controversies in psa screening - urology of central pa in psa screening why the controversy?...

CONTROVERSIES IN PSACONTROVERSIES IN PSASCREENINGSCREENING

Joshua Shipley, M.D.

(Andrews and Patel, Associates)


Why the controversy?

Randomized trials.

Recommendations from organizations.

2

Why The Controversy?Why The Controversy?

PSA originally introduced as a tumormarker to detect disease recurrence aftertherapy and to monitor effect of treatment.

PSA became adopted for prostate cancerscreening in the absence of studiesdemonstrating its efficacy for thispurpose.

3

Why The Controversy?Why The Controversy?

Harms and costs associated withscreening and treatments that occur as aresult of screening.

Two large randomized studies hadconflicting results and several factors thatimpact how the results are interpreted.

Several organizations have developedrecommendations that are varying andsometimes conflicting. 4

Randomized TrialsRandomized Trials

United States- PLCO (Prostate, Lung,Colon, and Ovarian Cancer ScreeningTrial)

Europe- ERSPC (European RandomizedStudy of Screening for Prostate Cancer)

– Initiated in the early 1990’s to determine whetherPSA-based screening results in a reduction inprostate cancer related mortality.

5

PLCOPLCO

From 1993-2001, men and women, ages55-74, enrolled at 10 centers across theU.S.

Exclusion: history of a PLCO cancer,current cancer treatment, starting in 1995-having had more than one PSA test inprior 3 years.

Andriole GL et al. N Engl J Med 2009;360:1310-1319. 6

PLCOPLCO

Annual PSA for 6 years and annual DREfor 4 years.

PSA >4.0 ng/mL was considered positive. If positive PSA or abnormal DRE,

diagnostic evaluation was decided by thepatients and their PCP’s.


PLCOPLCO

Primary Endpoint: Cause-specificmortality for each of the PLCO cancers.

Secondary Endpoints: Cancer incidence,staging, and survival.


Andriole GL et al. N Engl J Med 2009;360:1310-1319.

Characteristics of the Subjects at Baseline.

9

PLCOPLCO

Compliance with screening protocol was85% for PSA testing and 86% for DRE.

Control group:– 40% PSA testing in 1st year.

– 52% PSA tested by 6th year.– DRE 41-46%.

Andriole GL et al. N Engl J Med 2009;360:1310-1319.10

PLCOPLCO

At 10 years, prostate cancer diagnosed:– 3452 subjects in screened group.– 2974 subjects in control group.– Rate ratio 1.17, 95% CI, 1.11-1.22.

At 10 years, prostate cancer deaths:– 92 subjects in the screened group.

– 82 subjects in the control group.– Rate ratio 1.11, 95% CI, 0.83-1.50.



Number of Diagnoses of All Prostate Cancers (Panel A) andNumber of Prostate-Cancer Deaths (Panel B).

12


Tumor Stage, Histopathological Type, and Gleason Score forAll Prostate Cancers at 10 Years, According to Method of

Detection and Time of Diagnosis.

13

RR= 1.12 (1.07-1.17) 14

RR= 1.09 (0.87-1.36) 15

PLCOPLCO

Wide confidence intervals. ERSPC used lower PSA cutoff. High level of contamination (52% by year

6) in control arm in terms of number ofsubjects who underwent screening.

~44% of men in each study group hadundergone PSA testing at baseline.

Improvements in therapy potentiallyleading to fewer prostate cancer deaths.

16

ERSPCERSPC

Initiated in early 1990’s To determine whether a 25% reduction in

prostate cancer mortality could beachieved by PSA-based screening.

Men age 50-74.– Age 55-69 (core age group).

Most centers used a PSA cutoff of 3.0ng/mL.

Schroder FH et al. N Engl J Med 2009;360:1320-1328.17

ERSPCERSPC

In Finland, PSA cutoff of 4.0 ng/mL, PSAof 3.0-3.9 ng/mL referred for ancillarytesting, and if positive, referred for biopsy.

In Italy, PSA cutoff of 4.0 ng/mL, PSA of2.5-3.0 ng/mL referred for ancillary testing.

In Dutch and Belgian centers, up to 1997,DRE, TRUS, and PSA was used, after 1997,just PSA.

Schroder FH et al. N Engl J Med 2009;360:1320-1328. 18

ERSPCERSPC

PSA tested every 4 years, except 2-yearinterval was used in Sweden.

In Belgium, interval between first andsecond screen was 7 years due to aninterruption in funding.


ERSPCERSPC

Great deal of variability from one countryto the next.

20

ERSPCERSPC

Among men assigned to screening, 76%attended first screening.

Among men assigned to control, 31% hadat least one PSA test.


Schröder FH et al. N Engl J Med 2009;360:1320-1328.

Enrollment and Outcomes, According to Age Group atRandomization.

22

ERSPCERSPC

After 9 years of follow up: Rate ratio for death from prostate cancer

in the screened group was 0.80 (95% CI,0.67-0.95, p=0.01).

Number of men that need to be screenedto prevent one prostate cancer death was1410.

Number of men that need to be treated toprevent one prostate cancer death was 48.


ERSPCERSPC

In an intention to screen analysis (menwho actually underwent screening):– Rate ratio for death from prostate cancer was

0.71– Number of men needed to screen to prevent

one prostate cancer death was 1068.– Number of men that need to be treated to

prevent on prostate cancer death was 48.


ERSPCERSPC

Updated analysis:– 11 years follow up

• NNI- 979• NNT- 35

– 13 years follow up• NNI- 781• NNT- 27

Schroder FH, et al. Lancet 2014; 384 (9959): 2027-2035. 25

PLCO vs. ERSPCPLCO vs. ERSPC

“Why are the results different?”

26


Variations in study protocol from onecountry to the next in the ERSPC.– PLCO had uniform protocol.

Higher contamination rate in control armof PLCO

High number of subjects had undergonePSA testing prior to study entry in PLCO.– Number not known in ERSPC.

27


Lower PSA cutoff used in ERSPC vs.PLCO.

Differential treatment between study andcontrol groups.– This was equal in the PLCO.

– In the ERSPC, a control subject with high-riskdisease was more likely than a screen subjectto receive radiation (OR: 1.43; 1.01-2.05,p=0.047), expectant management (OR: 2.92;1.33-6.42, p=0.007), or hormonal therapy (OR:1.77; 1.07-2.94, p=0.026), instead ofprostatectomy.

Wolters T, et al. Int J Cancer. 2010; 126(10)L 2387-93.28


How is this being interpreted and applied?

29

RecommendationsRecommendations

USPSTF NCCN (National Comprehensive Cancer

Network) American Cancer Society AUA (American Urological Association) ACP ASCO (American Society of Clinical

Oncology)

30

USPSTF (2012)USPSTF (2012)

Recommends against PSA-basedscreening for prostate cancer.

Grade D: Moderate or high certainty thatthe test has no net benefit or the harmsoutweigh the benefits.

http://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/prostate-cancer-screening31

NCCNNCCN

Baseline PSA testing should be offered tohealthy, well-informed men aged 45-75years. May be complemented by DRE.

Testing every 2-4 years if PSA is <1.0ng/mL.

Testing every 1-2 years if PSA is 1.0 ng/mLor greater.

www.nccn.org 32

NCCNNCCN

If PSA >3.0 ng/mL, biopsy should beconsidered, but should incorporate othervariables including age, family history,PSA kinetics, race, health status, andpatient preference.

PSA testing be considered only in veryselect men >75 years.

PSA testing not recommended for menunlikely to benefit based onage/comorbidities.

www.nccn.org 33

NCCNNCCN

Consideration may be given to biomarkersthat improve biopsy specificity such as %free PSA, 4K score, PHI, PCA3 beforebiopsy in men with PSA >3.0 ng/mL.

www.nccn.org 34

American Cancer SocietyAmerican Cancer Society

Men should have a chance to make aninformed decision about being screened.

Age 50, for average risk men expected tolive 10 years or more.

Age 45, for high risk men (African-American with a first-degree relative withprostate cancer diagnosed age <65).

Age 40, for higher risk men (more thanone first-degree reltive with prostatecancer at an early age).

www.cancer.org/cancer/prostatecancer35

American Cancer SocietyAmerican Cancer Society

PSA <2.5 ng/mL, test every 2 years. PSA 2.5 ng/mL or greater, test annually.

Testing should not be offered to men witha life expectancy <10 years.

www.cancer.org/cancer/prostatecancer 36

AUAAUA

Recommends against PSA screening inmen <40 years.

Recommends against PSA screening inaverage-risk men age 40-54 years.

Recommend shared decision making indeciding to screen men age 55-69.– Screening interval of 2 years or more– Intervals can be individualized by baseline

PSA

www.auanet.org/education/guidelines/prostate-cancer-detection.cfm37

AUAAUA

Recommends against routine screening inmen 70+ years or with <10-15 year lifeexpectancy.

Some men age 70+ years in excellenthealth may benefit.

www.auanet.org/education/guidelines/prostate-cancer-detection.cfm38

ACPACP

Recommends against PSA testing inaverage risk men <50 or >69 years, or lifeexpectancy <10-15 years.

Men age 50-69 years should make aninformed decision.

https://www.acponline.org/newsroom/prostate_cancer_screening.htm39

ASCOASCO

Recommends against screening in menwith life expectancy <10 years.

For men with a life expectancy 10+ years,they should make an informed decisionabout screening.

http://jop.ascopubs.org/content 40

SummarySummary

Clearly a controversial area.

Personal perspective:– “Blanket approach” to screening the

population with PSA testing leads to somesaved lives at the expense of the harms ofscreening and treatment, and unnecessarytreatments being performed.

41

SummarySummary

Personal perspective:– Prostate cancer screening should not be

abandoned, but improved.– “What can we do?”

42

SummarySummary

Personal perspective:– “Modified approach” to screening.

• Be selective in whom we screen.• Risk-adapted screening• Complementary tests

– Biomarker/molecular– Imaging

– May decrease the NNT to save a life.– Improvements in therapies may also lead to

increased cures and further decrease the NNTto save a life.

43


Joshua Shipley, M.D.

(Andrews and Patel, Associates)

controversies in psa screening - urology of central pa in psa screening why the controversy?...

Documents