2. PSA Screening and Cancer Treatment Douglas S. Scherr, M.D. Assistant Professor of Urology Clinical Director, Urologic Oncology Weill Medical College-Cornell University

3. Criteria of a Screening Program The Disorder The Test The Treatment The Screening Program

4. Criteria of a Screening Program The Disorder -Prostate Cancer The Test The Treatment The Screening Program

6. U.S. Incidence and Mortality of Prostate Cancer Surveillance, Epidemiology and End Results (SEER) Data

7. Prevalence of Prostate Cancer Decade % Men With PIN Or CaP Sakr et al., J Urol, 150: 379, 1993

8. Criteria of a Screening Test 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 The Disorder “Prostate Cancer”

9. Lifetime Risk of Developing or Dying of Prostate Cancer for a 50-Year-Old Man in the United States Risk Proportional Lifetime Risk of Risk Ratio Risk Developing histologic cancer42 % 11.7 100 Developing clinical cancer16 % 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.

10. Criteria of a Screening Program The Disorder The Test The Treatment The Screening Program

11. 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

12. Criteria of a Screening Test The Test “DRE and PSA” Bangma et al., Urology, 46(6): 773, 1995

13. Rate of Detection of Prostate Cancer by Needle Biopsy Positive Predictive Value of DRE and PSA (n=6630) PSA (ng/ml) 0-22-44-10>10 DRE-1%15%25% >50% DRE+5%20%45% >75% Modified from Catalona et al: J Urol 1994: 151:1283.

14. Positive Predictive Value of PSA and DRE for Prostate Cancer 25.5 31.6 14.6 23.2 46.6 24.6

15. 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 DRE FINDINGS NOT SUSPICIOUS FOR CANCERSUSPICIOUS FOR CANCER 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)

16. Serum PSA Levels Rise Prior to the Development of Significant Cancer From Carter HB et al. JAMA 267:2215,1992

17. 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

18. 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

19. 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

20. Improvements on PSA Age-adjusted PSA Free-to-Total PSA (14-28%) PSA Velocity (>0.75ng/ml/yr) AgePSA Cutoff (ng/ml) <40-502.5 50-603.5 60-704.5 >706.5

21. Criteria of a Screening Program The Disorder The Test The Treatment The Screening Program

22. Criteria of a Screening Test “The Treatment” Watchful Waiting Hormonal Deprivation Therapy Radiation Therapy Radical Prostatectomy

23. Criteria of a Screening Program The Disorder The Test The Treatment The Screening Program

24. Policies of Prostate Cancer Screening GroupPolicy StatementRecommendations 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 EU Introduction as policy is premature Provide risk and benefit, await randomized trials

25. 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%

26. Howard. J Health Econ., 24(5): 891-906, Sept. 2005 Cost per annual adjusted life year for annual Prostate cancer screening

27. Practice Patterns of General Practitioner Howard. J Health Econ., 24(5): 891-906, Sept. 2005

28. Questionn (%)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 Would you refer asymptomatic patients with elevated PSA? 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 Jonler et al., Scan J Uol Nephol, 39: 214-218, 2005 Practice Patterns Amongst General Practitioners

29. Side effects of screening Flip side: Screening cause harm Impact of treatment on overall survival Gain in LE (Mo ) Myocardial revascularization 1 vessel 7 2 vessels 0-8 3 vessels 4-14 Heart Transplantation 31-99 Cholecystectomy 2-3 Appendectomy 2-31 Treatment of prostate cancer (Fleming) 1-11 Gl 5-7 30-60 Gl 8-10 Wright & Weinstein NEJM 1998:339:380-6

30. 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

31. Quebec City Screening Study

32. 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

33. Tyrol Prostate Cancer Screening Group 1993-1998, PSA screening offered to 65,123 men in Tyrol, Austria 42% reduction in prostate cancer mortality Bartsch et al., Urology, 58(3): 417-24, 2001 Mortality Rates Incidence by Stage

34. Olmstead County Screening Trial Retrospective analysis of death record between 1980- 1997 Decline in mortality of 22% between the earliest and most recent time periods Trends in Prostate Cancer Mortality Roberts et al., J Urol, 161: 529, 1999

35. Cost Effectiveness of PSA Screening Intervention Cost Per Quality-Adjusted Life- Year Gained Liver Transplantation $237,000 Screening Mammography (age <50) $232,000 Worst Case – CaP Screening $145,000 CABG-2 vessels (angina) $106,600 Captopril for HTN $82,600 HCTZ for HTN $23,500 Best Case- CaP Screening $8,700 Stop Smoking-MD Message $1,300 Thompson et al., Oncology, 9: 141-5, 1995

36. Problems with Screening Lead Time Bias Length Time Bias Thompson, Recent Advances in Prostate Cancer

37. Breast Cancer vs. Prostate Cancer 1998 PROSTATE CA BREAST CA PROSTATE CA BREAST CA New Cases/Yr. 184,500 180,300 Deaths/Yr. 39,200 43,900 Deaths/Cases 21 % 24 % Lifetime risk of Developing 17% 14% Mets at Diagnosis 9 % 6 % Mortality Rate Trend (22 yr.) + 17 % - 3 % 5 Yr. Relative Survival Rate 93 % 85 % Median Age at Diagnosis 71 yr 64 yr Median Age at Death 77 yr 68 yr Scardino, MSKCC

38. 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?

39. 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:PSA and DRE Lung:CXR Colorectal:Flexible sigmoidoscopy Ovarian:Pelvic exam, CA125, Transvaginal ultrasound

40. 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

41. ERSPC Trial

42. Impact of PSA on Survival Tsodikov et al. UC Davis

43. 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

44. 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

45. MRN 309468 Endo-rectal coil MRI

46. Image 8 I 54.44 mm Image 9 I 57.56 mm H H H H H H H H H H H H H H H H H H H H H H H H * * * sc vc vc

47. Treatment Stratifications Allow for improvement in patient understanding More objective in guiding treatment decisions Less physician bias

48. Biopsy Gleason Grade  2+  2 3+3  3+  4  2+3  4+  Total Points 0 20 40 60 80100120140160180200 60 Month Rec. Free Prob..96.93.9.85.8.7.6.5.4.3.2.1.05 3+  2 Clinical Stage T1cT1ab T2aT2cT3a T2b Points 0 10 20 30 40 50 60 70 80 90100 PSA 0.11236891012163045701107 20 4 Preoperative Nomogram for Prostate Cancer Recurrence 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 and to remain free of their disease at 5 years following radical prostatectomy, and recurrence after 5 years is very rare.”  1997Michael W. Kattan and Peter T. Scardino Kattan MW et al: JNCI 1998; 90:766-771.

49. 10 50 T2c T3c 2 4 6 3 5 3D Conformal Radiation Therapy Nomogram for PSA Recurrence

50. Palm Pilot Nomogram Software Includes pretreatment and postoperative predictions. Uses published nomograms in prostate cancer.

51. 10 3, Postoperative Nomogram for Prostate Cancer Recurrence  1998Michael W. Kattan and Peter T. Scardino

52. Technical Improvements in Surgery Cavernosal nerves necessary for post- operative 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

53. 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

54. 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.