Probing Your Prostate Health:  What Every Man Should Know

Prostate Cancer

Douglas S. Scherr, M.D. Clinical Director, Urologic Oncology

Weill Medical College of Cornell University

What is the Prostate?

Problems of the Prostate

• Prostatitis

• Benign Prostatic Hyperplasia (BPH)

• Prostate Cancer

• Infection

• Urinary Retention

• Urinary Bleeding

What Causes the Prostate To Grow?

• Testosterone

• Dihydrotestosterone (DHT)

Testosterone DHT

Finasteride (Proscar)

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

Prostate Cancer

• In 2007, 225,000 new cases of prostate cancer

• 28,900 men will die from prostate cancer

• Highest death rates in Caribbean and African American Men

• 1 in 6 men in the U.S. will development prostate cancer

Prostate Cancer in African American Men

• 275.3 per 100,000 men

• Incidence in African American men is 60% higher than among white men

• Between 1992-1999 the death rate from prostate cancer was 2.3 times higher than white men and 3.3 times higher than Hispanic men

• More men present with metastatic disease in the African American population

Prostate Cancer in African American Men

• 5 year survival rates have improved over the last 3 decades for African American men

• 40% of prostate cancers occurring in men under age 55 have a hereditary basis

• Risk of developing prostate cancer doubles for men with a father or brother with prostate cancer

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

Myths of Prostate Cancer in Asian Men

• Asian men do not get prostate cancer

• Asian men have small prostates that do not cause problems

• Not important to check PSA levels in Asian Men

Prostate Cancer in Asian- American Men

• Higher % of foreign born Asian Americans are diagnosed with distant disease at presentation (controlled for socioeconomic status and co-morbidities)

• Distribution of Stage for North American-born Asian Americans is similar to whitesand both groups are diagnosed at the same age

• Foreign-born Asian Americans are diagnosed at older ages

• Death rates higher for foreign-born Asian Americans but no difference for North American-born Asian Americans

Oakley-Girvan et al. Am J Pub Health, Vol 93(10): 1753, 2003

Why the Differences?

• Lack of screening programs in Asia

• Socioeconomic Status

• Cultural barriers to medical care

• Biological Explanation?

• Birthplace?

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%

Does Screening for Prostate Cancer Help?

• Mortality decreased by 27% between 1991-1997 in white men and by 17% in African American men

• Less men present with advanced disease and thus potential for cure increases

Diet and Prostate Cancer

• Saturated fat intake is associated with prostate cancer

• High red meat intake may increase risk of prostate cancer

• High soy intake may have a protective effect

• Vitamin E, Selenium, Lycopene

High Risk Prostate Cancer

• Single treatments often not effective

• Surgery does have a role

• Quality of life can be maintained

The Problem

Low Risk High Risk

D’Amico AV, et al. JAMA. 1998;280:969-974.

RP

External Beam Radiation Therapy

Implant and Neoadjuvant Hormonal Therapy

Implant

100

90

80

70

60

50

40

30

20

10

0

PSASurvival

(%)

0 1 2 3 4 5

Time (Years)

164 147 117 83 55 36109 77 42 17 4 2 10 8 5 2 1 0 6 4 3 3 2 1

100

90

80

70

60

50

40

30

20

10

0

PSASurvival

(%)

0 1 2 3 4 5

Time (Years)

239 158 102 47 26 11309 218 99 38 12 0 23 14 3 0 0 0 19 13 4 0 0 0

Prostate Cancer Risk Stratification

Cooperberg et al, J Urol 170: S21-7, 2003.

Why is high-risk disease “bad”?

• Primary therapy inadequate-positive surgical margins-unrecognized node positive

disease

• Early tumor dissemination

Occult Node-Positive Disease

Schumacher et al, Eur Urol, 2006

• 231 patients: PSA < 10, RP + PLND (extended)

• Positive nodes:

• 11% overall

• 25% in men with Gl ≥ 7

• Distribution:

• 23% obturator only

• 31% internal only

• 73% with some internal involvement

Recurrence in NED Patients

12/14

44/84

0

20

40

60

80

100

Pat

ient

s with

DTC (%

)

Recurrence No recurrence

Recurrence in all NED patients after RRP

* p<0.01

Recurrence: PSA ≥ 0.4 ng/ml or salvage Recurrence: PSA ≥ 0.4 ng/ml or salvage radiation Rxradiation Rx

• Early tumor dissemination

– Circulating tumor cell data

Why is high-risk disease “bad”?

Improved Cancer Detection Through Imaging

Endorectal MRI/Spectroscopy• Potential improvement over ultrasound

• Biochemical gradients to decipher cancer from benign

• Possible role in high risk patients

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.

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

PSA Kinetics

• PSA Velocity (PSAV) in year preceding diagnosis1

– 1095 pts, clinically localized CaP undergoing RP– PSAV > 2 ng/ml/yr predicted disease-free, cancer-

specific, and overall survival

• PSA Doubling Time (PSADT) at recurrence2

– 8,669 pts treated by RP or XRT for localized CaP– PSADT < 3 months associated with cancer-specific

mortality (HR 19.6, 12.5-30.9, p<0.001)

1D’Amico, NEJM 351:125, 2004

2D’Amico, JNCI 95:1376, 2003

Technical Improvements in SurgeryNerve Grafts

• 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

Robotic Prostatectomy

Conclusion

• Prostate Cancer is a common disease

• Family history is important

• Screening can lead to earlier diagnosis

• Treatment strategies have improved and quality of life concerns are addressed

Adjuvant Radiation after RP

Two completed, randomized studies:

SWOG 87941 and EORTC 229112

• Patients with pT3/T4, +/- pos margins

• Adjuvant RT (prostatic fossa) vs. Observation

• Primary endpoint – metastasis free survival

1. Thompson, JAMA, 2006

2. Bolla, Lancet, 2005

Adjuvant RT vs Observation for pT3+ CaP

1. Bolla, Lancet, 20052. Thompson, JAMA, 2006

EORTC1 SWOG2

(RT vs. Obs) (RT vs. Obs)

Number 1005 473

Median F/U 5 yrs 10 yrs

PSA failure 26% vs 44% 35% vs. 64%

(HR 0.48, 0.37-0.62) (HR 0.43, 0.31-0.58)

Metastasis-free survival NR NS

(HR 0.75, 0.55-1.02)

Overall survival NS NS

(HR 1.09, 0.67-1.79) (HR 0.80, 0.58-1.09)

Stephenson et al, J Clin Onc, 2007

Progression-Free Probability After Salvage RT

≤ 0.5

1.01-1.50

0.51-1.00

> 1.5

Pre-RT PSA

Neoadjuvant Therapy in High-risk Localized Prostate Cancer: CALGB 90203

RA

ND

OM

IZE

RA

ND

OM

IZE

Docetaxel 70 mg/m2 IV day(6 cycles)ADT X 4 months

Q 21 days Radical prostatectomy

Entry Criteria: cT1-3aNXM0 and nomogram probability of <60% PFS at 5 yrs.N: 750 patientsOutcome: 5-yr bPFS (45 mo. to 60 mo.) HR 1.35

Radical prostatectomy

Patients post-RP

pT3, G7-10, N0Kattan

nomogram

Docetaxel (6 cycles) + prednisone

SurveillanceRA

ND

OM

IZE

RA

ND

OM

IZE

VA Cooperative Studies # 553: Adjuvant Therapy in High Risk Disease

Primary endpoint: PSA progression

Secondary endpoints: OS, CSS, mets-free survival

Docetaxel 75mg/m2 q 3wks x 6 cycles

n = 700

•Gleason ≥ 9, PSA ≤ 150, any T category

•Gleason 8, PSA < 20, ≥ T2

•Gleason 7-8, PSA 20-150, any T category

RT + Hormonal therapy (2 yrs)

RT + Hormonal therapy (2 yrs) + 6 cycles adjuvant docetaxel (starting 1 mo after RT)

RA

ND

OM

IZE

RA

ND

OM

IZE

RTOG 0521: Adjuvant Docetaxel

Docetaxel 75mg/m2 q 3wks x 6 cycles

n ~ 600

Take Home Points

• High-risk disease difficult– Inadequate primary therapy, early tumor

dissemination, tumor biology

• Predictive models with improved ability to identify high-risk patients– Biopsy information– Tertiary grade– PSA kinetics – Emerging biomarkers

Take Home Points

• Adjuvant therapy– RT : Efficacy in subset with positive margin,

undetectable PSA, low/int Gleason– ADT: in N+ disease– Substantial side effects

• Future– Neoadjuvant or adjuvant chemo/chemohormonal

therapy in high-risk disease– Await RCTs

200(1%)

Clinical

trials

20,000/yearHigh Risk

100,000/yearHave surgery

~230,000/year

Prostate Cancer in the USARadical Prostatectomy

-M. Eisenberger, JHU