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

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

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, 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
N Engl J Med, 360: , 2009
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: Schröder F, et al. N Engl J Med. 2009;360: 4

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 Göteborg Trial: 44% reduction in mortality
N Engl J Med, 360: , 2009
Andriole G, et al. N Engl J Med. 2009;360:
Schröder F, et al. N Engl J Med. 2009;360: 7

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 screening Increased survival is not a legitimate measure of success outside of a randomized clinical trial Reduction 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 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 neoplasia Sakr WA, et al. J Urol ;150:

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
Cancer spreads to lymph nodes
Zone of detection when cure is possible
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
Cancer spreads to lymph nodes
Zone of detection when cure is possible
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
Cancer spreads to lymph nodes
Zone of detection when cure is possible
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!
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 &

21. Concern #4: High Risk of 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 in two 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.