00\00\03122\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\00Tx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_/\01\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt"Iversen, Madsen, et al. 1995 #1650\00"\00 122 RCT comparing RP plus oral placebo to oral placebo alone (i.e. expectant treatment).76 men aged 50-84 years (mean 65.9) with Stage A PC and 66 men aged 44-78 years (mean 62.3) with Stage B disease were enrolled From 15 VA hospitals between 1967-1975 18 men randomized to placebo only and 13 men randomized to RP not evaluable for follow up because they refused treatment, were misstaged, or violated the protocolThe main endpoint was overall survival, including all causes of death Survival status updated by contacting the participating hospitals, patients or their relatives, or by Vital Records offices Could not ascertain cause of death39 men with Stage A and 29 men with Stage B disease randomized to oral placebo only; other 74 men randomized to RP and placebo Median length of follow up was 23 yearsFor all patients, the median survival in the RP group was 10.6 years compared to 8 years in the placebo group (p=Ns) Within each stage, age adjusted survival comparison by treatment was not significantHow these patients specifically recruited not reported Major loss to follow-up Quality: poorHolmberg L et al., 2002 QUOTE "124"  ADDIN PROCITE \11\05 \19\02\00\00\00\03124\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00Sx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\07\00\00 45% initial PSA > 10 Prostate cancer specific mortality All-cause mortality Independent endpoint committeeRP with lymph node dissection WW no treatment until symptoms or signs of progressionProstate cancer specific mortality: no difference at 5 years (4.6% WW vs 2.6% RP); 8 years (13.6% WW vs 7.1% RP); Relative hazard 0.50 (0.27-0.91) No difference in all cause mortalityAbout 75% of men had palpable prostate cancer. Quality: good Evidence Table 5A: Efficacy of treatment with androgen deprivation therapy (Key Question 6) CitationDescriptionHow recruited?MeasurementsInterventions/co-InterventionsResultsConclusions (by authors)Quality commentsDesignGranfors et al., 1998 QUOTE "139"  ADDIN PROCITE \11\05 \19\02\00\00\00\03139\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 Sx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\00\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt!Granfors, Modig, et al. 1998 #880\00!\00 139 RCT comparing XRT with and without orchiectomy in men with and without lymph node disease400 men expected to be enrolled, but study terminated due to an interim analysis revealing high rate of progression in group treated with XRT alone 91 men with Stage B and C enrolled; mean patient age 68.8 years (49.2-75.3) Patients with early stage and well or moderately well differentiated lymph node negative tumors were excludedMen with newly diagnosed PC between 1986 and 1991 in three urologic clinics were invited to participatePatients were followed for 3 years with history and DRE; bone scans done when clinical progression or suspicion of metastatic disease Progression defined as occurrence of clinically evident local tumor growth or bone or other metastases All patients underwent bilateral staging pelvic lymphadenectomy and were randomized to XRT with or without orchiectomy with stratification for tumor and nodal status 45 patients were in the XRT and orchiectomy (combined) group and 46 in the XRT alone group. XRT was begun a few weeks after orchiectomy. All patients received XRT to pelvis and a boost to the prostatic areaPatient characteristics of groups similar; patients followed for median of 9.3 years (6.0-11.4) XRT alone group, progression occurred in 61% (44% of node negative and 84% of node postive) patients for combined group, progression occurred in 31% (32% of node negative and 30% of node positive) patients 44% of XRT alone group and 27% of combined group died of PC (p=0.06); overall, 61% of XRT alone group and 38% of combined group died (p=0.02) (statistically significant for node + but not for node - disease)Immediate androgen deprivation is better than deferred endocine treatment for clinically localized PC, particularly in patients with positive lymph nodes Lymph node staging for clinically localized PC is extremely importantUnclear how men were recruited, but once enrolled there was good follow up Diagnosing disease progression was subjective, and criteria for attributing death to prostate cancer were not described One of a few studies to clearly stratify, analyze, and report results regarding nodal status Quality: good Evidence Table 5A: Efficacy of treatment with androgen deprivation therapy (Key Question 6) (continued) CitationDescriptionHow recruited?MeasurementsInterventions/co-InterventionsResultsConclusions (by authors)Quality commentsDesignSchmidt et al., 1996 QUOTE "207"  ADDIN PROCITE \11\05\19\02\00\00\00\03207\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@Sx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\18\01\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt#Schmidt, Gibbons, et al. 1996 #1420\00#\00 207 RCT composing adjuvant therapy (cyclophosphamide estramustine or observation) in two protocols, as part of the National Prostate Cancer Project, clinically localized PC184 men enrolled in Protocol 900 and 235 enrolled in Protocol 1000 Follow up information was available for 170 and 233 men respectively No description of participants, 29% of those in Protocol 900 and 63% of those in Protocol 1000 had positive pelvic lymph nodesRecruitment was not describedOutcomes: recurrence rates (metastatic disease, increases in serum acid phosphatase, and increases in PSA), median PFS (not defined), and overall survival. Protocol assignment at the discretion of the investigator Protocol 900 included patients receiving radical surgery or cryosurgery; Protocol 1000 included patients receiving XRT Men in both protocols randomized to cyclophosphamide for up to 2 yrs (C), estramustine phophate for up to 2 yrs (E), or observation (O)Follow up information available for 403 patients (92%) for an average 11 years For Protocol 900 (prostatectomy), overall recurrence rate 53%, (71% in those with positive nodes); differences among adjuvant treatments not statistically significant for with and without nodal disease For Protocol 1000 (XRT), overall recurrence rate 66%, (82% in those with positive nodes); differences among adjuvant treatments not statistically significant in negative node group; in positive node group rates of recurrence for C, E, and O were 75%, 57%, and 66% respectively, and were significantly different In Protocol 900, the PFS for Groups C, E, and O were 79, 155, and 104 months (p=0.13); in Protocol 1000, the PFS for Groups C, E, and O were 35, 52, and 46 months (p=0.18)Overall survival and PFS greater in Protocol 900 (prostatectomy) compared to Protocol 1000 (XRT) A beneficial effect of estramustine observedEntry into one protocol versus the other was not randomized Groups had different rates of positive nodes, but no other comparison between the two groups upon entry was presented, so comparing the two groups is of little value Randomization to aduvant therapy within the protocols and follow up appears well done, but the evaluators do not appear to have been blinded to the treatment received Paper essentially two studies: one to compare adjuvant treatments in men having prostatectomy, and one comparing adjuvant treatments in men receiving XRT Paper does not evaluate or discuss the primary treatment (prostatectomy versus XRT) Quality: fair Evidence Table 5A: Efficacy of treatment with androgen deprivation therapy (Key Question 6) (continued) CitationDescriptionHow recruited?MeasurementsInterventions/co-InterventionsResultsConclusions (by authors)Quality commentsDesignLundgren et al., 1995138 RCT comparing immediate to deferred endocrine treatment of clinically localized PC285 men previously untreated PC; Mean age 70 years; 99 men had Stage A, 107 had Stage B; 22 Stage C 57 excluded after randomization (mostly for protocal violations and incorrect randomization)Patients from 5 urological or surgical clinics in Sweden were eligiblePatients followed with DRE, blood work, bone scan, and prostate biopsyDiagnosis and tumor differentiation determined by TURP or by prostate biopsy 81 patients to receive polyestradiol plus ethinylestradiol (PE); 93 patients to receive estramustine (E); and 98 patients deferred endocrine treatment D Progression defined as appearance of metastases, poorly differentiated cancer, local progression with pain and/or ureteral dilitation remaining after TURP. (D)More Stage B tumors in the E group and more Stage C tumors in the D group. Overall 125 (55%) had disease progression Metastasis in 22%: 17% in group PE, 20% in group E, and 28% in group 46 (20%) died from PC: 12% in PE group, 18% in E group, and 28% in D group (p=0.03) Overall, 128 patients (56%) died from any cause: 53% in PE group, 54% in E group, and 60% in D group (p=0.48).More people died from PC in the deferred group than in the immediate treatment groups After 10 years of follow up, the probability in the deferred treatment group of dying of PC was 26% and that of dying of intercurrent disease was 25% The probability of dying from PC is higher than that previously reported, and men with at least 10 years life expectancy should receive early treatment57 patients regarded as nonevaluable, created dissimilarities among treatment groups Unclear how cause of death determined or attributed PC Study provides good information on natural history of PC. Although deferred treatment group had higher rates of death from PC, overall survival rates not different Quality: fair Evidence Table 5A: Efficacy of treatment with androgen deprivation therapy (Key Question 6) (continued) CitationDescriptionHow recruited?MeasurementsInterventions/co-InterventionsResultsConclusions (by authors)Quality commentsDesignPilepich, M.V., et al., 1995 QUOTE "144"  ADDIN PROCITE \11\05 \19\02\00\00\00\03144\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00Rx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_C\01\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt(Pilepich, Buzydlowski, et al. 1995 #1850\00(\00 144 RCT203 patients assessed Median f/u time of 107.8 mos. Actual median f/u of alive pts. was 78.9 mos. March 1983-June 1986 198 pts. total randomized to Megestrol Acetate (n=100) or DES (n=98) Eligible if had locally advanced prostate CA, stage B (42 Megace group, 45 DES group) or stage C (58 Megace, 53 DES) 90% compliance in Megestrol, 82% in DES armNo mention of recruitment specificsEndpts = tumor clearance rate (rand. To 1st tumor-free assess.), effect of rx on serum testosterone levels, evaluation of loco-regional control (prog. Of clinc. Detectable disease or + biopsy after 2nd post-rad. year), incidence of distant mestastases (end pt. of metast=occurrence of disease outside pelvic region), survival (failure=death from any cause), and assessment of effects of tx on sexual fxnMegestrol 40 mg 3x daily po DES 1 mg 3x daily po All received radiotherapy 44-46 Gy, 1.8-2 Gy daily to regional lymphatics, followed by boost to prostatic are of 20-25 Gy, 1.8-2 Gy daily, to a total of 65-70 Gy Tumor response assessed clinically and by CT Serum test. levels recorded: "throughout trial"Median increase in test. levels higher in DES (94.5% vs. 77%, p<0.0001) No difference in tumor clearance No diff. in loco-regional occurrence (no p value from Fig. 2) Difference in metastatic rate not significant (p= 0.73) Survival rates not different and appear to be insignificant from Fig. 4, but no p values Return of sexual potency @ 1 year= 81% Megestrol arm, 58% DES armComparable efficacy in tx using Megestrol or DES DES appears more effective @ suppressing testosterone, but also associated with higher incidnce of drug-related toxicityNo mention of blinding, in either randomization or assessment of results Need p values or CI's for several figures Survival as death from any cause suspect No median age of subjects (or age range) Quality: fair Evidence Table 5A: Efficacy of treatment with androgen deprivation therapy (Key Question 6) (continued) CitationDescriptionHow recruited?MeasurementsInterventions/co-InterventionsResultsConclusions (by authors)Quality commentsDesignBolla, Michel, et al., 1997 QUOTE "141"  ADDIN PROCITE \11\05 \19\02\00\00\00\03141\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 Rx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\00\00\00555667788W8^8p9}999::w;;G<L<v=~=0>=>>>??@@A(AABBBQCdCCCDDEEFFFFGGHHyIItJJKKHLPL MMN5NNNOOPPdQkQ!R)RSSSSfTnTeVrVh@A h@A6]a6718s89 ::;_<=O>>?@?ABBxCCD0E.FFGHIJK`7$8$H$^``KbL$MENNOP}Q;R"SS~TUVNW!XXYjZ[M\4]]g^8__o`a`7$8$H$^``rV+W>W XXXXYYGZXZq[y[&\9\]]]]D^U^_%___R`^`a aaabbccVd]ddddffOmPmsmmmmmmm4s5sWs[sssssʻ h@Ahh8 h@ACJ h@A\#h8h@ACJOJQJmHnHuh8CJOJQJmHnHuh8h@ACJOJQJ h@A6hUh@A5CJ OJQJh@ACJ OJQJ h@A6]h@A:abbcodpdqdrdsdtdudvdwdddd9giOmPmQmRmSmTmUm*)gdw$a$$a$7$8$H$`7$8$H$^``Umrmsmmmmmmmgkd!$$IfT403T8! 0apT$If)gdw)$a$mmmmm%jkdY#$$IfT03T8!0aT$Ifjkd"$$IfT03T8!0aTmmmmmmjkd#$$IfT03T8!0aT$Ifmnnnn%jkdK%$$IfT03T8!0aT$Ifjkd$$$IfT03T8!0aTnn%n&n*nGnjkd%$$IfT03T8!0aT$IfGnHnKnRnSn%jkd='$$IfT03T8!0aT$Ifjkd&$$IfT03T8!0aTSnVn]n^nanunjkd'$$IfT03T8!0aT$Ifunvnynnn%jkd/)$$IfT03T8!0aT$Ifjkd($$IfT03T8!0aTnnnnnnjkd)$$IfT03T8!0aT$Ifnnnnn%jkd!+$$IfT03T8!0aT$Ifjkd{*$$IfT03T8!0aTnnnnnojkd+$$IfT03T8!0aT$Ifooo"o#o%jkd-$$IfT03T8!0aT$Ifjkdm,$$IfT03T8!0aT#o)odoeoiosojkd-$$IfT03T8!0aT$Ifsotoxooo%jkd/$$IfT03T8!0aT$Ifjkd_.$$IfT03T8!0aToooooojkd/$$IfT03T8!0aT$Ifooooo%jkd0$$IfT03T8!0aT$IfjkdQ0$$IfT03T8!0aTooooo pjkd1$$IfT03T8!0aT$If p pp/p0p%jkd2$$IfT03T8!0aT$IfjkdC2$$IfT03T8!0aT0p4pApBpFpapjkd3$$IfT03T8!0aT$Ifapbpfpmpnp%jkd4$$IfT03T8!0aT$Ifjkd54$$IfT03T8!0aTnpspppppjkd5$$IfT03T8!0aT$Ifppppp%jkd6$$IfT03T8!0aT$Ifjkd'6$$IfT03T8!0aTppppppjkds7$$IfT03T8!0aT$Ifpppqq%jkd8$$IfT03T8!0aT$Ifjkd8$$IfT03T8!0aTqq5q6q9qDqjkde9$$IfT03T8!0aT$IfDqEqIqYqZq%jkd:$$IfT03T8!0aT$Ifjkd :$$IfT03T8!0aTZq\qhqiqlq|qjkdW;$$IfT03T8!0aT$If|q}qqqq%jkd<$$IfT03T8!0aT$Ifjkd;$$IfT03T8!0aTqqqqqqjkdI=$$IfT03T8!0aT$Ifqqqqq%jkd>$$IfT03T8!0aT$Ifjkd=$$IfT03T8!0aTqqqqr$rjkd;?$$IfT03T8!0aT$If$r%r(r>r?r%jkd@$$IfT03T8!0aT$Ifjkd?$$IfT03T8!0aT?rDrxryr}rrjkd-A$$IfT03T8!0aT$Ifrrrrr%jkdyB$$IfT03T8!0aT$IfjkdA$$IfT03T8!0aTrrrrrrjkdC$$IfT03T8!0aT$Ifrrr ss%jkdkD$$IfT03T8!0aT$IfjkdC$$IfT03T8!0aTsss s#s4sjkdE$$IfT03T8!0aT$If4s5s9sKsLs%jkd]F$$IfT03T8!0aT$IfjkdE$$IfT03T8!0aTLsPsVsWsXsYsZs[sssss tt.t<$IfjkdG$$IfT03T8!0aT$Ifsss t ttt,t>tHtJtttvtttttUvVvWvYvZv[vvxxxxzzzO{P{X{Z{\{|~~~~~o~59rs&CDLNPQh@A5B*phh@AB*phh8 h@ACJ h@ACJ h@A<jh@A<U h@AH*jh@AU h@A5h@A h@AhE.t0t>t@tBtDtFtHtJt[vvv wNwwwwwZxxxSyTyy z_z~z$If=$IfFf0M<$IfFfbI~zzzzzz@:82<$Ifkd7O$$Iflֈ> x*4T2    04 la=$Ifzzz%{-{6{7{~7~U~o~u~~ rs؀;du=$IfFfQ<$Ifڂ'( @kdS$$Iflֈ8N )T3Tp 2 ~ 04 laP=$If #$2CBf=$IfS\mzF@::::$If 2kdT$$Iflֈ8N )T3Tp 2 ~ 04 laP'1;BSefstÊĊ̊ΊЊъč܍ލ  "JLĎȎ̎Ύqrsuv01VX֒ؒVWxy”Ôþþh@AOJQJ h@ANH h@A<jh@A<U h@AH*jh@AU h@A5h@ACJNH h@ACJh@Ah8 h@Ah h8hEkdU$$Ifl4rZc) 3V ` ` ` 204 laf4p2$If & F$If $$Ifa$$Ifƍ=$Ifkd W$$Ifl4ֈ Zc) 3V       04 laf4pƍ>ZnwNV} k]v w?$If?$If=$IfÔ*+ !FG–Ζϖ RSrsԗޗCKae~"$46:< !^_ʡˡstãģs h@A<jh@A<U h@AH*jh@AU h@ACJ h@A5h8 h8h h@Ah h@ANHh@AL %2:CA;;;;<$IfkdoX$$Ifl4ֈ Zc) 3V   04 laf4:CDkd_Y$$Ifl4rg!-5U` `M `P 204 laf4p2<$IfDKUabcdefghijϘ=$If=$IfFf{\ $$Ifa$ $$Ifa$ $$Ifa$ϘИ)kF>>>>>>=$Ifkd~^$$Iflֈgg!-5U~   M P04 la`˝؞Ѡ>kdZ_$$Iflֈgg!-5U~   M P04 la=$IfѠ ;GաkTĤ=$IfstƤ ^f| 048:*+,./   @JT[kͰѰ   dfhnp h@A5CJ h@A<jh@A<U h@AH*jh@AU h@ACJ h@A5h8 h@Ah h8hh@A h@ANHHĤŤ&/@MU^FD>>>>><$Ifkd6`$$Iflֈgg!-5U~   M P04 la^_kda$$Ifl4rg!-5U` `M `P 204 laf4p2_fp|}~=$IfFf.d $$Ifa$ $$Ifa$ $$Ifa$ 0?OϨF@@@@@@=$Ifkd1f$$Iflֈgg!-5U~   M P04 la-ͩ=ɪ=$Ifɪʪ EmF@@@@@@=$Ifkd g$$Iflֈgg!-5U~   M P04 laJݯ@kdg$$Iflֈgg!-5U~   M P04 la=$Ifw<$Ifkdh$$Ifl4rg!-5U` `M `P 204 laf4p2ͰΰϰаѰ ZyѴIr=$IfFfk $$Ifa$ $$Ifa$ $$Ifa$r:bF@@@@@@=$Ifkdm$$Iflֈgg!-5U~   M P04 la9:1345Smʼ˼Ӽռ׼ؼprtxzbv~78v)-.DEMPRS߷ h@A5CJ h@A>* h@A<jh@A<U h@AH*jh@AU h@A5h8 h@ACJ h@Ahh@Ah@AB*phHb6Y$2=$If234mvFDD999 =$$Ifa$kdn$$Iflֈgg!-5U~   M P04 la =$$Ifa$|=$Ifkdo$$Ifl4rL#3)1 k 7 204 lap2|^&`bv "&*z=$If=$If$Ifkdq$$Ifl4ִL#3f!%)1`` `k (8`70    4 laf4 D\] & F 8$If^`=$If & F$If & F $If]^*:CTNNNNNNN=$Ifkdr$$Ifl4rL#3)1   k  704 laf4C['567PNLkdt$$Ifl4rL#3)1 k 704 laf4=$If)*+,-.)6EQ_FfRz =$$Ifa$=$IfFfv =$$Ifa$=$If_t 7e?$If=$If %ITdB<<<<<=$Ifkdd|$$IfTlֈ 0"+4F$ 2   04 laT #$?H   &(:<>BD026z{|&(*02^`ptxz h@A5h@A5CJOJQJh8 h@ACJh@A h@AH*jh@AUjh@A<U h@A<N-.[?$If?$If=$If ?HB=;2 $$Ifa$$a$kdR}$$IfTlֈ 0"+4F$ 2   04 laTHSbr*vx>=$If=$IfFf $$Ifa$Ff =$$Ifa$-?$If=$IfF B<<<<<=$Ifkd$$IfTlֈ+(>G!h,4  ! 04 laT f.0?$If=$If 024B=;00 =$$Ifa$$a$kd$$IfTlֈ+(>G!h,4  ! 04 laT!1GO\iz{|4Ff=$IfFf2 =$$Ifa$(,020124545=@BRSfj~嶯 h>aH*aJh>a h@ACJh@A5B*ph h@A5CJ h@A5h8 h@ACJ h@A<h@A h@AH*jh@AUjh@A<UD =I,c?$If=$If 6Dr?9999=$Ifkd$$IfTl4ֈ7 ,5 1  v04 laf4Tr<=$If?$If ?=;00 =$$Ifa$kd$$IfTl4ֈ7 ,5 1  v04 laf4T =$$Ifa$=$Ifkdܐ$$Iflrl|) 3($   204 lap2)v 5q?$If?$If=$If&3@HQYWUOOOOOO<$Ifkd-$$Iflrl|) 3($   04 la QRSfghijk&nUc%{=$IfFfg $$Ifa$ $$Ifa$Ff&nTU45=@B           :[ 餘鮾h@A5B*CJphh@AB*CJphh@AB*CJhphh8 h@Ah h@A\ h@A<jh@A<U h@AH*jh@AU h@A>*h@Ah@AB*phh>ah@AH*aJ<kD>>>>>>=$Ifkdq$$Ifl ֈL),"-4 1 0p54 lav @      =$If     : R u F@@@@@@=$Ifkdԛ$$IflֈL),"-4 1 0p54 lau     =$IfR[gvFDB<<<<$Ifkdќ$$IflֈL),"-4 1 0p54 lavv W-=$IfFfFfП<$If+q4=$If E9711<$If  d1$kd4$$Ifִ l&-R5H(w    4 a'''''x(y((((((( 0 0 0,000P0}000011#1$1,1/111244444_;;;<<<<<<<h@AB*CJphh>ah@AH*aJ h>aH*aJh8 h@A<jh@A<U h@AH*jh@AUh@A5B*CJphh@AB*CJhphh@AB*phh@A?.;Zb{B |  {!!=$IfFfgFf4<$If!"#w$$%A%%&('|''=$If ''''' ((ECA;;;<$Ifkd$$IfִT l&-R5r`H(w    4 a(&(E(M(f(x(y((((((((((((X)))C**)++>,,F-=$IfFf˶Ff<$IfF--2../V// 0=$If 0 0 0t0}000ECA;;;<$Ifkd$$Ifִ l&-R5H(w    4 a00000000111111114444R4444O5{5537P7=$IfFfFf<$IfP7e7848d888 9D999::::%;N;\;=$If\;];^;;;;;ECA;;;<$IfkdD$$Ifִ :&-R5TT    4 a;;.<><p<<<<<<<<<<<<>>>>>K????@N@l@=$IfFfMFf(<$If<<===>>>>>EEEEEjFkFrFyFzFFFFFFFdIfIhInIpIO]OOP PP&P(PXPZPjPpPtPvPLRMRNRQRRRRR]]]]]] ^^^^^^^^,_ԼԼԼhOh>a h@ACJh@A5B*CJphh@AB*CJhphh@AB*phh8jh@AU h@A<jh@A<U h@AH*h@ABl@@@AkA@BB CCC=DlDDDEQEnE|E?$If=$If|E}E~EEEE FECA;;;<$Ifkd~$$Ifִ :&-R5TT    4 a FF7F?FXFjFkFrFsFtFuFvFwFxFyFzFrIIAJwJJJJ!KKKK-L=$IfFfFf<$If-LILLLIMpMMsNNNOO?$If=$If OOOOOOOECA;;;<$Ifkd$$Ifִ :&-R5TT    4 aOOOOOP PPPPP P"P$P&P(PSRRR\SST3TVTTUBUU=$IfFf#Ff<$IfUVVVUWWLXX0YYZkZZh[[\\]]]=$If]]]^ ^^'^ECA;;;<$IfkdT$$Ifִ :&-R5TT    4 a'^4^S^[^t^^^^^^^^^^^^^^^(_)_*_+_,_=$IfFfFfb<$If,_-_.____E9711<$If  d1$kd$$Ifִ :&-R5TT    4 a,_-_/_s__4`6`D`R`T````aaabbbbbl4l8lXlllmmmm"m#m+m.m0mn pppppyy*zzzzzzz'{({){I{M{m{u{{{{{{{{{{{{ͭh>a h@A<jh@A<U h@AH*jh@AUh@A5B*CJphh@AB*CJhphh@AB*phh@Ah8 h@Ah h@A5D_____`4`6`D`F`H`J`L`N`P`R`T`bxccc7ddehee-ff=$IfFfFf<$IfffEggidiijnjj(kkkll=$Iflll|llllECA;;;<$Ifkd$$Ifִ :&-R5TT    4 allllllmmm m m m m mmmpvpppPqvqq-rrks=$IfFfOFf*<$Ifkss@tttsuvvFwwBxxx1yyy=$If = 8$Ifyyy!z*z6zEzECA;;;<$Ifkd$$Ifִ :&-R5TT    4 aEzRzqzyzzzzzzzzzzzzzzzz{ {!{"{#{=$IfFfFf<$If#{${%{&{'{{ECCA7  ^ `kd$$Ifִ :&-R5TT    4 a{{{{{{/kd$$Ifl44\^*4   (04 laf4p(<$If{{{{{}}}}}MNWwӁԁ   Džȅ!3>RSՋ24Z\lptvKLMOPEFPpؓٓ h@A>* h@ACJ h@A5CJ h@A5h8 h@Ahjh@AU h@A<jh@A<U h@AH*h@AL{}.~A~O~~~/J?$If=$If JKLMʁӁjhfdYYYYYY =$$Ifa$kd>$$Ifl \^*4  04 la Ӂԁ r}Dž?$If=$IfFf DžȅgшF@@@@@@=$Ifkd $$Iflֈ0.5p y.y04 laш)Y=$IfA;;;;=$Ifkd $$Ifl4ֈ0.5`p` `y`.y`04 laf4  !$'+/3>AEIMQR=$If =$$Ifa$RST=$Ifkd $$Ifl4ִ_#/)0.5 p  y . 0    4 laf4TUVW؊?$If=$IfՋދA<:// =$$Ifa$$a$kd$$Ifl4ֈ0.5 p   y .y 04 laf4 24Q+7;EhyƏޏ t{ӑ6?$If=$IfFf =$$Ifa$7EF97kd$$IfTl4ֈ$E.5! W04 laf4T=$IfǓϓؓٓGϖ7Pԗ˜CQ=$IfFfP =$$Ifa$  QRjksvx6z{Z\^df @ܨި   & ( ( * : @ D F ` b d j l j X U h@Ah h@A5h8 h@ACJ h@A<jh@A<U h@AH*h@Ajh@AUOQR`r?99999=$Ifkd[$$IfTl4ֈX -5? ,04 laf4TԜޜ`ٝK؟?$If=$If6?L?=;00 =$$Ifa$kdO$$IfTl4ֈX -5? ,04 laf4TLWiqz{hܤ] ק =$If^=$IfFf =$$Ifa$@Rl?=;00 =$$Ifa$kd$$IfTl4ֈX -5? ,04 laf4Tl =$$Ifa$* =$Ifkd$$Ifl44rZn /5 j  204 laf4p2 ADDIN PROCITE \11\05 \19\02\00\00\00\03155\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@ox\00\01\00\00\00\01\00\00\00\00\00\00\00hI_;\03\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt#Robinson, Dufour, et al. 1997 #4840\00#\00 155Comprehensive literature review and meta-analysis of rates of erectile dysfunction associated with RP and EBRT 40 articles found Pretreatment sexual function must be known18 studies used chart reviews Questionnaires used in 5 studies, interviews in 8 studies Physiologic measures used in 2 studiesLogistic regression model Probability of maintaining normal erectile function: RP: 0.42 EBRT: 0.69 (p<0.0001)Quality: fair (included some studies with measurements of uncertain validity)Fowler, FJ et al., 1996 QUOTE "179"  ADDIN PROCITE \11\05 \19\02\00\00\00\03179\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\00ox\00\01\00\00\00\01\00\00\00\00\00\00\00hI_ \03\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt Fowler, Barry, et al. 1996 #5570\00 \00 179 N=373 Sample of Medicare beneficiaries who had RP for PC Patients treated with EBRT from SEER registries Self-administered mailed questionnaire several years after treatment 91% response rate for RP patients 83% response rate for EBRT patients Sexual function (% inadequate erection for intercourse) Age < 70 RP: 89% EBRT: 67% Age e" 70 RP: 88% EBRT: 73% Urinary function (% wearing pads) RP: 32% EBRT: 7% Bowel function (% medium/big problem with frequent bowel movements) RP: 3% EBRT: 10%Quality: good Evidence Table 7: Harms of treatment (Key Question 8) (continued) CitationParticipantsMeasurementsResultsCommentsWidmark, A et al., 1994 QUOTE "180"  ADDIN PROCITE \11\05 \19\02\00\00\00\03180\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00nx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\1A\04\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt$Widmark, Fransson, et al. 1994 #7100\00$\00 180 Fransson, P. and Widmark, A., 1996 QUOTE "175"  ADDIN PROCITE \11\05 \19\02\00\00\00\03175\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 nx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_n\03\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt\1DFransson & Widmark 1996 #5350\00\1D\00 175 Umea, Sweden N=200 patients with PC treated by EBRT N=200 age-matched controlsPre-tested mailed questionnaire, some linear-analog and some multiple responses93% response rate in PC group 71% response rate in control group Sexual function: (% failure to achieve erection) EBRT+ADT: 87% Control: 12% EBRT: 56% Urinary function (% leakage quite a bit/very much) Control: 4% EBRT: 15% Bowel function (% have problems with intestine quite a bit/very much) Control: 5% EBRT: 30%Quality: goodHelgason, AR et al., 1996 QUOTE "168"  ADDIN PROCITE \11\05 \19\02\00\00\00\03168\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@nx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\03\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt&Helgason, Adolfsson, et al. 1996 #5780\00&\00 168 Helgason, AR et al., 1997 QUOTE "165"  ADDIN PROCITE \11\05 \19\02\00\00\00\03165\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\00nx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\17\03\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt&Helgason, Adolfsson, et al. 1997 #4460\00&\00 165 Adolfsson, Jet al., 1998 QUOTE "174"  ADDIN PROCITE \11\05 \19\02\00\00\00\03174\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00mx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\00\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt%Adolfsson, Helgason, et al. 1998 #970\00%\00 174Stockholm area N=431 men with PC treated in various ways N=435 age-matched controls Self-administered questionnaire assessing urinary, bowel, sexual function Response rate 79% in PC group and 73% in control group Sexual function: (% distressed with erection capacity) Control: 63% RP: 82% EBRT: 81% ADT: 63% Urinary function (% with any leakage) Control: 14% RP: 65% EBRT: 33% No Rx: 30% Bowel function (% urgency) Control: 10% RP: 10% EBRT: 35% No Rx: 18%Quality: fair (uncertain validation of questionnaire) Evidence Table 7: Harms of treatment (Key Question 8) (continued) CitationParticipantsMeasurementsResultsCommentsLitwin, MS et al., 1995 QUOTE "169"  ADDIN PROCITE \11\05 \19\02\00\00\00\03169\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 mx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\03\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt\1FLitwin, Hays, et al. 1995 #6780\00\1F\00 169 Litwin MS, 2000 QUOTE "171"  ADDIN PROCITE \11\05 \19\02\00\00\00\03171\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@mx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\04\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt\16Litwin M.S. 1995 #9220\00\16\00 171 N=214 with clinically localized PC treated in different ways N=273 aged-matched controls without PC Retrospective cross-sectional study Patients from large managed-care population HRQol surveys Self-administered mailed questionnaires Prostate-targeted functional items79% response rate among PC patients 46% responses rate in control group No group differences in potential confounders Sexual function (% poor/very poor) Control: 46% Watchful waiting: 49% RP: 79% EBRT: 71% Urinary function (% frequent dribbling/no control) Control: 6% Watchful waiting: 9% RP: 21% EBRT: 8% Bowel function (% rectal urgency 1+times/day) Control: 13% Watching waiting: 18% RP: 13% EBRT: 23% No differences among groups in overall Qol measuresQuality: fair (low response rate in control group) Evidence Table 7: Harms of treatment (Key Question 8) (continued) CitationParticipantsMeasurementsResultsCommentsStanford, JL et al., 2000 QUOTE "161"  ADDIN PROCITE \11\05 \19\02\00\00\00\03161\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\00mx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\01\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt Stanford, Feng, et al. 2000 #950\00 \00 161 Potosky AL et al., 2000170Patients diagnosed with PC in 6 SEER areas, random sample of 5,672 patients 83.5% contacted and invited to participate 62.3% completed 6 and/or 12-month survey (N=3,533) 2nd study reports on subset of 1,591 patients given 6,12 and/or 24-month surveysMailed, self-administered questionnaire at 6, 12, and 24 months after diagnosis Patients asked to recall baseline (before treatment) functionSexual function (% sexual function moderate to big problem) Baseline 24 Months All RP ages: 17.9% 41.9% % erections not firm enough for intercourse) Baseline 24 Months All RP ages: 15.8% 59.9% Age < 60: 7.4% 61% 75-79: 51.4% 80.9% Urinary function (% frequency of incontinence > 2/day) Baseline 24 Months All RP ages: 2.6% 11.9% Age < 60: 1.7% 10.0% 75-79: 4.1% 40.8% 2nd study: (24-month survey) (% wore pads to stay dry) RP: 28.3% EBRT: 2.5% % erection insufficient for intercourse RP: 82.1% EBRT: 50.3% % bowel urgency) RP: 16.1% EBRT: 30.5%Quality: fair (low response rate) Evidence Table 7: Harms of treatment (Key Question 8) (continued) CitationParticipantsMeasurementsResultsCommentsTalcott, JA et al., 1998 QUOTE "163"  ADDIN PROCITE \11\05 \19\02\00\00\00\03163\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 lx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\02\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt"Talcott, Rieker, et al. 1998 #3510\00"\00 163 Talcott, JA et al., 1997 QUOTE "164"  ADDIN PROCITE \11\05 \19\02\00\00\00\03164\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@lx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\0E\03\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt"Talcott, Rieker, et al. 1997 #4370\00"\00 164 Men with newly diagnosed PC, nonmetastatic; 398 approached; 80 refused and 29 did not complete baseline questionnaire Final N=287 (72%) 48.4% had EBRT 44.8% had RP 6.5% no TxPreviously validated self-administered questionnaire before treatment and at 3 and 12 months afterward Sexual function (% erections inadequate for intercourse) Baseline 12 Months RP: 32% 93% EBRT: 45% 67% Urinary function (% wearing pads) Baseline 12 Months RP: 3% 35% EBRT: 1% 5% Bowel function (% bowel urgency or tenderness) Baseline 12 Months RP: 7% 6% EBRT: 1% 19% Nerve-sparing RP resulted in same amount of sexual or urinary dysfunction as non-nerve sparing RPQuality: good Evidence Table 7: Harms of treatment (Key Question 8) (continued) CitationParticipantsMeasurementsResultsCommentsBrandeis, JM et al., 2000 QUOTE "187"  ADDIN PROCITE \11\05 \19\02\00\00\00\03187\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\00lx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\01\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt"Brandeis, Litwin, et al. 2000 #780\00"\00 187 N=48 men with clinically localized PC treated at UCLA with brachytherapy N=74 similar men treated with RP Retrospective cross-sectional study Literature controlsSelf-administered mailed questionnaires 3-17 months after treatment 86% response rate from brachytherapy patients 73% response rate from RP patients General quality of life questionnaires and symptom specific questionnairesRP patients younger RP and brachytherapy patients similar in general quality of life measures Urinary bother scores (higher scores=better outcomes): RP: 74 Brachy: 65 Controls: 86 Bowel bother: RP: 90 Brachy: 81 Controls: 89 Sexual bother: RP: 34 Brachy: 39 Controls: 53Quality: goodLee, W R et al., 199918946 men with clinically localized PC consecutively treated with brachytherapy Complete information on 44Self-administered questionnaire, validated Completed before treatment and at 1 and 3 months after treatmentModest decrease in quality of life at 1 month, returning to baseline at 3 months Score of lower urinary tract symptoms (I-PSS) mean at: T0: 8.3 T1: 19.7 T3: 15.4 indicating an increase in symptomsQuality: fair (no absolute percentage of patients having various degrees of problems given)Steineck, G et al., 2002 QUOTE "173"  ADDIN PROCITE \11\05 \19\02\00\00\00\03173\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00 kx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\07\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt&Steineck, Helgesen, et al. 2002 #15710\00&\00 173 One point survey of men in an RCT comparing RP and WW326 of 376 eligible men (87%) responses from survey about 4 years after randomization Mean age 64-65Validated scales, some disease-specific and some generalErectile dysfunction: 80% RP 45% WW Urinary Leakage: 49% RP 21% WW Weak urinary stream: 28% RP 44% WW No difference in anxiety, bowel function, depression, subjective quality of lifeNo pre-treatment measure Quality: goodEvidence Table 8: Cost-effectiveness of screening (Key Question 9) CitationMethodsResultsCommentsBarry MJ et al., 1995 QUOTE "210"  ADDIN PROCITE \11\05 \19\02\00\00\00\03210\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00@kx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_S\06\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt!Barry, Fleming, et al. 1995 #6700\00!\00 210 Coley CM et al., 1997 QUOTE "204"  ADDIN PROCITE \11\05 \19\02\00\00\00\03204\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00\00kx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_j\00\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt\1EColey, Barry, et al. 1997 #250\00\1E\00 204 MEDLINE search for studies of efficacy of treatment Developed decision analysis for one-time PSA and DRE screening of men ages 50 years and older Markov models Efficacy assumptions favorable for screeningWith favorable assumptions, one-time screening would increase discounted average life-expectancy by 7-11 days for screened men ages 50-69 and 3 days for men ages 70-79, but with considerable iatrogenic morbidity With favorable assumptions, dollars per life-year saved (no adjustment for iatrogenic morbidity): Age 50-59: $12,491 Age 60-69: $18,769 Age 70-79: $65,909 Relaxation of favorable assumptions about treatment efficacy and cancer-specific mortality lead to dramatically increased cost-effectiveness ratios, still without adjusting for iatrogenic morbidityQuality: goodKattan MW et al., 1997 QUOTE "211"  ADDIN PROCITE \11\05 \19\02\00\00\00\03211\01\01\00\03\00\00\01\00\00\00\1BM_\01\00\00\00\00\11"!\00jx\00\01\00\00\00\01\00\00\00\00\00\00\00hI_\05\00\00<S:\5CUSPSTF\5CProstate Cancer\5CDatabases\5Cprostate_annals_2002.pdt$Kattan, Stapleton, et al. 1997 #4940\00$\00 211 Built on Barry and Coley model after analysis showed it to be accurate Markov model All patients begin with localized PC, compares RP with watchful waiting Utilities come from small interview study of men without PC using time trade-off concerning relevant health states Secondary Monte-Carlo sensitivity analysisQuality of life adjustment downgrades watchful waiting benefit because of concern about living with cancer QALY benefit of RP over watchful waiting for men with PC: Age Grade Benefit 60 poor 2.43 years 60 moderate 1.16 years 60 well 0.90 years 75 poor 1.05 years 75 moderate .042 years 75 well 0.28 years These numbers are not discounted; with discounting, RP benefit is reduced If more recent morbidity figures are used, RP benefit is reduced Authors conclude that men under 70 do better with RP, but that men ages 70 and over face a toss-up (unless higher co-morbidity, in which watchful waiting is superior) Quality: good (The USPSTF is an independent panel of experts in primary care and prevention first convened by the U.S. Public Health Service in 1984. The USPSTF systematically reviews the evidence on the effectiveness of providing clinical preventive services--including screening, counseling, immunization, and chemoprevention--in the primary care setting. AHRQ convened the third USPSTF in November 1998 to update existing Task Force recommendations and to address new topics.  PAGE i PAGE   PAGE v Structured Abstract Table of Contents PAGE 1 I. Introduction  PAGE 1 II. Methods  PAGE 10 PAGE 16 II. Methods III. Results IV. Discussion References  PAGE 105 Appendix A. Acknowledgements Appendix B. Evidence Tables Appendix B. Evidence Tables 730 (~600) Watchful waiting7 Harms8/Costs9 Early detection of prostate cancer Reduced mortality and/or morbidity Androgen deprivation6 Radiation5 Surgery4 Harms3/Costs9 Screening2 Screening1 Population at risk 90 Prostate Cancer (~100) 180 No Prostate Cancer (~300) Figure 4: Ages 70-79 - estimated uield of screening with PSA (or PSA and DRE) (prevalence screen) 1000 Asymptomatic Men no previous screening 270 (~400) Biopsy PSA<4.0 (and negative DRE) PSAe"4.0 (or positive DRE) 63 Pathologically Organ Confined (~70) 27 Pathologically Extracapsular (~30) 840-890 (720-840) 33-48 Prostate Cancer (40-70) 77-112 No Prostate Cancer (120-210) Figure 3: Ages 60-69 - estimated yield of screening with PSA (or PSA and DRE) (prevalence screen) 1000 Asymptomatic Men no previous screening 110-160 (160-280) Biopsy PSAe"4.0 (or positive DRE) PSA<4.0 (and negative DRE) 23-34 Pathologically Organ Confined (28-49) 10-14 Pathologically Extracapsular (12-21) 1000 Asymptomatic Men no previous screening Figure 2: Ages 50-59 - estimated yield of screening with PSA (or PSA and DRE) (prevalence screen) 40-60 (~150) Biopsy 9-14 Pathologically Organ Confined (~21) 4-6 Pathologically Extracapsular (~9) 940-960 (~850) 13-20 Prostate Cancer (~30) 27-40 No Prostate Cancer (~120) PSA<4.0 (and negative DRE) PSAe"4.0 (or positive DRE)  PAGE 111 *  ,   2   \  ?$If=$If   p |  D   \ WQQQQQQQ=$Ifkd6 $$IflrZn /5 j 04 la\   8 H d f h MKkdK!$$IflrZn /5 j 04 la=$If?$Ifh   6 F X =$$Ifa$X Z =$Ifkd$"$$Ifl44rZn /5 j  204 laf4p2   , 2 6 8 P R T Z \ h j z               0 2 4 : < n p              J ! # # # &# (# H# J# Z# `# d# f# p% r% t% z% |% % ' + h@A5h8h@AB*ph h@AH*jh@AU h@A<jh@A<Uh@AR ` z       `  4 ?$If=$If 4 6  >   , d  TNNNNNNN=$Ifkd#$$Ifl4HrZn /5 j 04 laf4 h &  R    HFkdt$$$Ifl4HrZn /5 j 04 laf4?$If=$If J \ v =$$Ifa$ *# ?$IfkdW%$$Ifl44rZn /5 j  204 laf4p2*# % % H& & & ' ' ' ,( ( 8) * * 0+ + ?$If+ + + ", 4, N, h, x, TRPEEEE =$$Ifa$kd&$$Ifl4HrZn /5 j 04 laf4+ + ", , , , , , , , . . . / / / 6/ / 0 0 P2 2 2 2 2 3 3 3 3 4 4 4 5 5 5 @7 z7 7 08 b8 d8 t8 z8 ~8 8 : : : : : : : : : : : = = = = = "= R? ? ? ôϪ h@A>*h@AB*H*phh>ah@AB*H*aJphh>aB*H*aJphh@AB*ph h@A<jh@A<U h@AH*jh@AU h@A5h@Ah8Ax, , =$$Ifa$, , / =$Ifkd'$$Ifl44rZn /5 j  204 laf4p2/ >/ / ,0 0 41 1 P2 2 2 23 43 3 3 4 04 Z4 \4 4 5 >5 j5 5 5 ,6 6 6 :7 ?$If=$If=$If:7 <7 >7 7 7 7 8 8 TRPEEEE =$$Ifa$kd)$$Ifl4* rZn /5 j 04 laf48 08 =$$Ifa$08 28 : =$Ifkd)$$Ifl44rZn /5 j  204 laf4p2: $= > 4> R> l> > R? ? ? @ D@ F@ @ @ @ A A pA A A A A B B =$If? ? ? @ @ @ @ tA A A A B C fC C D D D D D D >F @F BF HF JF NF TI K K K jM |N ~N N N N N O O O O O O R R "R (R *R R S U U U V 0V BV PV RV bV dV V V V V ù h@ACJ h@ACJh h@A\ h@AH*h>ah@AH*aJ h>aH*aJh@AB*ph h@A<jh@A<U h@AH*jh@AU h@A5h8 h@A>*h@A@B B B fC xC C C C TRPEEEE =$$Ifa$kdd+$$Ifl4* rZn /5 j 04 laf4C C =$$Ifa$C C NF =$IfkdG,$$Ifl44rZn /5 j  20p54 laf4p2NF F "G lG G H xH H TI |I J J K rK K ?$If=$IfK K K \L L L jM N N TNNNNNNH?$If=$Ifkd-$$Ifl4* rZn /5 j 0p54 laf4N N O O ,R R DS bS S Nkd.$$Ifl4rZn /5 j 0p54 laf4=$IfS T T T T @T NT \T ^T T T T T HU zU U =$If =$If^=$IfU U V 2V BV RV dV TRIIII $$Ifa$kdz/$$Ifl4rZn /5 j 0p54 laf4dV fV X L[ [ p\ :4444=$Ifkd]0$$Ifl4\Z-s+5F v  (04 lap(V V V X X X X X Y Y Y Y Y Y <[ >[ @[ F[ H[ J[ Ra pa a a a a a a c c c c c g g g g g g i pk rk o o o "o $o س؟؟؟~ hH0J'jhH0J'Uh"1hH j*hH0JBh@A>*B*phh@A<B*phjh@A<B*Uphh@AB*H*phjh@AB*Uphh@AB*ph h@AH*jh@AU h@A<jh@A<Uh@A.p\ \ \ ^ R_ x_ _ _ _ Ra na =$If^=$If na pa c vd d e f \f 2g g g lffffffff^=$If=$Ifkd1$$Ifl\Z-s+5F v 04 la g g .h Zh h h h zi i i Lk hk =$If=$If hk jk lk nk pk o o *o ,o >o ljhhcj^jU%&`#$&gd Agd(kd2$$Ifl\Z-s+5F v 04 la $o &o (o *o ,o .o :o o Fo Ho To Vo Xo Zo \o o o o o o o o o o o o o o p p p p "p $p &p 2p 4p 8p :p

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SmithLP                           ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                                   ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O Oh+'0(4H dp     01report.doco%Systematic Evidence Review Number 16sof+Agency for Healthcare Research and Qualityogengen Normal.dotHCharles L. 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