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GlaxoSmithKline
The Role of the Primary Care Practitioner Within the Continuum of
Care for Prostate Cancer Prevention
Learning Objectives
• Identify the risk factors for prostate cancer, the benefits and challenges of current screening methods,
•
and the role of the primary care practitioner in identifying high-risk patients.
Describe the screening, diagnosis, and ongoing management in the prevention of prostate cancer as
these processes relate to the underlying biology of the disorder and the optimal roles for primary and
specialty care.
Faculty
David M. Albala, MD
Professor of Urology
Duke University Medical Center
Durham, North Carolina
David M. Albala, MD, is professor of urology at Duke University Medical Center, Durham, North Carolina.
Dr Albala received a geology degree from Lafayette College, Easton, Pennsylvania. He completed his
medical school training at Michigan State University and his surgical residency at the DartmouthHitchcock Medical Center, Hanover, New Hampshire. Dr Albala then completed an endourology
fellowship at Washington University Medical Center, St. Louis, Missouri, under the direction of Ralph V.
Clayman. He practiced at Loyola University Medical Center, Chicago, and rose from the ranks of instructor
to professor in urology and radiology in 8 years. He has over 140 publications in peer-reviewed journals
and has authored 2 textbooks in endourology. He serves on the editorial board for Journal of Endourology,
Current Opinions in Urology, and Urology Index and Reviews.
Dr Albala is currently a tenured professor at Duke University Medical Center. He is co-director of the
endourology fellowship at Duke and director for the Center of Minimally Invasive and Robotic Urological
Surgery. He is considered a national and international authority in laparoscopic urological surgery and has
been an active teacher in this area for over 17 years. His research and clinical interests have focused on
robotic urology. In addition, other clinical interests include minimally invasive treatment of benign
prostatic hypertrophy (BPH) and the use of fibrin sealants in surgery. He has been a visiting professor at
numerous institutions across the US, as well as in India, China, Iceland, Germany, France, Japan, Brazil,
Australia, and Singapore.
Notably, Dr Albala is a past White House Fellow who acted as a special assistant to Federico Pena,
Secretary of Transportation, on classified and unclassified public health–related issues.
Leonard G. Gomella, MD, FACS
Professor of Prostate Cancer
Chairman, Department of Urology
Associate Director of Clinical Affairs, Kimmel Cancer Center
Thomas Jefferson University
Philadelphia, Pennsylvania
Leonard G. Gomella, MD, is the Bernard W Godwin, Jr Professor of Prostate Cancer, chairman of the
Department of Urology at Jefferson Medical College, and associate director of the Kimmel Cancer Center,
Philadelphia. Originally from New York, Dr Gomella completed medical school and general surgery and
urology training at the University of Kentucky, Lexington. After a urologic oncology fellowship in the
Surgery Branch of the National Cancer Institute, Bethesda, Maryland, he joined the faculty of Jefferson
Medical College in 1988 and was appointed chair in 2002.
Dr Gomella is involved in both basic science and clinical research in the development of new diagnostic
techniques and treatments for prostate, bladder and kidney cancer through Jefferson’s Kimmel Cancer
Center. Dr Gomella’s team was first to use RT-PCR to detect micrometastasis in patients with prostate
cancer. He serves as director of clinical affairs for Kimmel Cancer and urology chair for RTOG. Dr
Gomella is also recognized as an expert in urologic laparoscopy, having initiated the program at Jefferson
in 1990.
In addition to having given over 400 presentations at local, national, and international meetings, he has
written over 250 papers, book chapters, and monographs in the field of urology and has served as a member
of the Editorial Board of the Investigative Section of Journal of Urology, as co-editor in chief of
Techniques in Urology, and on the board of Urologic Oncology and Journal of Laparoendoscopic Surgery.
He is a consultant to numerous journals in the field of urology and oncology and, in 2006, was appointed
associate editor of Canadian Journal of Urology.
Dr Gomella has authored and edited over 40 books for medical students, house officers, and practicing
physicians, many of which have been translated into foreign languages. He is the editor of the 5 Minute
Urology Consult and co-editor of Laparoscopic Urologic Surgery, the field’s first color atlas. Currently, he
is the laparoscopy editor for Glenn’s Urologic Surgery. Dr Gomella’s Recovering From Prostate Cancer
was the first book for the public dedicated to this topic. In the field of medicine, Dr Gomella is known for
the Clinician's Pocket Reference, now in its 11th edition, which is a widely used reference for medical
students and health care providers. He is the series editor for McGraw-Hill’s On Call resident series. He
has been recognized for many years in Best Doctors in America, and Philadelphia Magazine’s “Top
Doctors” for urologic oncology, and received a Volunteer Achievement Award from the Pennsylvania
Chapter of the American Cancer Society, as well as an NCI Achievement Award, in 2000. In 2006, Dr
Gomella served as president of the Mid-Atlantic Section of the American Urologic Association.
Faculty Financial Disclosure Statements
As a continuing medical education provider accredited by the ACCME, it is the policy of Pri-Med Institute
to require any individual in a position to influence educational content to disclose the existence of any
financial interest or other personal relationship with the manufacturer(s) of any commercial product(s).
The presenting faculty reported the following:
Dr Albala receives honoraria from GlaxoSmithKline and sanofi-aventis U.S. He serves as a consultant for
Applied Medical.
Dr Gomella serves as a consultant for GlaxoSmithKline. He receives honoraria from AstraZeneca
Pharmaceuticals LP. He receives research support from Dendreon and GlaxoSmithKline.
Education Partner Financial Disclosure Statement
The content collaborators at The France Foundation have reported that they have nothing to disclose.
Conflict of Interest Resolution Statement
When individuals in a position to control content have reported financial relationships with one or more
commercial interests, as listed above, Pri-Med Institute works with them to resolve such conflicts to ensure
that the content presented is free of commercial bias. The content of this presentation was vetted by the
following mechanisms and modified as required to meet this standard:
• Content peer review by external topic expert
• Content validation by external topic expert and internal Pri-Med Institute clinical editorial staff
Off-label/Investigational Disclosure
In accordance with Pri-Med Institute policy, faculty have been asked to disclose discussion of unlabeled or
unapproved use(s) of drugs or devices during the course of their presentations.
Drug List
Generic
diethylstilbestrol
finasteride
dutasteride
Trade
Stilbestrol
Proscar
Avodart
Suggested Reading List
Adlercreutz H. Western diet and Western diseases: some hormonal and biochemical mechanisms and
associations. Scand J Clin Lab Invest Suppl. 1990;201:3-23.
Brawley OW, Parnes H. Prostate cancer prevention trials in the USA. Eur J Cancer. 2000;36(10):13121315.
D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy,
external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer.
JAMA. 1998;280(11):969-974.
Etminan M, Takkouche B, Caamaño-Isorna F. The role of tomato products and lycopene in the prevention
of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev.
2004;13(3):340-345.
Freedland SJ, Aronson WJ, Kane CJ, et al. Impact of obesity on biochemical control after radical
prostatectomy for clinically localized prostate cancer: a report by the Shared Equal Access Regional Cancer
Hospital database study group. J Clin Oncol. 2004;22(3):446-453.
Giovannucci E, Rimm EB, Colditz GA, et al. A prospective study of dietary fat and risk of prostate cancer.
J Natl Cancer Inst. 1993;85(19):1571-1579.
Gomella L. Chemoprevention using dutasteride: the REDUCE trial. Curr Opin Urol. 2005;15(1):29-32.
Kattan MW, Wheeler TM, Scardino PT. Postoperative nomogram for disease recurrence after radical
prostatectomy for prostate cancer. J Clin Oncol. 1999;17(5):1499-1507.
Kulkarni GS, Al-Azab R, Lockwood G, et al. Evidence for a biopsy derived grade artifact among larger
prostate glands. J Urol. 2006;175(2):505-509.
Moul J, Sesterhenn IA, Connelly RR, et al. Prostate-specific antigen values at the time of prostate cancer
diagnosis in African-American men. JAMA. 1995; 274(16):1277-1281.
Moyad MA. Selenium and vitamin E supplements for prostate cancer: evidence or embellishment? Urology.
2002;59(4 suppl 1):9-19.
Naslund MJ, Costa FJ, Miner MM. Managing enlarged prostate in primary care. Int J Clin Pract.
2006;60(12):1609-1615.
Richardson TD, Oesterling JE. Age-specific reference ranges for serum prostate-specific antigen. Urol Clin
North Am. 1997; 24(2):339-351.
Roehrborn CG, McConnell JD. In: Walsh PC, et al, eds. Campbell’s Urology. 8th ed. Philadelphia, PA:
Saunders; 2002:1297-1336.
Stanford JL, Stephenson RA, Coyle LM, et al. Prostate Cancer Trends 1973-1995. Bethesda, MD: SEER
Program, National Cancer Institute; 1999. NIH Pub. No. 99-4543.
Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostatespecific antigen level < or =4.0 ng per milliliter. N Engl J Med. 2004;350(22):2239-2246.
Learning Objectives
The Ongoing Burden of Prostate Cancer
and Emerging Theories on Its Origins
•
Leonard G. Gomella, MD
Professor and Chairman, Department of Urology
Kimmel Cancer Center
Thomas Jefferson University
Philadelphia, PA
•
David M. Albala, MD
Professor of Urology
Director of Minimally Invasive Urologic and Robotic Surgery
Duke University Medical Center
Durham, NC
Identify the risk factors for prostate cancer, the
benefits and challenges of current screening
methods, and the role of the primary care
practitioner in identifying high risk patients
Describe the screening, diagnosis and
ongoing management in the prevention of
prostate cancer as these processes relate to
the underlying biology of the disorder and the
optimal roles for primary and specialty care
BPH: Gross Appearance
Prostates are like people:
Everyone is different
David M Albala MD, personal collection
Effect of Testosterone on Prostate
Cancer Pioneered by Charles Huggins
Prostate Gland
• Inferior to bladder
• Contains urethra
• Milky secretion that
makes up ~1/3 of
semen
• Fibromuscular and
glandular organ
• Cancer develops in the
peripheral zone; BPH in
the transitional zone
60
Units per 100 mL Serum
Diethylstilbestrol 1 mg daily
Acid Phosphatase
40
20
Alkaline Phosphatase
0
40
50
60
Time (Days)
http://www.harthosp.org/cancer/prostate.htm. Accessed May 2008.
Huggins C, Hodges CV. Cancer Res. 1941;1:293-297.
1
70
80
Hypothalamic-Pituitary-Gonadal
Axis and the Prostate
Male Population Trend in
the United States
7
M
M
Hypothalamus
35,000,000
M
M
2.
1
> 85 Yr
M
M
29
1.
2
M
M
M
M
> 65 Yr
M
21
.6
5,000,000
M
10,000,000
Prostate
Other
Target
Tissues
84
0,
00
0
15,000,000
13
.1
LH
20,000,000
M
Leydig
Cells
25,000,000
M
Male Population
GnRH
Pituitary Receptor
30,000,000
11
.6
6
LHRH
Testes
0
1990
Testosterone
2000
2020
2050
Year
DHT Receptor
http://www.census.gov.
In: Walsh PC et al, eds. Campbell’s Urology. 8th ed. Philadelphia, PA: Saunders; 2002.
Prostate Disorders
18%
2%
Prostate Cancer in the News...
Prostate Cancer
Prostatitis
80%
BPH
Roehrborn CG, McConnell JD. In: Walsh PC, et al, eds. Campbell’s Urology. 8th ed. Philadelphia, PA:
Saunders; 2002:1297-1336.
Prostate Cancer USA: 2008
•
•
•
•
•
•
Prostate Cancer Statistics
186,320 new cases (down from 218,890 in 2007)
28,660 deaths (up from 27,050 in 2007)
1 in 6 lifetime probability (17.2%)
33% of all new male cancer cases
10% of all male cancer deaths
In 2005, cancer surpassed heart disease as the top
killer of Americans under 85 for the first time
http://www.cancer.org. Cancer Facts and Figures 2008. Accessed May 2008.
Leaf C. “Why we’re losing the war on cancer.” Fortune Magazine. March 22, 2004.
2
Report to the Nation on Prostate Cancer
http://www.seer.cancer.gov. Accessed May 2008.
Renal & Urology News. Dec 2007;6(12).
Metastatic Prostate Cancer
in the 1990s
40
Minimal metastatic prostate
cancer at first presentation
35
Metastatic prostate cancer
at first presentation
30
Risk Factors: Classical
(in order of importance)
• Age
• Race (African Americans increased, Asians
decreased)
• Family history
25
%
20
15
10
5
0
1990
1991
1992
1993
Year
1994
1995
1996
1997
Pienta K, et al. Urology. 1995;45(1):93-102.
Tewari A, et al. J Urology. 2004;171(4):1531-1539.
Incidence Increases with Age
Percent of patients
Prostate Cancer Incidence by Age
HGPIN
CaP
70
60
50
40
30
20
10
0
20-30
30-40
40-50
50-60
60-70
Age (years)
HGPIN: high-grade prostatic intraepithelial neoplasia
CaP: carcinoma of the prostate
Sakr W, et al. In Vivo. 1994;8(3):439-443.
In: Walsh PC et al, eds. Campbell’s Urology. 8th ed. Philadelphia, PA: Saunders; 2002.
3
Why is There a Racial Disparity in
Prostate Cancer?
Autopsy Prevalence of CaP (%)
US (W) US
Age
(years)
(AA)
Europe Japan
Spain
21–30
31–40
41–50
51–60
61–70
71–80
81–90
0%
27%
20%
28%
44%
58%
73%
4%
9%
14%
24%
32%
33%
?
8%
31%
37%
44%
65%
83%
?
8%
31%
43%
46%
70%
81%
?
0%
20%
13%
22%
35%
41%
48%
• Decreased awareness
• Lack of early detection
Never Had DRE (%)
Never
Heard of
CaP = cancer of the prostate; W = white; AA = African-American
Haas GP. Urol Times. December 2005.
Had DRE (%)
Heard of but
Never Had
For Health
Problem
For Screening
1-2 yrs ago
< yr ago
White
20.2
19.0
11.0
18.1
11.3
Black
38.2
16.4
10.8
15.7
5.9
American Cancer Society, 1994.
Prostate Cancer in
African American Men
Racial Disparity in Prostate Cancer
1,750
• Higher incidence, death rate
• Higher PSA, tumor volume
• Unknown etiology for difference: behavioral
vs biologic
• Consider screening – age 40
Rate, per 100,000 men
1,500
“Black Americans may have the world’s highest incidence of prostate cancer, and they
are twice as likely as white Americans to die from the disease.”
—Garnick, MB. Scientific American, 1994
Incidence: Black
Incidence: White
1,250
Death: Black
Death: White
1,000
750
500
250
0
50-54
55-59
60-64
65-69
70-74
75-79
80-84
≥ 85
Age Group, years
Moul J, et al. JAMA. 1995;274(16):1277-1281.
Freedland S, Isaacs W. Prostate. 2005;62(3):243-252.
Moul J, et al. JAMA. 1995;274(16):1277-1281.
Prostate Cancer Stage by Race:
1996 to 2002
Prostate Cancer Stage by Race:
1973 to 1995
Historically, AA men more likely to present with
distant disease (eg
(eg metastasis)
PSA screening has leveled the playing field between
black and white men in stage at presentation
Stanford JL, et al. Prostate Cancer Trends 1973-1995, SEER Program, National Cancer Institute.
NIH Pub. No. 99-4543. Bethesda, MD, 1999.
Jemal A, et al. CA Cancer J Clin. 2007;57:43-66.
4
Potential Reasons for Prostate Cancer
Racial Disparity
Relative 5-Year Prostate Cancer
Survival Rates by Race
(Grouped by Year of Diagnosis)
• Socioecomonic
– Education/income/literacy
– Access to care
– Bias in which treatments are given
1960-1963 1970-1973 1974-1976 1980-1982 1986-1991
Caucasian
50%
63%
68%
74%
87%*
African-American
35%
55%
56%
65%
71%*
• Diet and lifestyle
• Genetic/hormonal
Rates are based on End Results Group data from a series of hospital registries
and one population-based registry.
Rates are from the SEER program and are based on data from population-based
registries in Connecticut, New Mexico, Utah, Iowa, Hawaii, Atlanta, Detroit, SeattlePuget Sound and San Francisco-Oakland. Rates are based on follow-up of
patients through 1983.
– ie, AA men have predisposition to more
cancer and more aggressive cancer
* The difference in rates between 1974-1976 and 1986-1991 is statistically
significant (P > 0.05).
http://www.cancer.org. Cancer Facts and Figures 1996. Accessed May 2008.
Powell I, et al. Cancer. 1999;85:472-477.
Family History
Family History
Thompson IM, et al. N Engl J Med. 2003;349(3):215-224.
Unger J, et al. Cancer. 2005;103:1375-1380.
Steinberg G, et al. Prostate. 1990;17(4):337-347.
Risk factors: “New”
(reasonable evidence though perhaps
not fully accepted yet)
Summary:
Risk Factors for Prostate Cancer
•
•
•
Age
•
•
•
•
- Median age at diagnosis: 71 years
- Median age at death: 78 years
Race
Family history
Diet – particularly “Western” diet
“Inflammation”
Tomatoes (preventative)
Obesity
- One first degree relative: 2-3 fold risk
- Hereditary PCA accounts for < 10% of PCA
In: Walsh PC et al, eds. Campbell’s Urology. 8th ed. Philadelphia, PA: Saunders; 2002.
Giovannucci E, et al. J Natl Cancer Inst. 1993;85(19):1571-1579.
Adlercreutz H. Scand J Clin Lab Invest. 1990;201:3-23.
5
If true, what does it mean?
Diet
• Hypothesis: Western diet increases
prostate cancer risk
• What specifically in the western diet?
• Possibly insulin
• If true, then diabetes (a low insulin
state) should be protective
• Recent meta-analysis
• “Western lifestyle”
• Data somewhat mixed
• Issues
– How to accurately measure “diet”
– Recall bias
– How food is processed
• Cooked vs. uncooked
– Fat: animal vs. vegetable, monounsaturated,
polyunsaturated, saturated, etc.
– RR = 0.91, 95% CI 0.86-0.96
Bonovas S, et al. Diabetologia. 2004;47(6):1071-1078.
Adlercreutz H. Scand J Clin Lab Invest. 1990;201:3-23.
Normal Prostate
Stromoglandular Nodule
Acute Inflammation
Chronic Inflammation
Inflammation
• Often found in the prostate at the time
of prostatectomy
• Proliferative inflammatory atrophy (PIA)
• Hereditary prostate cancer genes
– MSR 1
– RNase L
• Link with prostatitis
– Detection bias?
Roehrborn C, et al. J Urol. 2005;173(S4):346 (abstract 1277).
Roehrborn C, et al. J Urol. 2005;173(S4):346 (abstract 1277).
Inflammation
Tomatoes
• If true, then…
• Anti-inflammatory agents should be
protective
• Recent meta-analysis on aspirin use
and prostate cancer risk
• Contain lycopene
• Animal study suggests that prevention
of CaP growth: tomatoes > lycopene
• Meta-analysis
– Raw: RR = 0.89 (95% CI 0.80-1.00)
– Cooked: RR = 0.81 (95% CI 0.71-0.92)
– OR = 0.9 (95% CI 0.82-0.99)
Mahmud S, et al. Br J Cancer. 2004;90(1):93-99.
Etminan M, et al. Cancer Epidemiol Biomarkers Prev. 2004;13(3):340–345.
6
Obesity and Prostate Cancer
100
90
80
70
60
50
40
30
20
10
0
Black
White
50
Recurrence Free Survival
Percent of Patients
Race and Obesity in Prostate Cancer
40
30
20
10
0
Normal
weight
(< 25)
P = 0.001
Overweight Mildly obese Moderate &
(25-29.9)
(30-34.9)
Severe
obesity
(> =35)
BMI (kg/m2)
Normal (< 25 kg/m2)
Overweight (25 to 29.9 kg/m2)
P = 0.007
Mildly obese (30 to 34.9 kg/m2)
Moderately and severely obese (≥ 35 kg/m2)
0
1
2
3
4
Years after surgery
5
6
Freedland S, et al. J Clin Oncol. 2004; 22(3):446-453.
Freedland S, et al. J Clin Oncol. 2004;22(3):446-453.
Obesity and Prostate Cancer
Recurrence
Recurrence Free Survival
Race, Obesity, and Prostate Cancer
100
• AA men are more likely to be obese
– At least more likely to be extremely obese
• Obesity linked with increased risk of prostate
cancer death
• Is obesity associated with worse outcomes after
surgery?
• Can obesity explain some or all of why AA men
have poorer outcomes after surgery in some
series?
75
50
Nonobese (< 30 kg/m2)
25
P = 0.02
Obese (≥ 30 kg/m2)
0
0
2
4
6
8
Years after Surgery
Freedland S, et al. Clin Cancer Res. 2005;11(8):2883-2888.
Initial Evaluation of Men for PCa:
Recommended Sequence
Enhancing Prostate Cancer Screening,
Diagnostic and Prevention Skills in the
Primary Care Setting
Leonard G. Gomella, MD
Professor and Chairman, Department of Urology
Kimmel Cancer Center
Thomas Jefferson University
Philadelphia, PA
David M. Albala, MD
Professor of Urology
Director of Minimally Invasive Urologic and Robotic Surgery
Duke University Medical Center
Durham, NC
Step
Rationale
Medical history
Identify potential risk factors, comorbidities that may
complicate treatment
Symptom
assessment
Determine severity of symptoms
DRE
Recommended for men > 50 years of age with life
expectancy > 10 years, or men > 40 years of age
who are African-American or have a family history
PSA
PSA = useful screen for prostate cancer
-Age-specific PSA
-PSA velocity
Urinalysis
Rule out hematuria, UTI
Adapted from: Naslund MJ, et al. Int J Clin Pract. 2006;60(12):1609-1615.
7
10
Age-Specific PSA Levels
Prostate-Specific Antigen (PSA)
Definition/background
• Glycoprotein secreted by
the prostate
• Approved by FDA as
Disease Status Monitor
(1986) and to aid prostate
cancer detection (1994)
• After 1986, used in
patients not previously
diagnosed
Use
• Widely used for screening
• Easy to do, cheap
• Not absolutely reliable
Age (yrs)
40-49
50-59
60-69
70-79
– Benign enlargement
– Some prostate cancer
cases have low PSA
– “Normal” result may have
associated false positives
and false negatives
PSA Level
0-2.5 ng/mL
0-3.5 ng/mL
0-4.5 ng/mL
0-6.5 ng/mL
The AUA encourages physicians to offer PCa testing
to men who have an anticipated lifespan of 10 or more years
– Resulted in diagnosis of
many early tumors
PSA velocity > 0.75 ng/mL/year is considered abnormal
Han M, et al. Med Clin N Am. 2004;88:245-265.
Roehrborn CG, McConnell JD. In: Walsh PC et al, eds. Campbell’s Urology. 8th ed. Philadelphia, PA:
Saunders; 2002.
2002
Oesterling JE, et al. JAMA. 1993;270(7):860-864.
Prevalence of Prostate Cancer
with PSA < 4.0 ng/mL
Data from PCPT
AUA PSA Best Practice Guidelines:
Age-Adjusted PSA Values by Ethnic Group
Age Range
Asians
AfricanAmericans
Caucasians
40-49
0-2.0
0-2.0
0-2.5
50-59
0-3.0
0-4.0
0-3.5
60-69
0-4.0
0-4.5
0-4.5
70-79
0-5.0
0-5.5
0-6.5
30
25
20
%
0-1.0
1.1-2.0
2.1-3.0
3.1-4.0
15
10
5
0
Prevalence
Richardson T, Oesterling J. Urol Clin North Amer. 1997;24(2):339-351.
High Grade
Thompson IM, et al. N Engl J Med. 2004;350(22):2239-2246.
AUA PSA Best Practice Guidelines:
Reasons for Elevated PSA
High-grade disease: Gleason score ≥ 7
Prostate Cancer Screening
• Adenocarcinoma of the prostate
• Architectural distortions in the gland that allow PSA
greater access to the circulation
• Benign prostatic hyperplasia
• Biopsy of the prostate
• Transurethral resection of the prostate (TURP)
• Acute urinary retention
• Acute prostatitis
• Subclinical inflammation of the prostate
• Ejaculation (no data for men in their 40s)
• Potential benefits and risks widely debated
in the US
• Many medical specialties express cynicism
regarding rationale and outcomes
• Major differences exist in the
recommendations of various specialty
organizations
Rectal Exams will not affect PSA levels
From the American Urological Association. Oncology. 2000;14(2):267-286.
8
PSA Screening
AUA Guidelines
• Life expectancy (LE)
• Age ≥ 50 yrs
ADVANTAGES
ADVANTAGES
≥ 10 yrs
Early diagnosis when cure is possible
Reduced risk of mets and morbidity
Reduced risk of death from PCa
Improved overall survival
- no risk factors
• Age ≥ 40 yr
- African-American
- Family history
• Individualize decisions to screen
• Discuss potential benefits and consequences
DISADVANTAGES
No reduction in current QoL
No immediate cost
DISADVANTAGES
Patient anxiety
Overtreatment of some tumors
Increased cost of screening
Complications of treatment
Detection of cancer too late for cure
May increase cost at end of life
Morbidity from metastatic disease
From the American Urological Association. Oncology. 2000;14(2): 267-286.
From the American Urological Association. Oncology. 2000;14(2): 267-286.
AUA PSA Best Practice Guidelines:
Early Detection of Prostate Cancer
Screening Tests
Candidates for Early Detection Testing
All men > age 50 with expected lifespan > 10 years
Men age 40-50 with first-degree relative with prostate cancer
or of African-American ethnic background
• Digital Rectal Examination (DRE)
• Prostate-Specific Antigen (PSA)
What tests should be offered?
• Transrectal Ultrasound
PSA and DRE
If 1 or more test is abnormal,
consider prostate cancer, BPH, prostatitis
If both tests normal,
return annually for PSA and DRE
For definitive diagnosis,
use prostate biopsy
If biopsy positive,
discuss treatment options
If biopsy negative,
return annually for PSA and DRE
From the American Urological Association. Oncology. 2000;14(2):267-286.
Effect of PSA Testing on Volume of Prostate Cancer
AUA PSA Best Practice Policy:
The Use of PSA and DRE in a
Screening Study
• The PSA test detected 45% more cases
of cancer than the DRE alone
• The DRE detected 18% more cases of
cancer than the PSA test alone
• Each test detects cancers missed by
the other even in younger men
Ritchie J, et al. Urology. 1993;42(4):365-374.
Men’s Urologic Health. 2007;1(4).
9
Prostate Cancer Chemoprevention:
Good News
PSA Screening
• Recommendations
– Annual PSA and DRE from 50 yrs
– Earlier in men with FH of early onset of PCa
– Prospectively monitoring PSA velocity
– Biopsy for suspicious DRE or PSA > 2.5 ng/ml
– Biopsy for PSA velocity of > 0.75 ng/ml/yr
– Use of percentage free PSA, complexed PSA,
PSA density, PSA velocity
• Selenium
• Vitamin E, Vitamin D
• Soy Extract
• 5-alpha reductase inhibitors (finasteride/dutasteride)
From the American Urological Association. Oncology. 2000;14(2):267-286.
Why Prostate Cancer Prevention?
Normal prostate
cells at risk
• Leading solid tumor in men
• Second cause of male cancer death
• Precursor lesion (PIN/ASAP)
• Cancer takes many years to grow
Bad News
Premalignant
Localized PCa
Locally advanced PCa
Metastatic
disease
USA Today, Wednesday, May 16, 2007.
Prostate Cancer Prevention Trial
(PCPT)
Prostate Cancer Prevention
•
•
•
•
•
•
• Studies
– Finasteride (PCPT)
– Selenium and vitamin E (SELECT)
– Dutasteride (REDUCE)
• Reasonable recommendations
–
–
–
–
Low fat diet, exercise, veggies: Yes!
Vitamin E and selenium: Maybe ?
Vitamin D, soy supplementation: Maybe ?
Encourage screening, especially if high risk: Yes!
N = 18,882
Age ≥ 55; PSA ≤ 3.0 ng/mL
Finasteride vs placebo
End-point: PCa on 7-year prostate biopsy
803/4368 (18.4%) PCa – finasteride arm
1147/4692 (24.4%) PCa – placebo arm
• 24.8% reduction in PCa prevalence (P < 0.001)
Brawley OW, Parnes H. Eur J Cancer. 2000;36(10):1312-1315.
Moyad MA. Urology. 2002;59(4S1):9-19.
Thompson IM, et al. N Engl J Med. 2003;349(3):215-224.
Thompson IM, et al. N Engl J Med. 2003;349(3):215-224.
10
PCPT: Proportions of Biopsies
with Gleason Score 7-10
Chemoprevention of PCa:
Results from PCPT
25% risk reduction in the prevalence of cancer with finasteride
0.08
Probability of
PCa
Gleason score
N = 9060
0.07
Placebo
Placebo
Finasteride
Relative risk
—
3
8 (0.7%)
1 (0.1%)
0.05
7
184 (17.2%)
190 (25.1%)
—
0.04
8, 9, 10
53 (4.6%)
90 (11.2%)
—
7–10
237 (22.2%)
280 (37.0%)
1.67
(1.44, 1.93)
P < 0.001
0.06
0.03
Finasteride
(P < 0.001)
0.02
0.01
0
0
1
2
3
4
5
6
7
Years after randomization
Patients who developed cancer, developed more aggressive tumors
Analysis of data showed excess of high-grade lesions in the finasteride group
Thompson IM, et al. N Engl J Med. 2003;349(3):215-224.
Thompson IM, et al. N Engl J Med. 2003;349(3):215-224.
Reducing Prostate Volume Increases
Detection of High-Grade Cancer
Grade Shift Is a Sampling Artifact
Fewer total apples in crate,
more chance of finding rotten apples
Intact
More total apples in crate,
less chance of finding rotten apples
Finasteride-treated
• Crate containing 15 bad apples
– Apples are added to crate
– As number of apples in crate increases, chances of finding
rotten apples diminishes
Biopsy
Needle
– Conversely, if number of apples in crate decrease, chances of
finding rotten apples increases
– Rotten apples in crate represent the total cancer present, of
which 2/3 were Grade 3 and 1/3 were Grade 4 in PCPT
Biopsy
Needle
Kulkarni GS, et al. J Urol. 2006;175(2):505–509.
Reduced Incidence of Prostate Cancer
with 5-ARIs: Pooled Analysis From
Dutasteride BPH Studies
REDUCE Study Design
Kaplan-Meier Estimates of Proportion of Subjects Experiencing a
Prostate Cancer Adverse Event with Onset After Randomization
Probability of
Prostate Cancer
0.04
0.02
0.01
0
•Primary endpoint: biopsy-determined prostate cancer after 2 and 4 yrs of treatment
•Enrollment complete January 2005
•Interim analysis 2007
•Full analysis early 2009
Placebo (N = 2158)
Dutasteride 0.5 mg (N = 2167)
0.03
0
3
6
Andriole GL, et al. Urology. 2004;64:537-541.
Gomella L. Curr Opin Urol. 2005;15:29-32.
11
9
12
15
Month
18
21
24
27
SELECT Study Design
(Selenium and Vitamin E)
Differences Between PCPT and
REDUCE Chemoprevention Trials
PCPT
REDUCE
Study Duration
7 years
4 years
No. of subjects
18,882
~ 8000
Location
US only
International
Baseline biopsies
No
Yes (1 neg bx)
Follow-up biopsies
7 years
2 and 4 years
PSA entry criteria
< 3.0
2.5 – 10.0
Free PSA
---
< 25%
Age
> 55
> 50
Andriole GL, et al. Urology. 2004;64:537-541.
Klein E. Ann NY Acad Sci. 2004;1031:234-241.
The Ideal Candidate for 5-ARI
Chemoprevention
Prostate Chemoprevention
• PCPT is the first clinical trial in which an
intervention in healthy men reduced the risk
of prostate cancer
• A 24.8% reduction could have a tremendous
impact on the disease
• The secondary endpoint of more Gleason ≥
7 tumors in the Finasteride arm may be due
to artifact of appearance and not that the
drug makes disease more aggressive
• REDUCE trial looks at higher risk patients
•
•
•
•
•
•
•
•
Thompson IM, et al. N Engl J Med. 2003;349(3):215-224.
Andriole GL, et al. Urology. 2004;64:537-541.
Thompson IM, et al. N Engl J Med. 2003;349(3):215-224.
Andriole GL, et al. Urology. 2004;64:537-541.
Touted But Not Validated
BPH: Effect of 5-ARI blockers
•
•
•
•
•
•
•
•
•
•
•
•
Patients placed on 5-ARIs will have a 50% reduction in PSA
Before
Man who is 55 years old or older
Prostate > 40 cc
Symptomatic: AUA score > 10 or so
Risk factor for prostate cancer: AA, family hx
Elevated PSA with prior negative biopsy x 2
Male pattern baldness
Wants to prevent prostate cancer
Already on Alpha-Blocker (MTOPS)
After
Androstenedione/DHEA (ED supplements)
Beta-carotene supplements
Conjugated linoleic acid (CLA)
Coenzyme Q10 (CoQ10)
Fish oil pills
Garlic pills
Green tea supplements
Lycopene supplements
MGN/shark supplements
Saw palmetto
Vitamin C
Zinc...
Brawley OW, Parnes H. Eur J Cancer. 2000;36(10):1312-1315.
Moyad MA. Urology. 2002;59(4S1):9-19.
Thompson IM, et al. N Engl J Med. 2003;349(3):215-224.
David M Albala MD, personal collection
Roehrborn C. Rev Urol. 2004;6(9):S22-S30.
12
AUA Prostate Cancer 2007
Guidelines
The Treatment Challenge
•
•
•
•
•
•
•
•
•
•
•
•
Stage
Grade
PSA
Health status
Pt Preference
QoL
Match
WW
Surgery
Conformal XRT
Brachytherapy
Cryotherapy
Neoadjuvant
Hormonal Therapy
• Androgen
Withdrawal
• Investigational
• 2007: literature from 1991 to 2004
– 13,888 articles, 436 evidence-based
– Clinical stage T1 to T2N0M0
– “Standard“ the least flexibility as
treatment policy
– “Recommendation" has significantly
more flexibility
– “Option" is even more flexible
Thompson I, et al. J Urol. 2007;177(6):2106-2131.
Mr. Jones
•
•
•
•
•
•
Case Study for Prostate Cancer
60 y/o man
Father died of prostate cancer
Wants to be checked
African-American?
Positive family history?
Any other risk factors?
?
Current Screening Guidelines
Does PSA Work ?
• Mr. Jones heard that prostate-specific antigen (PSA) test
doesn’t really work
• What do you tell him?
• AUA/ACS – Men over 50 with 10 year life
expectancy: PSA and DRE screening
Mr. Jones, you are:
1.) Correct, the test doesn’t work
2.) Well, Mr. Jones, the test actually works quite well
3.) Mr. Jones, that is a really good question. It depends…
• US Preventive Services Task Force
– Age 40 for AA and men with a family h/o prostate
cancer
– Evidence is insufficient to recommend for or
against PSA screening; weigh risks/benefits
• ACPM 2008: insufficient evidence to
recommend routine PSA/DRE screening
From the American Urological Association. Oncology. 2000;14(2):267-286.
http://www.cdc.gov/nccdphp/dnpa/hwi/resources/screening_matrix.htm#Prostate%20Cancer
Lim LS, Sherin K. ACPM Prevention Practice Committee. Am J Prev Med. 2008;34(2):164-70.
[Faculty will discuss the answers]
13
Prostate Cancer Incidence
Normal PSA
• PSA was normal (1.0 ng/mL)
• DRE was normal
• Can you tell him he does not have prostate
cancer?
In: Walsh PC, et al, eds. Campbell’s Urology. 8th ed. Philadelphia, PA: Saunders; 2002.
Tyrol Study
Tyrol vs Austria
Tyrol Study
• 1993: All men between ages 45-75 in Tyrol,
Austria, offered free PSA screening
• 32% of men in Tyrol had PSA in 1993
• 66% of men in Tyrol had PSA in next 5 years
• Prostate biopsy if:
•
•
•
•
Prostate cancer incidence – increased
Organ-confined rate – increased
Extraprostatic disease – decreased
Mortality – decreased
– PSA > Age-specific reference range
– Free/total PSA < 22%
Bartsch G, et al. Br J Urol. 2008;101(7):809-816.
Bartsch G, et al. Br J Urol. 2008;101(7):809-816.
Tyrol Study
Mortality
Tyrol Study
Stage Migration
Bartsch G, et al. Br J Urol. 2008;101(7):809-816.
Bartsch G, et al. Br J Urol. 2008;101(7):809-816.
14
?
Age-Adjusted PSA Values
Elevated PSA
•
•
Patient returns 2 years later; PSA is 5 ng/mL
Normal prostate on exam
Age range (yr.)
What would you do?
1.) Perform a biopsy
2.) Repeat PSA (+/- antibiotics)
3.) Check free/total PSA
4.) Refer to a urologist
[Faculty will discuss the answers]
40 - 49
Median range
ng/mL
0.7
Reference range
ng/mL
0.0 - 2.5
50 - 59
1.0
0.0 - 3.5
60 - 69
1.4
0.0 - 4.5
70 - 79
2.0
0.0 - 6.5
Oesterling JE, et al. JAMA. 1993;270(7):860-864.
PSA Velocity
What Can Influence the Serum PSA?
• PSA level increases over time in men with
prostate cancer
• PSA rise > 0.75 ng/mL/yr = increased risk of
cancer
• Prostate cancer
• Prostatitis
– Response to antibiotics not effective in separating benign
from malignant PSA rises
• BPH
• Physical Activity
• Medications
– 78% sensitivity
– 90% specificity
– 5-alpha reductase inhibitors (finasteride/dutasteride)
– PC-SPES
• Based on levels over 3 years
• Can’t extrapolate to months
• DRE and ejaculation
– Can increase PSA but not from normal to abnormal
• Prostate biopsy/cysto
– Wait 4-8 weeks
From the American Urological Association. Oncology. 2000;14(2):267-286.
From the American Urological Association. Oncology. 2000;14(2):267-286.
PSA Velocity
Prior Negative Biopsy
• Recent study suggests sudden increase in
PSA during the year prior to diagnosis is
predictive of outcome
• PSA is 6.2 ng/mL
• Normal prostate on exam
• Sextant biopsy one year ago was normal by
urologist
• He has not followed up with the urologist
• What do you do?
– PSA velocity > 2 ng/mL
• Increased risk of death from prostate cancer
• Not affected by treatment
– Needs to be normalized for obesity, prostate size,
and age
From the American Urological Association. Oncology. 2000;14(2):267-286.
15
One Negative Extended Biopsy
Many Negative Biopsies
• PSA is now 5.7 ng/mL
• Normal prostate on exam
• 12-core biopsy one year ago was normal
(PSA was 6.2 ng/mL)
• What do you do?
• 2 years later the PSA is now 8 ng/mL
• He has had two sets of 12-core biopsies that
were negative
• What do you do?
?
Is Prostate Cancer Preventable?
Prostate Cancer Prevention
• Mr. Jones wants to know if he can take anything to
prevent prostate cancer?
• Studies
– Finasteride (PCPT)
– Dutasteride (REDUCE)
– Selenium and Vitamin E (SELECT)
What do you recommend?
1.) Dutasteride
2.) Finasteride
3.) Selenium and Vitamin E
4.) Combination of 1 or 2 and 3
5.) There is nothing to prevent prostate cancer
6.) Other
[Faculty will discuss the answers]
Take Home Messages
Questions & Answers
• The combination of DRE and PSA offers
greater advantages for screening than either
one alone
• PSA velocity may be more specific and a
better indicator for performing a prostate
biopsy to rule out cancer than static PSA
determinations
• There are promising new developments with
prostate cancer chemoprevention
16
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