PSA in 2010

James L. Mohler, MDChair, NCCN Prostate Cancer Panel

Department of UrologyProstate Cancer Research Program

Roswell Park Cancer Institute, Buffalo, NY

Every 3 Minutes an American is Diagnosed with Prostate Cancer

Every 18 Minutes an American Dies of Prostate Cancer

The Prostate Cancer Challenge

• Complex disease

• Many controversial aspects of management

• Lack of sound data to support most recommendations

• Several variables must be considered to tailor prostate cancer therapy to an individual patient

• Guidelines provide a framework on which to base treatment decisions

Prostate Cancer:

#1 Incidence(192,280)

#2 Deaths(27,360)

Cancer Statistics, 2009

U.S. Annual Age-Adjusted

Incidence Rates

1975 – 2005

Cancer Statistics, 2009

U.S. Annual Age-Adjusted Mortality Rates, 1930 – 2005 Cancer Statistics, 2009

CaP Screening Recommendations

• American Urological Association

– Annual PSA & DRE

- From age 50 until LE <10 yrs

- From age 40 if high risk (AA or family history)

• American Cancer Society (3/3/2010)

- Annual PSA ± DRE

- From age 50 until LE <10 yrs

- From age 45 if high risk (AA or family history)

- From age 40 if multiple family members

CaP Screening Recommendations• American College of Physicians; American Academy

of Family Physicians

– Counsel men 50 to 65 regarding risk vs. benefit

• U.S. Preventive Services Task Force

– Routine screening not advocated especially >75

• NCCN (the best recommendation)

– PSA and DRE at 40, if <1, at 45

– PSA and DRE at 45, if <1, at 50

– If high risk because African American, family history or PSA >1, annual PSA and DRE

– Routine screening less frequent in older men (65-75) and not advocated especially >75

How reliable is PSA ?

• 70% of men with elevated PSA have negative biopsies

• PSA can fluctuate by 36% day to day

• Rate of rise more accurate– PSA Velocity or PSA Doubling Time– Requires ≥ 3 PSAs over ≥ 18 mo

• PSAV ≥ 0.75 ng/ml or PSADT ≤ 3 yrs

How Reliable is Prostate Biopsy?

• Biopsies sample prostate• Biopsy detection rate

– First: 75% of existing cancers– Second: 91%– Third: 97%– Fourth: 99%

• Accuracy of Gleason grade compared to RP– 30% grade increases– 5% grade decreases

PSA and Prostate Cancer Screening

• PSA increases the detection of organ confined CaP

• Serial PSA screening improves the ability to detect organ confined prostate cancer

• PSA detects 2x as many cancers as DRE

Screening Performance

Mammography PSA

+ Predictive Value 7-17% 33%

Organ Confined 50% 80%

+ Lymph Nodes 20% 2%

“Latent” Cancer 8% 7%

Screening Men with a

Family History

• 2-3 fold increased risk if first-degree relative with CaP (Keetch, J Urol, 1995; Walsh, Cancer, 1997)

• Younger age at presentation

• Comparable results with RP (Beva, J Urol, 1998)

• Begin screening at age 40

Prostate Cancer Incidence and Death Rates by Race and Ethnicity,

2001 - 2005 Cancer Statistics, 2009

Caucasian American

African American

Asian American

and Pacific

Islander

American Indian and

Alaska Native

Hispanic Latino

Incidence 156.7 248.5 93.8 73.3 138

Mortality 24.6 59.4 11.0 21.1 20.6

Use of PSA for Early Detection is Most Appropriate for:

A) African Americans

B) Men with CaP in father or brother

C) Men with life expectancy ≥ 10 yrs

D) Men with BRAC1 mutation

E) All of the above

March 26, 2009 CaP Explosion

NEJM 360:1310-19 and 1320-28

ERSPC (European) Trial• 182,000 men ages 50-74• Statistics on 162,387 men ages 55-69• Mean number of PSA tests 2.1• Median f/u 9 yrs

PSA cutoff Design Biopsy Interval

Finland 4.0 Pop-based 10-12 4

Italy 4.0 Pop-based 6 (transperineal) 4

Netherlands 4.0 Efficacy 6 4

Belgium 4.0 (originally 10) Efficacy 6 4-7

Switzerland 3.0 Efficacy 6 4

Spain 3.0 Efficacy 6 4

Sweden 3.0 Pop-based 6 2

European Trial

Screening Control

Incidence 8.2% 4.8%

Prostate cancer deaths 214 327

Rate ratio for prostate cancer death 0.80 (p=0.04)

To prevent one death from prostate cancer: • 1410 men need screened• 48 additional cases of prostate cancer

need treated

European Trial

PLCO (American) Trial

• 76,693 men ages 55-74 at 10 centers• Annual PSA screening for 6 yrs vs.

usual care• Median f/u 11.5 years

American Trial

Screening Control

PSA testing 86% 40%

Incidence 7.5% 6.1%

No. of advanced cases 122 135

Prostate cancer deaths

7 years 50 44

10 years (f/u for 67% of subjects) 92 82

Non-prostate cancer deaths (10 yrs) 312 225

Possible Reasons for a Negative Trial

• PSA cutoff 4 ng/ml too high

• Control arm contaminated - 38% contamination anticipated- PSA within past year

- 86% in screened group- 40% in control group

Possible Reasons for a Negative Trial

• Widespread PSA testing removed prostate cancer patients from consideration for enrollment

• Improved treatments for prostate cancer applied to both arms blunted effects of screening

• Follow-up too short

PSA Screening?

“ …our results support the validity of the recent recommendations of the U.S. Preventive Services TaskForce, especially against screening all men over the age of 75 years.”

NEJM: Authors of PLCO trial

“The real impact and tragedy of prostate cancer screening is the doubling of the lifetime risk of a diagnosis of prostate cancer with little if any decrease in the risk of dying from this disease,” 

Otis Brawley, Chief Medical Officer, American Cancer Society

What does all this mean?

• PSA was doomed to failure (screened older men and didn’t include many African Americans or men with family history of CaP)

• Over-treatment may blunt benefits of treatment• Even with longer followup, the American study is

unlikely to be positive. Even if it is, the impact of screening will be so small that it may not be clinically significant.

• Annual screening may be too frequent• In the European study, screening was every 4 yrs• In the American study, the majority of subjects in

the control arm were screened and the control arm looks rather similar to the q 4 yrs screening arm of the European study

What does all this mean?

• PSA was doomed to failure (screened older men and didn’t include many African Americans or men with family history of CaP)

• Over-treatment may blunt benefits of treatment• Even with longer followup, the American study is

unlikely to be positive. Even if it is, the impact of screening will be so small that it may not be clinically significant.

• Annual screening may be too frequent• In the European study, screening was every 4 yrs• In the American study, the majority of subjects in

the control arm were screened and the control arm looks rather similar to the q 4 yrs screening arm of the European study

2010 Guideline Updates

1. Defined new risk category: very low risk CaP

2. Active surveillance only recommendation for men with

a. low risk CaP and L Exp < 10 yrs

b. very low risk CaP and L Exp < 20 yrs3. Active surveillance program defined

Preoperative Criteria associated with Clinically Insignificant Disease in the

Radical Prostatectomy Specimen

• Gleason Sum <7• PSA <10• No. positive biopsy cores <3• CaP <50% in any biopsy• PSAD <0.15

 Epstein, JAMA, 1994

2010 NCCN Concerns

• Approximately 3% of all men will die of prostate cancer (2007)

• Second leading cause of cancer mortality• Mortality from prostate cancer has declined by

31% over past 13 yrs- Screening?- Treatment?

• Any active treatment will significantly decrease quality of life

2010 Guideline Updates

1. Very low risk CaPLow Risk- T1-T2a- GS 2-6- PSA<10

Very Low Risk- T1c- GS 2-6- PSA<10- <3 cores positive- <50% CaP in any core- PSAD<0.15

• Incorporates the strictest Epstein criteria from all definitions for clinically insignificant CaP (Epstein, JAMA, 1994)

• New nomogram may be better (Chun, Cancer, 2008)

2010 Guideline Updates

2. Active surveillance only recommendation for men with a. Low risk CaP and L Exp < 10 yrsb. Very low risk CaP and L Exp < 20 yrs

Concern: “problems of over-treatment related to the increased diagnosis of early CaP from PSA testing”

2010 Guideline Updates

3. Active surveillance program

a. PSA as often as every 6 mo

b. DRE as often as every 12 mo

c. Prostate biopsy as often as every 12 mo when L Exp > 10 yrs

d. Uncertain what the progression criteria should be to warrant treatment