PSA and Active Surveillance: Less of one, more of the other

1. PSA and Active Surveillance: Less of one, more of the other Terence N Chapman MD August 30, 2012

2. Terence Chapman MD – Bio • Residencies: General Surgery and Urology • University of Virginia • Fellowship: Urologic Oncology / Robotic Surgery • Roswell Park Cancer Institute (where PSA was discovered!) • Member • Society of Urologic Oncology • Society of Urologic Robotic Surgeons

3. Prostate Cancer- Quick Facts • 50% of men over 50 harbor prostate cancer (Franks, LM Cancer 1973) • Men in North America have an 18% risk of diagnosis • 241,740 new cases; 28,170 deaths in 2012 (Cancer Facts and Figures) • Probability of CaP related mortality is 2.8% (Klotz, L JCO 2010) • Most men with screen-detected cancers will not die of their disease (Thompson IM NEJM 2004)

4. USPSTF on PSA testing - Headlines "Prostate Test Recommendation Draws Mixed Reviews," MedPage Today "Editorial: If PSA test saves lives, averages don't matter," USA Today "Panel's Advice on Prostate Test Sets Up Battle," The New York Times "Task Force to Men: Don't Get PSA Test," KSBY "Report Resets Prostate Testing Debate," The Wall Street Journal "Should I get screened for that?," CNN

5. Prostate Cancer USPSTF made final recommendation against routine PSA screening (“Grade D”) based on available evidence comparing harms and benefits (PLCO, ERSPC, PIVOT) “Five randomized controlled trials (two fair- and three poor-quality) and two meta-analyses evaluating the impact of PSA-based screening on prostate cancer mortality were identified” (http://www.ncbi.nlm.nih.gov/books/NBK82303) Should not be interpreted as “no man should ever have a PSA test”

6. Prostate Cancer – PSA trials

7. PSA - trials Analysis of the two “negative” trials does show trend toward survival benefit in intermediate and high risk cancer Further analysis of the ERSPC trial showed a 50% reduction in mortality in group with longest followup Could it be that treatment of low risk men (with no effect) may be “cancelling out” the effect of treating men at higher risk?

8. Prostate Cancer • USPSTF recommendation did not address: • Men in high risk groups • African-American men • Strong family history • Morbidity of prostate cancer (quality of life) • Metastases - bone • Voiding dysfunction • Role of PSA in reduced death rate from prostate cancer since its widespread use

9. Prostate Cancer According to SEER data, in 1990 the incidence of newly diagnosed metastatic prostate cancer was 67 per 100,000 and in 2005 it had dropped to 23 per 100,000 – a 66 percent decrease. The 1990 age-adjusted death rate from prostate cancer was 39 per 100,000. In 2009, the death rate from prostate cancer was 18.5 per 100,000 men(http://www.cdc.gov/uscs)

10. Prostate Cancer Models developed by the NIH-funded Cancer Intervention and Surveillance Modeling Network (CISNET) prostate group have demonstrated that early detection through screening could account for approximately 45% to 70% of the decline in prostate cancer mortality under a ‘‘stage-shift’’ mechanism for screening benefit (Etzioni R, et al Cancer Causes Control 2008)

11. Prostate Cancer – Mayo Clinic Study Not a single man with a baseline PSA < 1.0 ng/ml between the ages of 40-49 developed intermediate- or high-risk cancer with nearly 20 years of follow-up. Men with low PSAs were also very unlikely to develop a low-risk prostate cancer. 75 percent of men aged between 40 and 49 years of age could avoid annual PSA tests for the next 10 years if their baseline PSA is < 1.0 ng/ml.

12. PSA Pearls • AUA recommendation: Baseline PSA after age 40 to establish “baseline” • Median PSA of 0.7: if above = increased risk • PSA > 1.0 may warrant closer follow up • PSA < o.8 can defer repeat testing for 5-10 years • 90 % of prostate cancer deaths in men with PSA > 2 at age 60 (Lilja BMJ 2010) • Risk of death increases with PSA, but overall risk low

13. Risk of Prostate Cancer Death by PSA

14. PSA Pearls • PSA < 1.0 at age 60 associated with extremely low (0.3%) risk of prostate cancer mortality (Lilja BMJ 2010) • In the Baltimore Longitudinal Aging Study, not a single man over age 75 with a PSA below 3.0 ng/ml died of prostate cancer (Schaeffer, EM J Urol 2009) • Half of prostate cancer deaths were in men diagnosed over age 75

15. PSA - Conclusions • The mortality rate form prostate cancer has declined dramatically since PSA introduced • Likely significant PSA contribution to trend but debatable as to what degree • Overdiagnosis and overtreatment a problem • Active surveillance to the rescue!

16. PSA - Conclusions • Smarter use of PSA rather than mass screening • IDM: Informed Decision Making • Continued refinement of PSA performance (free PSA, PSA velocity) • Continued research into replacements and/or enhancements (PCA3) which might select only men with potentially lethal cancers

17. Active Surveillance - Definition Active Surveillance is a strategy with implied curative intent if necessary “Watchful waiting” implies palliative approach in men with short life expectancy Designed to monitor men with low-risk prostate cancer and intervene if/when progression occurs

18. Surveillance – For Whom? • T1c or T2a • PSA < 10 • Gleason ≤ 6 • Must have had extended (10-14 cores) biopsy • The above represent 45% of all newly diagnosed cancers in US and Canada (150,000 men)

19. Surveillance – For Whom? • PSA q 3 months x 2 years then q6 months • Repeat biopsy at 1 year • MRI can be helpful in rising PSAs with little disease • PSA doubling time • PSADT > 3 yrs is stable

20. Surveillance – Pros • Reduce morbidity and cost of unnecessary treatment • Though AS has significant costs • Low morbidity and mortality (Klotz, 2012) • Improved quality of life (Klotz, 2012) • Similar outcomes vs. men treated with immediate curative therapy(Klotz, L JCO 2010)

21. Surveillance – Cons Potential for understaging / missed chance for cure Relatively arbitrary clinical criteria to define “insignificant” tumors Limited ability to predict tumor biology or predict progression with only PSA kinetics and re-biopsy Psychological burden on some patients ? Risk of ED from biopsies ? Worse treatment outcomes on delayed basis

22. Patient Discussion • MSKCC nomogram output • Anatomical diagrams and models • Discussion of all options and outcomes/risks • Surgery • Radiation (and offer of consultation with Rad Onc) • Surveillance • Other (HIFU, cryotherapy) • Option to pursue treatment always present

23. Patient Discussion

24. Patient Discussion • MSKCC nomogram output • Anatomical diagrams and models • Discussion of all options and outcomes/risks • Surgery • Radiation (and offer of consultation with Rad Onc) • Surveillance • Other (HIFU, cryotherapy) • Option to pursue treatment always present

27. Surveillance - Outcomes Nine published series exist with 2,900 patients 77-100% OS, 97-100% DSS One-third have been definitively treated (8-51%) Median followup 43 mos Over 300 have ≥ 10 yrs of followup Klotz, LM JCO 2010

28. Final Analysis Many patients diagnosed in 2012 can and should reasonably consider AS as a treatment option though there is small but real risk of failure of delayed tx The decision is ultimately the patient’s and is best made after an educational discussion of options tailored to the patients capacity to process the information Future development of better tools will ideally eliminate need for surveillance

29. Final Analysis • Abandonment of PSA is probably a bad idea • No such thing as the good old days in prostate cancer! • Better, smarter use of PSA is a great idea • No more indiscriminate screening • Development of new tools is under way • Genetics, imaging • More use of active surveillance is a great idea