Prostate Cancer Screening: Con

Daniel P. Petrylak, MD

Yale University Cancer Center

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 / limitationsIn statistical methods

Thought to be well designed RCT with appropriate controls and respected steering committees, reported from 2009-2012

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

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

Andriole G, et al. N Engl J Med. 2009;360:1310-1319. Schröder F, et al. N Engl J Med. 2009;360:1320-1328.

PLCO: Prostate, Lung, Colorectal, and Ovarian Cancer Screening TrialERSPC: European Randomized Study of Screening for Prostate Cancer

ERSPC: Cumulative Risk of Death From Prostate Cancer

CI = confidence interval.Schroder et al, 2009.

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).

Andriole et al, 2009.

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

Pick level 1 evidence to make any point

NoPLCO: No reduction in prostate cancer mortality

YesERSPC: 20% reduction in mortality

25% reduction in metastatic disease

YesGöteborg 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.

Crawford, D JCO 2010

PLCO reanalysis: improved PCSM when comorbidities were considered.(22 v 38 deaths)

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

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

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

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.

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)

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."

Concern #1: Everybody Has Prostate Cancer—You Die with It

Not of It

PIN=prostatic intraepithelial neoplasiaSakr WA, et al. J Urol. 1993;150:379-385.

Look at the prevalence of prostate cancer!

Concern #2: You Don’t Help Most Men with Prostate Cancer When

You Find It

Death from prostate cancer

Metastatic disease develops

Cancer spreads to lymph nodes

Cancer spreads beyond prostate

Cancer detectable: PSA >4 ng/mL

Prostate cancer develops

Patient D

Patient C

Patient B

Patient A

Zone of detectionwhen cure is possible

Annual PSA and DRE

Death from prostate cancer

Metastatic disease develops

Cancer spreads to lymph nodes

Cancer spreads beyond prostate

Cancer detectable: PSA >4 ng/mL

Prostate cancer develops

Patient C

Zone of detectionwhen cure is possible

Annual PSA and DRE

Only this manbenefits

Concern #2: You Don’t Help Most Men with Prostate Cancer When You Find It

(cont’d)

Death from prostate cancer

Metastatic disease develops

Cancer spreads to lymph nodes

Cancer spreads beyond prostate

Cancer detectable: PSA >4 ng/mL

Prostate cancer develops

Patient D

Patient B

Patient A

Zone of detectionwhen cure is possible

Annual PSA and DRE

These three guysdo not benefit

Concern #2: You Don’t Help Most Men with Prostate Cancer When You Find It

(cont’d)

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…)

Cost

Expenditures

•Prostate- 8 billion 11.2%

•Lung- 9.6 billion 13.3%

•Breast 8.1 billion 11.2&

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

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

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.