Prostate Cancer Screening: Con

1. Prostate Cancer Screening: Con Daniel P. Petrylak, MD Yale University Cancer Center

2. Prostate Cancer “Screening” Trials Deviations / limitations In statistical methods • Norrköping • Quebec Study (RCT) – 1998 • Swedish Study (RCT) – 2004 • Tyrol Study – Population comparison (+ screen effect) • PLCO • ERSP • Göteborg • CAP and ProtecT (UK) are ongoing Thought to be well designed RCT with appropriate controls and respected steering committees, reported from 2009-2012

3. Three Largest Randomized PSA Screening Trials • ERSPC • PSA every 4 yrs in 182,000 men • PLCO • USA trial testing PSA every yr vs. no PSA screening in 76,693 men analyzed in ITT analysis • Göteborg • Randomized 20,000 man screening trial showed 44% reduction in death with little press • ERSPC subset ERSPC = European Randomized Study of Screening for Prostate Cancer; PLCO = prostate, lung, colorectal, ovarian; ITT = intent-to-treat. Schroder et al, 2009; Andriole et al, 2009. Hugosson J, 2010

4. Two Conflicting Studies:Originally Published Together PLCO: No reduction in PCa mortality (76,000 USA) Large number pre-screened = contaminated control group Limited follow up w/ single cut point for PSA 85% of the screened group had a PSA but 52% of the non-screened group had a PSA ERSPC: 20% reduction in mortality (182,000 EU) 25% reduction in metastatic disease No DRE, multiple countries with variable criteria 41% reduced metastasis, more cancers, lower Gleason Screen 1410, treat 48 to benefit 1 death PLCO: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial ERSPC: European Randomized Study of Screening for Prostate Cancer Andriole G, et al. N Engl J Med. 2009;360:1310-1319. Schröder F, et al. N Engl J Med. 2009;360:1320-1328.

5. ERSPC: Cumulative Risk of Death From Prostate Cancer • ERSPC demonstrates 20% reduction in prostate cancer death after 8.8 yrs of follow-up. The adjusted rate ratio for death from prostate cancer in the screening group was 0.8 (95% CI, 0.65–0.98; p = .04). CI = confidence interval. Schroder et al, 2009.

6. PLCO: Number of Prostate Cancers and Prostate Cancer Deaths PLCO trial suggested that PSA screening increases risk of cancer diagnosis but does not decrease risk of death Andriole et al, 2009.

7. Pick level 1 evidence to make any point No PLCO: No reduction in prostate cancer mortality Yes ERSPC: 20% reduction in mortality 25% reduction in metastatic disease Yes Göteborg Trial: 44% reduction in mortality Andriole G, et al. N Engl J Med. 2009;360:1310-1319. Schröder F, et al. N Engl J Med. 2009;360:1320-1328.

8. PLCO reanalysis: improved PCSM when comorbidities were considered. (22 v 38 deaths) Crawford, D JCO 2010

9. PLCO: no benefit for entire group • “contaminated” control arm • ~ 55% RRR for post-hoc defined subgroup. • ERSPC: 20% RRR; 25% reduction in metastatic disease • reduces if Goteborg or Rotterdam participants removed • improvements continue with time in NNS, NNT

10. Principles of Screening • Finding disease is not a measure of success in screeningIncreased survival is not a legitimate measure of success outside of a randomized clinical trialReduction of mortality in a randomized trial is the only true proof of effective screening

11. Cancer Screening • Well designed clinical studies have demonstrated the utility of: • Mammography and CBE for Breast Cancer • Stool Blood Testing, Sigmoidoscopy and Colonoscopy for Colorectal Cancer • Pap and HPV testing for Cervical Cancer

12. Thoughts • Screening doesn’t work for all cancers: Lung, neuroblastoma, and not all breast cancers • Need to separate diagnosis from treatment, clearly over treating men • But, need to remember that 28,000 men died in 2011 of CaP • We need to figure out who needs to be diagnosed and effectively treated.

13. USPSTF Prostate Cancer History • 2002: insufficient evidence to recommend for or against routine screening • 2008: against testing any man over age 75 years and gives “I” rating for prostate-cancer screening, (current evidence is insufficient to assess the balance of benefits and harms, for men younger than 75. • 2011: no healthy man undergo PSA screening unless symptoms of prostate cancer • Open to public comment until 11/8/2011 (NEW since 2009 mammography controversy)

14. Urology USPSTF Replies • Marberger EAU: "Clearly mortality is reduced by PSA screening, but it has to be done in younger and fit patients who have a life expectancy for whom this slow growing cancer can really be a threat,” • Lacy AUA: "We are concerned that the task force's recommendations will ultimately do more harm than good to the many men at risk for prostate cancer, both here in the US and around the world.“ "Until there is a better widespread test for this potentially devastating disease, the USPSTF -- by disparaging the test -- is doing a great disservice to the men worldwide who may benefit from the PSA test."

15. Concern #1: Everybody Has Prostate Cancer—You Die with It Not of It Look at the prevalence of prostate cancer! PIN=prostatic intraepithelial neoplasiaSakr WA, et al. J Urol. 1993;150:379-385.

16. Concern #2: You Don’t Help Most Men with Prostate Cancer When You Find It Death from prostate cancer Patient D Patient C Metastatic disease develops Zone of detectionwhen cure is possible Cancer spreads to lymph nodes Cancer spreads beyond prostate Patient B Cancer detectable: PSA >4 ng/mL Patient A Prostate cancer develops Annual PSA and DRE

17. Concern #2: You Don’t Help Most Men with Prostate Cancer When You Find It (cont’d) Death from prostate cancer Only this man benefits Patient C Metastatic disease develops Zone of detectionwhen cure is possible Cancer spreads to lymph nodes Cancer spreads beyond prostate Cancer detectable: PSA >4 ng/mL Prostate cancer develops Annual PSA and DRE

18. Concern #2: You Don’t Help Most Men with Prostate Cancer When You Find It (cont’d) Death from prostate cancer Patient D These three guys do not benefit Metastatic disease develops Zone of detectionwhen cure is possible Cancer spreads to lymph nodes Cancer spreads beyond prostate Patient B Cancer detectable: PSA >4 ng/mL Patient A Prostate cancer develops Annual PSA and DRE

19. Concern #3: It Costs Too Much! Cost • Initial estimates of screening men age 50–70 for prostate cancer • $25 billion during first year alone • Many countries don’t encourage it, fearing screening will “break the bank” (eg, England, Australia…)

20. Expenditures • Prostate- 8 billion 11.2% • Lung- 9.6 billion 13.3% • Breast 8.1 billion 11.2&

21. Concern #4: High Riskof Morbidity of Screening • Risks of screening: anxiety • Risks of biopsy: bleeding, infection, painful • Risks of treatment: impotence, incontinence, death, proctitis, cystitis, stricture • Risk of recurrence: as many as 1/3 of men will require a secondary treatment

22. And the Final Concern: No Proof that It Really Works in Reducing Deaths • Screening evaluated intwo trials • Prostate, lung, colorectal, ovarian (PLCO) screening study in the US (148,000 men and women randomized to screening or community standard of follow-up) • Europe: Rotterdam screening trial • Results of both: PLCO –Negative. ERSPC-? positive

23. Conclusions • A more rational policy is to screen appropriate men and treat only those with significant PCa. • The USPHSTF findings should be viewed as an opportunity to implement the above • Policy makers must consider risks and benefits to the USPHSTF recommendations on prostate cancer screening.