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PSA Screening and Cancer Treatment Douglas S. Scherr, M.D. Assistant Professor of Urology Clinical Director, Urologic Oncology Weill Medical College-Cornell University Criteria of a Screening Program • The Disorder • The Test • The Treatment • The Screening Program Criteria of a Screening Program • The Disorder -Prostate Cancer • The Test • The Treatment • The Screening Program PROSTATE CANCER Highest in Incidence and Second in Cause of Death from Cancer in American Males Incidence Cause of Death Melanoma of Skin 5% 3% Esophagus Oral Cavity & Pharynx 3% Lung & Bronchus 14% 31% Lung & Bronchus 5% Pancreas Pancreas 2% 3% Kidney Colon & Rectum 11% 3% Liver Kidney 3% 10% Colon & Rectum Prostate 30% 11% Prostate Urinary Bladder 7% Leukemia 3% 3% Urinary Bladder 4% Leukemia Non-Hodgkin’s Lymphoma 4% 5% Non-Hodgkin’s Lymphoma All Sites 637,500 189,000 New Cases 288,200 All Sites 2002 Estimates 30,200 Death U.S. Incidence and Mortality of Prostate Cancer Prevalence of Prostate Cancer 45 40 35 % Men With PIN Or CaP 30 25 PIN Prosate Cancer 20 15 10 5 0 2nd 3rd 4th Decade Sakr et al., J Urol, 150: 379, 1993 5th Criteria of a Screening Test The Disorder “Prostate Cancer” • Natural history understood: -To die of prostate cancer or die with prostate cancer? -Conservative Treatment: a.) Gleason 2-4: 4-7% chance of death b.) Gleason 6: 18-30% chance of death c.) Gleason 8-10: 60-80% chance of death** Frankel et al. Lancet, 361: 1122, March 2003 **Albertsen et al., JAMA, 280: 975, 1998 Lifetime Risk of Developing or Dying of Prostate Cancer for a 50-Year-Old Man in the United States Lifetime Risk of Risk Risk Ratio Developing histologic cancer 42 % 11.7 100 Developing clinical cancer 16 % 4 38 Dying of prostate cancer 3.6 % 1 8.6 Modified from Scardino PT. Urol Clin N Am 1989 and Hum Path 1992; and from CA Cancer J Clin Jan-Feb, 2000. Proportional Risk Criteria of a Screening Program • The Disorder • The Test • The Treatment • The Screening Program Criteria of a Screening Test The Test • Simple, safe and precise • Distribution in target population should be known • Appropriate cut-offs and age defined ranges • Test should be acceptable to the population Diagnostic tests performed when a positive test is found should be agreed upon Criteria of a Screening Test The Test “DRE and PSA” Bangma et al., Urology, 46(6): 773, 1995 Rate of Detection of Prostate Cancer by Needle Biopsy Positive Predictive Value of DRE and PSA (n=6630) PSA (ng/ml) 0-2 2-4 4-10 >10 DRE- 1% 15% 25% >50% DRE+ 5% 20% 45% >75% Modified from Catalona et al: J Urol 1994: 151:1283. Positive Predictive Value of PSA and DRE for Prostate Cancer 50 45 40 35 30 25 20 15 10 5 0 46.6 31.6 25.5 23.2 24.6 14.6 DRE+ PSA >4 PSA <4 & PSA >4 & PSA >4 & PSA >4 DRE+ DREDRE+ or DRE+ PREDICTIVE MODELING TABLES TO CALCULATE RISK OF POSITIVE BIOPSY BASED ON DRE, PSA, F/T PSA RATIO AND PSA DENSITY IN MEN WITH PSA < 10 NG/ML Tewari, Boorjan, Bartsch, 2005 NOT SUSPICIOUS FOR CANCER SUSPICIOUS FOR CANCER DRE FINDINGS AGE GROUPS <40 YEARS 41-50 YEARS 51-60 YEARS 61-70 YEARS >70 YEARS <40 YEARS 41-50 YEARS 51-60 YEARS 61-70 YEARS >70 YEARS F/T PSA RATIO PSA DENSITY PROBABILITY OF FINDING CANCER FOLLOWING SYSTEMIC SEXTANT BIOPSY OF THE PROSTATE MEAN PROBABILITY (95 % UPPER AND LOWER CONFIDENCE LEVELS) FREE VERSUS COMPLE X PSA RATIO >15% <.15 (Large prostate) 5 (3-6) 7 (6-9) 11 (10-13) 17 (15-20) 25 (22-29) 11 (7-16) 17 (12-22) 24 (19-30) 34 (28-41) 46 (39-54) .15-.2 (Medium prostate) 8 (6-11) 12 (9-16) 19 (15-22) 27 (23-32) 38 (32-43) 18 (12-26) 26 (19-34) 36 (29-45) 48 (40-56) 60 (52-68) >.20 (Small prostate) 10 (7-14) 15 (12-20) 23 (19-27) 33 (28-38) 44 (38-50) 22 (15-31) 31 (24-41) 43 (34-51) 55 (47-63) 66 (58-73) FREE VERSUS COMPLE X PSA RATIO <15% <.15 (Large prostate) 7 (6-9) 11 (10-13) 17 (15-19) 25 (22-28) 35 (31-40) 16 (12-22) 24 (19-31) 34 (28-41) 46 (39-53) 58 (50-65) .15-.2 (Medium prostate) 12 (9-16) 18 (15-22) 27 (23-31) 37 (33-42) 49 (43-55) 26 (18-35) 36 (28-45) 48 (40-56) 60 (52-67) 71 (64-77) >.20 (Small prostate) 15 (12-20) 23 (19-27) 32 (28-36) 44 (39-48) 56 (50-61) 31 (23-41) 42 (34-51) 54 (47-62) 66 (59-72) 76 (70-81) PSA density should be calculated by ultrasound. A new model will be available soon if PSA density is not available) Serum PSA Levels Rise Prior to the Development of Significant Cancer From Carter HB et al. JAMA 267:2215,1992 Criteria of a Screening Test The Test “DRE and PSA” AUA Best Practice Policy • PSA detects more tumors than does DRE and it detects them earlier • Most Sensitive method uses both DRE and PSA PSA Best Practice Policy, Oncology, 14(2), Feb. 2000 Factors That Affect PSA • • • • • • Prostatitis Benign Prostatic Hyperplasia (BPH) Prostate Cancer Physical Activity Infection Medications – finasteride (Proscar/Propecia) • • • • Herbal Medicines – Saw Palmetto, PC-SPES, Ejaculation Rectal Examination Urinary Retention/Cystoscopy Sensitivity/Specificity of PSA • Sensitivity: 67.5-80% (20-30% tumors will be missed if PSA<4.0 ng/ml used) Ways to Improve Sensitivity: a.) age-adjusted PSA b.) PSA velocity • Specificity: 60-70% (if PSA>4.0 ng/ml) (only ¼ prostate biopsies reveal CaP) Ways to Improve Specificity: a.) Age adjustment b.) Free-to-total PSA c.) PSA density Improvements on PSA • Age-adjusted PSA Age • Free-to-Total PSA (14-28%) PSA Cutoff (ng/ml) <40-50 2.5 50-60 3.5 60-70 4.5 >70 6.5 • PSA Velocity (>0.75ng/ml/yr) Criteria of a Screening Program • The Disorder • The Test • The Treatment • The Screening Program Criteria of a Screening Test “The Treatment” • Watchful Waiting • Hormonal Deprivation Therapy • Radiation Therapy • Radical Prostatectomy Criteria of a Screening Program • The Disorder • The Test • The Treatment • The Screening Program Policies of Prostate Cancer Screening Group Policy Statement AUA Screen annually at age 50 Take personal decision after consultation ACS Screen annually at age 50 Provide risk and benefit information AMA Mass screening is premature Allow “well informed” decision ACP Routine PSA is “inappropriate” Counsel patient Introduction as policy is premature Provide risk and benefit, await randomized trials EU Recommendations Evidence for the Effectiveness of Screening • PSA screening initiated in 1989 • A decrease in prostate cancer mortality has been demonstrated in the U.S. by 4.4%/year from 1994-97 • Total decrease in mortality of 17.6% Cost per annual adjusted life year for annual Prostate cancer screening Howard. J Health Econ., 24(5): 891-906, Sept. 2005 Practice Patterns of General Practitioner Howard. J Health Econ., 24(5): 891-906, Sept. 2005 Practice Patterns Amongst General Practitioners Question n (%) 95% CI for% Do you perform a DRE in all males with LUTS? 220 (76) 67.2–84.0 Do you measure PSA in all males with LUTS? 82 (28) 19.3–37.0 Is the decision to refer the patient to a urologist affected by the patient's PSA value? 230 (79) 71.1–87.0 Is the decision to refer affected by the patient's age? 190 (65) 55.9–74.6 Is the decision to refer affected by the patient's symptoms? 272 (93) 88.5–98.5 Is the decision to refer affected by the findings of DRE? 254 (87) 80.7–93.9 151 (52) 42.1–61.7 Do you measure PSA as part of a general health check-up? 29 (10) 4.1–15.8 If you perform PSA testing, do you tell the patient what a PSA test can show? 247 (85) 77.9–91.9 Do you perform PSA screening for PC? 41 (14) 7.2–21.0 Would you refer asymptomatic patients with elevated PSA? Jonler et al., Scan J Uol Nephol, 39: 214-218, 2005 Side effects of screening Flip side: Screening cause harm Impact of treatment on overall survival Gain in LE (Mo) Myocardial revascularization 1 vessel 2 vessels 3 vessels Heart Transplantation Cholecystectomy Appendectomy Treatment of prostate cancer (Fleming) Gl 5-7 Gl 8-10 Wright & Weinstein NEJM 1998:339:380-6 7 0-8 4-14 31-99 2-3 2-31 1-11 30-60 Controversies in Screening • Decline in mortality since 1989 is too rapid given the indolent natural history of prostate cancer • Improvements in locally advanced disease could explain decline in mortality • Decline in mortality has been seen in countries where screening is not prevalent Quebec City Screening Study Quebec City Screening Study • November 1988-Decmeber 1996 • 46,193 men randomized screening vs. non-screening • Screening Group: 8,137 were screened • Relative risk of dying of CaP was 3.7 times higher in the control group • 69% reduction in mortality with screening Labrie et al., Prostate, 38(2): 83-91, 1999 Tyrol Prostate Cancer Screening Group • 1993-1998, PSA screening offered to 65,123 men in Tyrol, Austria Mortality Rates • 42% reduction in prostate cancer mortality Bartsch et al., Urology, 58(3): 417-24, 2001 Incidence by Stage Olmstead County Screening Trial • Retrospective analysis of death record between 19801997 • Decline in mortality of 22% between the earliest and most recent time periods Roberts et al., J Urol, 161: 529, 1999 Trends in Prostate Cancer Mortality Cost Effectiveness of PSA Screening Intervention Liver Transplantation Screening Mammography (age <50) Worst Case – CaP Screening CABG-2 vessels (angina) Captopril for HTN HCTZ for HTN Best Case- CaP Screening Stop Smoking-MD Message Thompson et al., Oncology, 9: 141-5, 1995 Cost Per Quality-Adjusted LifeYear Gained $237,000 $232,000 $145,000 $106,600 $82,600 $23,500 $8,700 $1,300 Problems with Screening Lead Time Bias Length Time Bias Thompson, Recent Advances in Prostate Cancer Breast Cancer vs. Prostate Cancer 1998 PROSTATE CA New Cases/Yr. Deaths/Yr. Deaths/Cases Lifetime risk of Developing Mets at Diagnosis Mortality Rate Trend (22 yr.) 5 Yr. Relative Survival Rate Median Age at Diagnosis Median Age at Death Scardino, MSKCC 184,500 39,200 21% 17% 9% + 17% 93% 71 yr 77 yr BREAST CA 180,300 43,900 24% 14% 6% - 3% 85% 64 yr 68 yr Ongoing Randomized Screening Trials • Prostate, Lung, Colon and Ovarian (PLCO) Trial of the NCI Q: Does screening decrease mortality? • European Randomized Study of Screening for Prostate Cancer (ERSPC) Q: Difference in CaP mortality in screened vs. unscreened patients? Q: Quality of life differences in screened population? • Prostate Cancer Intervention Vs. Observation Trial (PIVOT) Q: Does early, aggressive treatment decrease mortality? • Prostate Cancer Prevention Trial (PCPT) Q: Can finasteride prevent prostate cancer? Prostate, Lung, Colorectal and Ovarian (PLCO) Trial Men (74,000) and women (74,000) ages 55 to 74 years will be randomized to a control arm (routine medical care) or a screening arm which includes: • • • • Prostate: Lung: Colorectal: Ovarian: PSA and DRE CXR Flexible sigmoidoscopy Pelvic exam, CA125, Transvaginal ultrasound ERSPC Trial • Large, International cooperative study initiated in 1994 • Goal is to compare prostate cancer mortality between screened and control arms • With 165,000 men age 55-69 with a 20% contamination rate, the trial will reach a power of 86% to show a 20-25% mortality reduction • Results expected in 2008 ERSPC Trial Impact of PSA on Survival Tsodikov et al. UC Davis What Can We Do While we Await the Results? • Improve diagnostics: 1.) Imaging 2.) More sensitive PSA • Improve Treatment Stratification: 1.) Nomograms • Improve Surgical Technique (lower morbidity) 1.) nerve sparing 2.) nerve grafts 3.) Laparoscopic Prostatectomy Improved Cancer Detection Through Imaging Endorectal MRI/Spectroscopy • Potential improvement over ultrasound • Biochemical gradients to decipher cancer from benign • Remains investigational • Possible role in high risk patients MRN 309468 Endo-rectal coil MRI * * * Image 8 I 54.44 mm Image 9 I 57.56 mm H H H H H H H H H H sc vc H H H H H H H H H vc H H H H H H H Treatment Stratifications • Allow for improvement in patient understanding • More objective in guiding treatment decisions • Less physician bias Preoperative Nomogram for Prostate Cancer Recurrence Points PSA 0 10 0.1 30 T1c 40 T2c 60 Month Rec. Free Prob. 9 10 12 70 80 90 100 16 20 30 45 70 110 T1ab T2b Biopsy Gleason Grade 2+ 2 0 60 T3a 2+3 3+ 2 Total Points 50 2 34 6 7 8 1 T2a Clinical Stage 20 20 4+ 3+ 4 3+3 40 .96 60 .93 .9 80 100 .85 .8 120 .7 140 160 .6 .5 .4 .3 .2 180 200 .1 .05 Instructions for Physician: Locate the patient’s PSA on the PSA axis. Draw a line straight upwards to the Points axis to determine how many points towards recurrence the patient receives for his PSA. Repeat this process for the Clinical Stage and Biopsy Gleason Sum axes, each time drawing straight upward to the Points axis. Sum the points achieved for each predictor and locate this sum on the Total Points axis. Draw a line straight down to find the patient’s probability of remaining recurrence free for 60 months assuming he does not die of another cause first. Note: This nomogram is not applicable to a man who is not otherwise a candidate for radical prostatectomy. You can use this only on a man who has already selected radical prostatectomy as treatment for his prostate cancer. Instruction to Patient: “Mr. X, if we had 100 men exactly like you, we would expect between <predicted percentage from nomogram - 10%> and <predicted percentage + 10%> to remain free of their disease at 5 years following radical prostatectomy, and recurrence after 5 years is very rare.” Kattan MW et al: JNCI 1998; 90:766-771. 1997 Michael W. Kattan and Peter T. Scardino 3D Conformal Radiation Therapy Nomogram for PSA Recurrence 0 Points Pretreatment PSA 10 20 0.3 Bx.Gl.Sum Dose (gy) 40 1 50 60 2 3 80 100 4 70 5 80 6 7 9 10 90 100 25 50 100 T3ab T3c T2a Clinical Stage 30 T2b T2c T1c 3 35 7 9 2 24 6 88 8 72 10 68 64 No Hormones Total Points Yes 0 20 40 60-Month Recurrence Free Prob. 0.99 60 0.98 0.95 0.9 0.8 0.7 120 0.5 140 0.3 0.1 160 0.01 180 Palm Pilot Nomogram Software • Includes pretreatment and postoperative predictions. • Uses published nomograms in prostate cancer. Postoperative Nomogram for Prostate Cancer Recurrence 0 Points Preop PSA 0.1 4 Gleason Sum Extraprostatic Ext. Surgical Margins 10 20 0.2 30 0.3 40 0.5 50 0.7 6 60 1 70 2 8 3,5 80 3 4 90 6 100 8 10 100 10 7 9 Inv.Capsule Established None Focal Pos Neg Yes Seminal Ves. Invasion Lymph Nodes No Pos Neg Total Points 84-Month Rec. Free Prob. 0 40 80 0.99 0.98 120 0.95 0.9 160 200 240 280 0.8 0.7 0.5 0.3 0.1 0.01 1998 Michael W. Kattan and Peter T. Scardino Technical Improvements in Surgery • Cavernosal nerves necessary for postoperative erectile functions • In advanced disease, nerves may need to be resected to obtain a negative margin • Sural nerve or genitofemoral nerve serve as sources of nerve grafts in this setting Laparoscopic/Robotic Prostatectomy • Minimally invasive form of prostatectomy • Shorter hospital stay, less blood loss, improved optical visualization • No long data regarding cancer control, potency or quality of life Conclusion • Prostate cancer screening is controversial • More cost-effective means at targeting high risk populations may be more reasonable • We await results of randomized screening trials • While we await results of screening trials, we continue to improve prostate cancer treatment with cancer control and quality of life as our primary aims.