1. Prostate Screening in 2009: New Findings and New Questions Durado Brooks, MD, MPH Director, Prostate and Colorectal Cancer

2. Screening Recommendations ACS Screening Guidelines - Process All American Cancer Society cancer prevention

3. ACS Screening Recommendations Prostate Cancer Early Detection Guidelines Men age 50 and over with at least a 10 year life expectancy should receive information regarding possible benefits and limitations of finding and treating prostate cancer early, and should be offered both the PSA blood test and digital rectal exam annually Men in high risk groups (African Americans, men with close family members---fathers, brothers, or sons---who have had prostate cancer diagnosed at a young age) should be informed of the benefits and limitations of testing and be offered testing starting at age 45

4. Testing Controversy. Types of Tests Diagnostic Tests - Tests done because of an identified problem (disease is suspected) Screening Tests -Test done on people who have no symptoms of disease There is widespread agreement on the use of diagnostic tests for prostate cancer Screening for prostate cancer is much more controversial What are Tests for Prostate Cancer?

5. Key Questions  Does screening extend men’s lives (are there benefits)?  Does screening lead to health problems (are there harms)?  Do the benefits outweigh the harms? Does screening for Prostate Cancer save lives?

6. Changes in the PSA Era.  Tyrol, Austria 42% mortality reduction  Olmstead County, Minnesota 22% mortality reduction  SEER Decreased mortality in white men  Department of Defense Increased early stage disease Does screening for Prostate Cancer save lives?

7. Five-year Relative Survival (%)* during Three Time Periods By Cancer Site *5-year relative survival rates based on follow up of patients through 2003. †Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates. Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control and Population Sciences, National Cancer Institute, 2006. Site1975-1977 1984-1986 1996-2002 All sites505366 Breast (female)757989 Colon 515965 Leukemia354249 Lung and bronchus131316 Melanoma828692 Non-Hodgkin lymphoma485363 Ovary3740 45 Pancreas23 5 Prostate6976100 Rectum495766 Urinary bladder737882

8. .  Prostate cancer death rates have fallen during the PSA era, but it is not clear this is primarily due to screening  Other possible reasons for this decline:  Disease is found earlier because of  increased awareness  utilization of diagnostic PSA testing  Improved treatments Does screening for Prostate Cancer save lives?

9. Limitations of screening.  False negative results  False positive results  Overdiagnosis Does screening for Prostate Cancer save lives?

10. Limitations of screening.  False negative results – PSA and DRE “normal”, but cancer is present – May lead to false reassurance, delayed diagnosis  Research has shown that no cut-off value of PSA is completely reliable to rule-out cancer – Prostate Cancer Prevention Trial end of study biopsies found cancer in some men with PSA less than 1.0 ng/ml Does screening for Prostate Cancer save lives?

11. Population Screening with PSA 4.0+ PSA 4+ 7.6% Positive biopsy 25% High grade 19% Screen 10,000 Men PSA 4+ 760 Cancer 190 High grade 36 PSA <4 9240 Cancer 1386 High grade 208 “Normal PSA” 92.4% Positive biopsy 15% High grade 15% <4.0 PSA SEER, PCAW, Prostate Cancer Prevention Trial Data

12. Limitations of screening.  False negative results  False positive results  PSA and/or DRE abnormal, but no cancer found  Can lead to worry, additional tests, and increased costs Does screening for Prostate Cancer save lives?

13. Limitations of Prostate Cancer tests Age (in years) # With PSA >4.0 # With Cancer # False Positives 50s51–23–4 60s153–510–12 70s27918 If 100 men in each age group are tested: False positive results False Positives = high PSA, but no cancer

14. Limitations of screening.  False negative results  False positive results  Overdiagnosis  Some (many?) cancers found by screening grow very slowly and will never cause problems Does screening for Prostate Cancer save lives?

15. Risk of Prostate Cancer Diagnosis by Age and by Race/Ethnicity Risk during the next 15 years (per 1000 men ) Race/EthnicityAt age 50At age 65 All50117 African American White 76 44 163 113 American Indian & Alaska Native 1435 Asian & Pacific Islanders 1884 Hispanic2994

16. Risk of Death From Prostate Cancer by Age and by Race/Ethnicity Risk during the next 15 years (per 1,000 men) Race/EthnicityAt age 50At age 65 All216 African American 534 White American Indian & Alaska Native 2222 14 9 Asian & Pacific Islanders 17 Hispanic112

17. New Findings in Screening. Results from 2 major, long-term studies reported this year – their findings conflict  ERSPC (European Randomized Screening for Prostate Cancer)  PLCO (Prostate, Lung, Colon and Ovarian) Does screening for Prostate Cancer save lives?

18. ERSPC Began in 1991 in seven European countries 162,000 men aged 55 to 69 randomized to screening vs usual care Median follow-up about nine years

19. ERSPC Findings More cancers detected with screening –5990 cancers in screening group –4307 cancers in control group Fewer prostate cancer deaths in screening group –261 deaths in screening group –363 deaths in control group Conclusion: 20% lower prostate cancer deaths in screening group

20. ERSPC Multiple concerns/questions: –Minimal-to-no participation of men of African origin –Different screening and follow-up protocols Different PSA levels and DRE usage Variable treatment and outcomes (quality questions) –To prevent one prostate cancer death 1410 men screened 48 men treated (with attendant risks, side-effects, complications) Bottom line –Screening every 4 years, with PSA threshold of 3 ng/ml may decrease chance of prostate cancer death Unclear how this correlates to current U.S. pattern of annual screening with different PSA “triggers” (2.5 – 4.0 ng/ml) –High level of overdiagnosis and overtreatment with this approach (although these numbers are likely to go down after longer follow up period) –Relevance of findings to African American men unclear

21. PLCO Began in 1993, ten U.S. Centers 73,000 men aged 55 to 74 randomized to screening annually vs routine follow- up Median follow-up about ten years

22. PLCO Findings At 7 years, screening found more cases of cancer –2,820 prostate cancers in annual screening group –2332 cases in “usual care” group More prostate cancer deaths in screening group –7 years: 50 deaths among annually screened compared with 44 in usual care group –10 years: 92 deaths in annually screened vs 82 in usual care Conclusion – No mortality benefit with screening –Prostate cancer deaths similar in both groups –Overall death rate slightly higher in screened (not statistically significant)

23. PLCO Questions/concerns with study –44% of men had at least one PSA test prior to study May have excluded more aggressive prevalent cancers Selectively included men with prostate cancers not detected by PSA screening (bias against showing a screening effect) –Many men in the “usual care” group were screened during the course of the study Initially powered for 20% contamination, later revised to 38% PSA screening in control group : 40% first year; 52% by year 6 –Less than half of those with a positive screen result had a biopsy –Insufficient African American participation (< 5%) to allow specific analysis of outcomes in this group Bottom line – no difference in death rates at 10 years between intensively screened and less- intensively screened men Relevance of these findings to African American men is unclear

24. Treatment Options New Findings in Treatment JAMA, September 2009

25. Watchful Waiting Study published September 2009 14,500 men aged 65 + with localized prostate cancer No active treatment for at least 6 mos following prostate cancer diagnosis At 10 years, 9% of men had died of prostate cancer –1017 men died of prostate cancer –5721 men died of other causes –7420 men still alive Approximately 11% African Americans in study population, but authors did not report findings separately for this group

26. PSA screening detects cancers earlier. Treating PSA-detected cancers may be more effective, but this is uncertain. PSA may contribute to the declining death rate but the extent is unclear False positives are common. Overdiagnosis and overtreatment is a problem, but magnitude is uncertain. Treatment-related side effects are fairly common. Potential Benefits Summary Potential Harms Bottom line: Uncertainty about degree of benefits and magnitude of harms

27. Screening Recommendations Current ACS Screening Guidelines Men age 50 and over with at least a 10 year life expectancy should receive information regarding possible benefits and limitations of finding and treating prostate cancer early, and should be offered both the PSA blood test and digital rectal exam annually Men in high risk groups (African Americans, men with close family members---fathers, brothers, or sons---who have had prostate cancer diagnosed at a young age) should be informed of the benefits and limitations of testing and be offered testing starting at age 45

28. Thank You!