1. Prostate Cancer Screening 2012 Paul L. Crispen, MD Department of Surgery University of Kentucky

2. Conflicts of Interest I am a Urologist I have a family member who died of prostate cancer

3. Critical Questions Should all men be screened? Who should be offered screening? How should men be screened?

4. Outline Purpose of screening Method of screening Contemporary screening trials Current Guidelines Questions

5. Purpose of Screening Early detection of potentially lethal malignancy Early treatment will confer advantages over treatment of clinically detected malignancy

6. Purpose of Screening Earlier detection of potentially lethal malignancy

7. Purpose of Screening Early treatment will confer advantages over treatment of clinically detected malignancy Five year survival

8. Method of Screening Digital Rectal Exam –Subjective Serum Prostate Specific Antigen (PSA) –Not specific

9. What causes a change in PSA? BPH Prostate Cancer Prostate inflammation/infection - prostatitis Medications: e.g. 5-alpha reductase’s, CAM Other causes: –Trauma/Instrumentation (e.g. cystoscopy, biopsy) –Radiation –Ejaculation and DRE (variable, inconsistent) –PSA assay

10. Prostate Specific Antigen (PSA) PSA <4 ng/mL considered “normal” PSA 4-10 ng/mL assoc. with 22-30% positive biopsy rate PSA >10 ng/mL assoc. with 66% positive biopsy rate Oesterling J, et al. Cancer: Principles & Practice of Oncology. 5th ed. 1997;1322-1386. Brawer MK. CA Cancer J Clin. 1999;49:264-281.

11. Prostate Cancer in low PSA PSA level Prevalence of Prostate Cancer High-Grade Disease 3.1 - 4.026.9%25.0% 2.1 - 3.023.9%19.1% 1.1 - 2.017.0%11.8% 0.6 - 1.010.1%10.0% <0.56.6% 12.5% Thompson et al, JAMA 294:66-70, 2005. Thompson et al, NEJM 350:2239-46, 2004.

12. Prostate Cancer Screening Trials

13. NY Times: Health Section 2011 U.S. Panel Says No to Prostate Screening for Healthy Men By GARDINER HARRIS Published: October 6, 2011 Healthy men should no longer receive a P.S.A. blood test to screen for prostate cancer because the test does not save lives over all and often leads to more tests and treatments that needlessly cause pain, impotence and incontinence in many, a key government health panel has decided.

14. Screening reduced rate of prostate cancer death by 20% (with associated overdiagnosis risk) 1410 pts needed to be screened, 48 treated to prevent one death Schroder et al, NEJM 360: 1320-8, 2009

15. ERSPC

16. 162,243 men randomized Screening q 2-4 years vs. usual care –Compliance in screening group 82% –Screening in the control group ?? 11 years of follow up (median) Detection was higher in screening group –6963 cases vs. 5396, or cumulative incidence of 9.6% vs. 6.0%

17. ERSPC Screening  21% reduction in prostate- cancer death* Number needed to screen: 1055 Number needed to treat: 37 * Up to 29% reduction if corrected for noncompliance in the screening arm and contamination of the control arm.

18. At 11 years, 299 prostate-cancer deaths in screening group and 462 in the control group. Rate ratio 0.79, 95% confidence interval 0.68-0.91, p=0.003.

19. Caveats: 1. 52% contamination in control group -Cancers in control group were stage I and II 2. Limited follow-up 3. Substantial proportion pre-screened (~44%) Andriole et al, NEJM 360: 1310-9, 2009

21. PLCO 76,693 men in the US randomized, 1993-2001 Annual screening vs. usual care –Compliance in screening group 86% –Screening in the control group 52% 13 years of follow-up (median) Complications of screening –PSA and DRE: minimal –Biopsy: 68 per 10,000; infection, bleeding, retention Andriole et al. J Natl Cancer Inst 2012;104:125–132

22. Number of Cases Identified More cancers identified in the screening group (4250 vs. 3815). Rate ratio 1.12, 95% confidence interval 1.07-1.17.

23. Number of Prostate Cancer Deaths At 13 years, 158 prostate-cancer deaths in screening group and 145 in the control group. Rate ratio 1.09, 95% confidence interval 0.87-1.36.

24. Why do PLCO and ERSPC have different results? Contamination in the non-screening arm –50% in PLCO, and negligible in Europe Location of treatment Type of treatment

25. Potential Harm Prostate Biopsy: Majority are negative Bleeding Infection Prostate Cancer Treatment Erectile Dysfunction Urinary Symptoms/Incontinence

26. Potential Harm Potential harms: For every one life saved… –Between 300 and 1000 men have to undergo screening –Between 10 and 40 men have to undergo treatment –Indiscriminate treatment of low-risk disease Estimates indicate over one million extra men have undergone treatment in the US due to PSA screening to save at most 56,000 lives Albersten JNCI 2009

27. U.S. Guidelines American Urological Association –40 years old –> 10 year life expectancy –Informed consent –PSA and DRE American Cancer Society: –50 years old (45 with increased risk) –Informed consent –PSA with or without DRE

28. American College of Physicians: –Patient counseling NCCN: –Patient counseling beginning at age 40 American Academy of Family Practitioners: –Recommends against screening US Preventive Services Task Force: –Recommends against screening U.S. Guidelines

29. International Guidelines European Association of Urology –Against national screening UK and NZ –Case by case basis following patient counseling Japanese Urological Association –Baseline PSA at 40 years –Annual at 50 years –No upper age limit for screening

30. How does prostate cancer screening efficacy compare with screening for other common cancers?

31. Breast Cancer Screening CISNET and STS Number needed to screen: –STS: 465 –CISNET: 40-49 years: 746 50-59 years: 351 60-69 years: 233 70-79 years: 377 Tabar et al, Journal of Medical Screening 2004. Hendrick and Helvie, AJR 2012

32. Colon Cancer Screening PCLO –Flexible sigmoidoscopy Relative risk reduction 12 years: –Incidence 21% –Cancer specific death 26% Number needed to screen: 871 Schoen et al. NEJM 2012

33. Screening for Prostate Cancer: Comparison with Other Cancers Possible risk reduction Greater number need to screen Recent study suggest that appropriately targeted screening may improve these figures substantially for prostate cancer…

34. PLCO Sub-set Analysis of Healthy Men Sub-set analysis of men with no comorbidities (that predict cardiovascular or cancer mortality) Adjusted hazard ratio for screening group vs. unscreened group was 0.56 (0.33-0.95), p=0.03. Number needed to treat to prevent one PCa death at 10 years was 5. Crawford et al, JCO 2011 No Comorbidities One or more Comorbidities

35. Summary of Randomized Trial Data on Screening PLCO – No benefit of screening – Flawed due to contamination of the control arm ERSPC – 21% relative risk reduction – 1055 needed to screen; 37 needed to treat Screening may be beneficial – In younger, healthier men – As follow up lengthens – Targeted screening reduces NNS to ~300 and NNT to 10 or 12.

36. Screening Summary There are potential benefits –Potential prostate-cancer specific survival benefit in appropriate populations –More likely to benefit younger, healthier patients There are potential harms –False-positive test leading to other tests –Detection of indolent prostate cancer leading to unnecessary treatment and treatment related side effects Screening decisions must –Balance potential benefits and potential harms –Involve the patient – “shared decision-making”

37. Questions These are my opinions based on available data Opinions will continue to change as more data becomes available

38. Should all men be screened for Prostate Cancer? No

39. Who should be offered screening for prostate cancer? Life expectancy greater than 10 years Patients who request screening Patients who understand risks and benefits

40. How should men be screened for prostate cancer? PSA and DRE Starting at age 40-50 Ending at age 70-75 Interval of screening –Depends on PSA and risk factors

41. Thank You crispen.paul@uky.edu