PSA Screening and Cancer Treatment

Douglas S. Scherr, M.D.

Assistant Professor of UrologyClinical Director, Urologic Oncology

Weill Medical College-Cornell University

Criteria of a Screening Program

• The Disorder

• The Test

• The Treatment

• The Screening Program

Criteria of a Screening Program

• The Disorder -Prostate Cancer

• The Test

• The Treatment

• The Screening Program

PROSTATE CANCERHighest in Incidence and Second in Cause of Death

from Cancer in American Males

Incidence Cause of DeathMelanoma of Skin 5%

Lung & Bronchus 14%

Oral Cavity & Pharynx 3%

Pancreas 2%

Colon & Rectum 11%

Kidney 3%

Prostate 30%Urinary Bladder 7%

Leukemia 3%

Non-Hodgkin’s Lymphoma 4%

All Sites 637,500All Sites 637,500

189,000 New Cases

3% Esophagus

31% Lung & Bronchus

5% Pancreas

3% Kidney

3% Liver

10% Colon & Rectum

11% Prostate3% Urinary Bladder 4% Leukemia

5% Non-Hodgkin’s Lymphoma

288,200 All Sites 288,200 All Sites

30,200 Death2002 Estimates

U.S. Incidence and Mortality of Prostate Cancer

Surveillance, Epidemiology and End Results (SEER) Data

Prevalence of Prostate Cancer

0

5

10

15

20

25

30

35

40

45

2nd 3rd 4th 5th

PIN

Prosate Cancer

Decade

% Men With PIN Or CaP

Sakr et al., J Urol, 150: 379, 1993

Criteria of a Screening Test

• Natural history understood:-To die of prostate cancer or die with prostate

cancer?

-Conservative Treatment:a.) Gleason 2-4: 4-7% chance of death b.) Gleason 6: 18-30% chance of deathc.) Gleason 8-10: 60-80% chance of

death**

Frankel et al. Lancet, 361: 1122, March 2003**Albertsen et al., JAMA, 280: 975, 1998

The Disorder“Prostate Cancer”

Lifetime Risk of Developing or Dying of Prostate Lifetime Risk of Developing or Dying of Prostate Cancer for a 50-Year-Old Man in the United StatesCancer for a 50-Year-Old Man in the United States

Risk Risk Proportional Proportional Lifetime Risk of Lifetime Risk of Risk Risk Ratio RiskRatio Risk

Developing histologic cancerDeveloping histologic cancer 42 %42 % 11.7 100 11.7 100

Developing clinical cancerDeveloping clinical cancer 16 % 4 3816 % 4 38

Dying of prostate cancerDying of prostate cancer 3.6 % 1 3.6 % 1 8.6 8.6

Modified from Scardino PT. Urol Clin N Am 1989 and Hum Path 1992; Modified from Scardino PT. Urol Clin N Am 1989 and Hum Path 1992; and from CA Cancer J Clin Jan-Feb, 2000.and from CA Cancer J Clin Jan-Feb, 2000.

Criteria of a Screening Program

• The Disorder

• The Test

• The Treatment

• The Screening Program

Criteria of a Screening Test The Test

• Simple, safe and precise

• Distribution in target population should be known

• Appropriate cut-offs and age defined ranges

• Test should be acceptable to the population

Diagnostic tests performed when a positive test is found should be agreed upon

Criteria of a Screening Test The Test

“DRE and PSA”

Bangma et al., Urology, 46(6): 773, 1995

Rate of Detection of Prostate Cancer by Needle BiopsyRate of Detection of Prostate Cancer by Needle BiopsyPositive Predictive Value of DRE and PSA (n=6630)Positive Predictive Value of DRE and PSA (n=6630)

PSA (ng/ml)PSA (ng/ml)

0-20-2 2-42-4 4-104-10 >10>10

DRE-DRE- 1%1% 15%15% 25%25% >50% >50%

DRE+DRE+ 5%5% 20%20% 45%45% >75% >75%

Modified from Catalona et al: J Urol 1994: 151:1283Modified from Catalona et al: J Urol 1994: 151:1283..

Positive Predictive Value of PSA and DRE for Prostate

Cancer

05

101520253035404550

DRE+ PSA >4 PSA <4 &DRE+

PSA >4 &DRE-

PSA >4 &DRE+

PSA >4or DRE+

25.5

31.6

14.6

23.2

46.6

24.6

PREDICTIVE MODELING TABLES TO CALCULATE RISK OF POSITIVE BIOPSY BASED ON DRE, PSA, F/T PSA RATIO AND PSA DENSITY IN MEN WITH PSA < 10 NG/MLTewari, Boorjan, Bartsch, 2005

DRE FINDINGSNOT SUSPICIOUS FOR CANCER SUSPICIOUS FOR CANCER

AGE GROUPS <40 YEARS

41-50 YEARS

51-60 YEARS

61-70 YEARS

>70 YEARS

<40 YEARS

41-50 YEARS

51-60 YEARS

61-70 YEARS

>70 YEARS

F/T PSA RATIO

PSA DENSITY

PROBABILITY OF FINDING CANCER FOLLOWING SYSTEMIC SEXTANT BIOPSY OF THE PROSTATE

MEAN PROBABILITY (95 % UPPER AND LOWER CONFIDENCE LEVELS)

FREE VERSUS COMPLE

X PSA RATIO >15%

<.15 (Large prostate)

5 (3-6) 7 (6-9) 11 (10-13) 17 (15-20) 25 (22-29) 11 (7-16) 17 (12-22) 24 (19-30) 34 (28-41) 46 (39-54)

.15-.2 (Medium prostate)

8 (6-11) 12 (9-16) 19 (15-22) 27 (23-32) 38 (32-43) 18 (12-26) 26 (19-34) 36 (29-45) 48 (40-56) 60 (52-68)

>.20 (Small prostate)

10 (7-14) 15 (12-20) 23 (19-27) 33 (28-38) 44 (38-50) 22 (15-31) 31 (24-41) 43 (34-51) 55 (47-63) 66 (58-73)

FREE VERSUS COMPLEX PSA RATIO <15%

<.15 (Large prostate)

7 (6-9) 11 (10-13) 17 (15-19) 25 (22-28) 35 (31-40) 16 (12-22) 24 (19-31) 34 (28-41) 46 (39-53) 58 (50-65)

.15-.2 (Medium prostate)

12 (9-16) 18 (15-22) 27 (23-31) 37 (33-42) 49 (43-55) 26 (18-35) 36 (28-45) 48 (40-56) 60 (52-67) 71 (64-77)

>.20 (Small prostate)

15 (12-20) 23 (19-27) 32 (28-36) 44 (39-48) 56 (50-61) 31 (23-41) 42 (34-51) 54 (47-62) 66 (59-72) 76 (70-81)

PSA density should be calculated by ultrasound. A new model will be available soon if PSA density is not available)

Serum PSA Levels Rise Prior to the Development of Significant

Cancer

From Carter HB et al. JAMA 267:2215,1992

Criteria of a Screening Test The Test

“DRE and PSA”AUA Best Practice Policy

• PSA detects more tumors than does DRE and it detects them earlier

• Most Sensitive method uses both DRE and PSA

PSA Best Practice Policy, Oncology, 14(2), Feb. 2000

Factors That Affect PSA

• Prostatitis• Benign Prostatic Hyperplasia (BPH)• Prostate Cancer• Physical Activity• Infection• Medications – finasteride (Proscar/Propecia)• Herbal Medicines – Saw Palmetto, PC-SPES, • Ejaculation• Rectal Examination• Urinary Retention/Cystoscopy

Sensitivity/Specificity of PSA

• Sensitivity: 67.5-80% (20-30% tumors will be missed if PSA<4.0 ng/ml used)

Ways to Improve Sensitivity:a.) age-adjusted PSAb.) PSA velocity

• Specificity: 60-70% (if PSA>4.0 ng/ml)(only ¼ prostate biopsies reveal CaP)

Ways to Improve Specificity:a.) Age adjustmentb.) Free-to-total PSAc.) PSA density

Improvements on PSA

• Age-adjusted PSA

• Free-to-Total PSA(14-28%)

• PSA Velocity (>0.75ng/ml/yr)

Age PSA Cutoff (ng/ml)

<40-50 2.5

50-60 3.5

60-70 4.5

>70 6.5

Criteria of a Screening Program

• The Disorder

• The Test

• The Treatment

• The Screening Program

Criteria of a Screening Test“The Treatment”

• Watchful Waiting

• Hormonal Deprivation Therapy

• Radiation Therapy

• Radical Prostatectomy

Criteria of a Screening Program

• The Disorder

• The Test

• The Treatment

• The Screening Program

Policies of Prostate Cancer Screening

Group Policy Statement Recommendations

AUA Screen annually at age 50

Take personal decision after consultation

ACS Screen annually at age 50

Provide risk and benefit information

AMA Mass screening is premature

Allow “well informed” decision

ACP Routine PSA is “inappropriate”

Counsel patient

EU Introduction as policy is premature

Provide risk and benefit, await randomized trials

Evidence for the Effectiveness of Screening

• PSA screening initiated in 1989

• A decrease in prostate cancer mortality has been demonstrated in the U.S. by 4.4%/year from 1994-97

• Total decrease in mortality of 17.6%

Howard. J Health Econ., 24(5): 891-906, Sept. 2005

Cost per annual adjusted life year for annual Prostate cancer screening

Practice Patterns of General Practitioner

Howard. J Health Econ., 24(5): 891-906, Sept. 2005

Question

n (%) 95% CI for%

Do you perform a DRE in all males with LUTS?

220 (76) 67.2–84.0

Do you measure PSA in all males with LUTS?

 82 (28) 19.3–37.0

Is the decision to refer the patient to a urologist affected by the patient's PSA value?

230 (79) 71.1–87.0

Is the decision to refer affected by the patient's age?

190 (65) 55.9–74.6

Is the decision to refer affected by the patient's symptoms?

272 (93) 88.5–98.5

Is the decision to refer affected by the findings of DRE?

254 (87) 80.7–93.9

Would you refer asymptomatic patients with elevated PSA?

151 (52) 42.1–61.7

Do you measure PSA as part of a general health check-up?

 29 (10)  4.1–15.8

If you perform PSA testing, do you tell the patient what a PSA test can show?

247 (85) 77.9–91.9

Do you perform PSA screening for PC?

 41 (14)  7.2–21.0

Jonler et al., Scan J Uol Nephol, 39: 214-218, 2005

Practice Patterns Amongst General Practitioners

Side effects of screening

Flip side: Screening cause harm Impact of treatment on overall survival

Gain in LE (MoGain in LE (Mo))

Myocardial revascularization 1 vessel 7

2 vessels 0-8

3 vessels 4-14

Heart Transplantation 31-99

Cholecystectomy 2-3

Appendectomy 2-31Treatment of prostate cancer (Fleming)

1-11 Gl 5-7 30-

60 Gl 8-10

Wright & Weinstein NEJM 1998:339:380-6

Controversies in Screening

• Decline in mortality since 1989 is too rapid given the indolent natural history of prostate cancer

• Improvements in locally advanced disease could explain decline in mortality

• Decline in mortality has been seen in countries where screening is not prevalent

Quebec City Screening Study

Quebec City Screening Study

• November 1988-Decmeber 1996

• 46,193 men randomizedscreening vs. non-screening

• Screening Group: 8,137 were screened

• Relative risk of dying of CaP was 3.7 times higher in the control group

• 69% reduction in mortality with screening

Labrie et al., Prostate, 38(2): 83-91, 1999

Tyrol Prostate Cancer Screening Group

• 1993-1998, PSA screening offered to 65,123 men in Tyrol, Austria

• 42% reduction in prostate cancer mortality

Bartsch et al., Urology, 58(3): 417-24, 2001

Mortality Rates

Incidence by Stage

Olmstead County Screening Trial

• Retrospective analysis of death record between 1980-1997

• Decline in mortality of 22% between the earliest and most recent time periods

Trends in Prostate Cancer Mortality

Roberts et al., J Urol, 161: 529, 1999

Cost Effectiveness of PSA Screening

Intervention Cost Per Quality-Adjusted Life-Year Gained

Liver Transplantation $237,000Screening Mammography (age <50)

$232,000

Worst Case – CaP Screening $145,000CABG-2 vessels (angina) $106,600Captopril for HTN $82,600HCTZ for HTN $23,500Best Case- CaP Screening $8,700Stop Smoking-MD Message $1,300

Thompson et al., Oncology, 9: 141-5, 1995

Problems with Screening

Lead Time Bias

Length Time Bias

Thompson, Recent Advances in Prostate Cancer

Breast Cancer vs. Prostate Cancer 1998

PROSTATE CA PROSTATE CA BREAST CABREAST CA

New Cases/Yr.New Cases/Yr. 184,500 184,500 180,300 180,300Deaths/Yr.Deaths/Yr. 39,200 39,200 43,900 43,900Deaths/CasesDeaths/Cases 21 21%% 24 24%%

Lifetime risk of Developing 17%Lifetime risk of Developing 17% 14% 14%Mets at DiagnosisMets at Diagnosis 9 9%% 6 6%%

Mortality Rate Trend (22 yr.) + 17Mortality Rate Trend (22 yr.) + 17%% - 3 - 3%%

5 Yr. Relative Survival Rate 935 Yr. Relative Survival Rate 93%% 85 85%%

Median Age at DiagnosisMedian Age at Diagnosis 71 71 yryr 64 64 yryr

Median Age at DeathMedian Age at Death 77 77 yryr 68 68 yryr

Scardino, MSKCC

Ongoing Randomized Screening Trials

• Prostate, Lung, Colon and Ovarian (PLCO) Trial of the NCI

Q: Does screening decrease mortality?

• European Randomized Study of Screening for Prostate Cancer (ERSPC)

Q: Difference in CaP mortality in screened vs. unscreened patients?Q: Quality of life differences in screened population?

• Prostate Cancer Intervention Vs. Observation Trial (PIVOT)

Q: Does early, aggressive treatment decrease mortality?

• Prostate Cancer Prevention Trial (PCPT)

Q: Can finasteride prevent prostate cancer?

Prostate, Lung, Colorectal and Ovarian (PLCO) Trial

Men (74,000) and women (74,000) ages 55 to 74 years will be randomized to a control arm (routine medical care) or a screening arm which includes:

• Prostate: PSA and DRE• Lung: CXR• Colorectal: Flexible sigmoidoscopy• Ovarian: Pelvic exam, CA125,

Transvaginal ultrasound

ERSPC Trial

• Large, International cooperative study initiated in 1994

• Goal is to compare prostate cancer mortality between screened and control arms

• With 165,000 men age 55-69 with a 20% contamination rate, the trial will reach a power of 86% to show a 20-25% mortality reduction

• Results expected in 2008

ERSPC Trial

Impact of PSA on Survival

Tsodikov et al. UC Davis

What Can We Do While we Await the Results?

• Improve diagnostics:1.) Imaging2.) More sensitive PSA

• Improve Treatment Stratification:1.) Nomograms

• Improve Surgical Technique (lower morbidity)

1.) nerve sparing2.) nerve grafts3.) Laparoscopic Prostatectomy

Improved Cancer Detection Through Imaging

Endorectal MRI/Spectroscopy• Potential improvement over ultrasound

• Biochemical gradients to decipher cancer from benign

• Remains investigational

• Possible role in high risk patients

MRN 309468

Endo-rectal coil MRI

Image 8 I 54.44 mm Image 9 I 57.56 mm

H

H H

H H H

H H H H

H H H

H H

H H

H H H H

H H H H H

* * *

sc vc vc

Treatment Stratifications

• Allow for improvement in patient understanding

• More objective in guiding treatment decisions

• Less physician bias

Biopsy Gleason Grade 2+ 2 3+3 3+ 4

2+3 4+

Total Points 0 20 40 60 80 100 120 140 160 180 200

60 Month Rec. Free Prob. .96 .93 .9 .85 .8 .7 .6 .5 .4 .3 .2 .1 .05

3+ 2

Clinical Stage T1c T1ab

T2a T2c T3a

T2b

Points 0 10 20 30 40 50 60 70 80 90 100

PSA 0.1 1 2 3 6 8 9 10 12 16 30 45 70 1107 204

Preoperative Nomogram for Prostate Cancer RecurrencePreoperative Nomogram for Prostate Cancer Recurrence

Instructions for Physician: Locate the patient’s PSA on the PSA axis. Draw a line straight upwards to the Points axis to determine how many points towards recurrence the patient receives for his PSA. Repeat this process for the Clinical Stage and Biopsy Gleason Sum axes, each time drawing straight upward to the Points axis. Sum the points achieved for each predictor and locate this sum on the Total Points axis. Draw a line straight down to find the patient’s probability of remaining recurrence free for 60 months assuming he does not die of another cause first.

Note: This nomogram is not applicable to a man who is not otherwise a candidate for radical prostatectomy. You can use this only on a man who has already selected radical prostatectomy as treatment for his prostate cancer.

Instruction to Patient: “Mr. X, if we had 100 men exactly like you, we would expect between <predicted percentage from nomogram - 10%> and <predicted percentage + 10%> to remain free of their disease at 5 years following radical prostatectomy, and recurrence after 5 years is very rare.”

1997 Michael W. Kattan and Peter T. ScardinoKattan MW et al: JNCI 1998; 90:766-771.

Points 0 10 20 30 40 50 60 70 80 90 100

Pretreatment PSA0.3 1 2 3 4 5 6 7 9 25 100

Clinical StageT1c T2b

T2a T3ab

Bx.Gl.Sum2 8 10

3 7 9

Dose (gy)88 72 68 64

HormonesYes

No

Total Points 0 20 40 60 80 100 120 140 160 180

60-Month Recurrence Free Prob.0.010.10.30.50.70.80.90.950.980.99

10 50

T2c

T3c

2 4 6

3 5

3D Conformal Radiation Therapy Nomogram for PSA Recurrence

Palm Pilot Nomogram Software

• Includes pretreatment and postoperative predictions.

• Uses published nomograms in prostate cancer.

Points 0 10 20 30 40 50 60 70 80 90 100

Preop PSA0.1 0.2 0.3 0.5 0.7 1 2 3 4 6 8 100

Gleason Sum5 7 9

4 6 8 10

Extraprostatic Ext.None Focal

Inv.Capsule Established

Surgical MarginsNeg

Pos

Seminal Ves. InvasionNo

Yes

Lymph NodesNeg

Pos

Total Points 0 40 80 120 160 200 240 280

84-Month Rec. Free Prob.0.010.10.30.50.70.80.90.950.980.99

10

3,

Postoperative Nomogram for Prostate Cancer Recurrence

19981998 Michael W. Kattan and Peter T. ScardinoMichael W. Kattan and Peter T. Scardino

Technical Improvements in Surgery

• Cavernosal nerves necessary for post-operative erectile functions

• In advanced disease, nerves may need to be resected to obtain a negative margin

• Sural nerve or genitofemoral nerve serve as sources of nerve grafts in this setting

Laparoscopic/Robotic Prostatectomy

• Minimally invasive form of prostatectomy

• Shorter hospital stay, less blood loss, improved optical visualization

• No long data regarding cancer control, potency or quality of life

Conclusion

• Prostate cancer screening is controversial

• More cost-effective means at targeting high risk populations may be more reasonable

• We await results of randomized screening trials

• While we await results of screening trials, we continue to improve prostate cancer treatment with cancer control and quality of life as our primary aims.