Download Selenium and Vitamin E

Background:
 Based on ACS data, nearly 217,730 men will be diagnosed with CaP in
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2010.
Over 32,050 men will die of this disease in 2010.
Over 2 million men are alive today in US with CaP.
The 5-yr survival rate is now almost 100% & 10-yr rate 91%.
The ACS attributes this to “modern detection & treatment” techniques
while they have not supported early detection.
Survival rates for A.A.’s are 10-15% lower than those of whites for the
most common cancers (other than lung).
The incidence of CaP among A.A. men is 73% higher than for white
men.
ACS. Cancer.org / June 30, 2010
Lu-Yao et al. The Prostate Patient Outcomes Research Team. JAMA 1993;269:2633-2636
The Diagnosis and Prevention of
Prostate Cancer:
A Challenge for the 21st Century Man
Brian A. Stone MD, FACS
Baptist Health Systems of Alabama
Jasper Urology Associates
Higher incidence of prostate cancer, greater mortality compared with
white men
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Access to care
Attitudes about care
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Distrust of medical institutions
Less likely to be screened
Socioeconomic, educational differences
Knowledge regarding prostate cancer dependent on education and income
Men without health insurance more likely to be diagnosed with advanced stage
disease
 Relationship between low income and advanced stage at diagnosis
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Differences in type and aggressiveness of treatment
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Genetic differences
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Less likely to be treated with aggressive therapy
More potent androgen receptor for given androgen concentration
Increased androgen receptor expression
Slower testosterone deactivation
Dietary differences?
Freedland S, Isaacs W. Prostate. 2005; 62(3):243-252.
 African Americans with advanced prostate cancer
exhibited:
 Socioeconomic status
 Under insured
 Incidence early detection
 Biologic differences in disease behavior
 Earlier age onset
 Pathologic, genetic differences (i.e., tumor volume,
androgen receptor pathway)
 Modifiable factors affecting gene expression (diet, obesity)
Hoffman R, et al. J Gen Intern Med. 2003;18:845-853.
To Screen or Not to Screen??????
Several studies have attempted to answer the big
question.
1) The Quebec Trial (Labrie et al) – 46,486 men
2) The Tyrol Study (Tyrol, Austria) – 21,079 men
3) ERSPC (European Study of Screening for CaP) –
162,243 men
4) PLCO Cancer Screening Trial – 154,942 men
Have They Succeeded????
 Quebec study criticism: Concerns over the study
design & absence of men of African descent.
 Tyrol study criticism: Follow up period not long
enough & absence of men of African descent.
 ERSPC study criticism: Follow up period inadequate to
assess mortality impact & absence of data on men of
African descent.
 PLCO study criticism: Follow up period not long
enough & absence of data analysis in African American
men.
Suggestive Benefits of Labrie Data
 Unscreened men had 41.6% death rate vs. 13.7% in the
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screened men. (Yields 3.85 odds ration advantage!)
6 deaths out of 7233 screened men vs. 69 deaths out of
14419 controls. (82% fewer deaths; even correcting for
the 4 vs 7 yr f/u there were 69% fewer deaths!)
Low stage Ca detection is enhanced.
Stage migration is clear.
Metastatic disease at Dx is reduced.
Suggests survival benefits.
New Findings of ERSPC
 5990 cancers found in screened men vs 4307 found in
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controls.
Cumulative CaP incidence is 8.2% vs 4.8%.
71% more cancers found in screened men!
72% of screened men had < G6 vs 55% of controls.
45% of controls had > G7 vs 28% of screened men.
Local disease favored in screened men.
20% reduction in cancer deaths in screened group vs
the controls.
Current evidence is insufficient to assess the balance of benefits and harms
of prostate cancer screening in men younger than 75 years
USPSTF recommends against screening for prostate cancer in men
age 75 years or older
A clinician should not order the PSA test without
first discussing with the patient the potential but
uncertain benefits and known harms of prostate
cancer screening and treatment
Men should be informed of the gaps in the evidence
and should be assisted in considering their personal
preferences before deciding whether to be tested
US Preventative Services Task Force. Ann Intern Med. 2008;149:185-191.
Who in the world should men listen to
regarding early detection????
 The US Preventative Services Task Force
 American College of Preventive Medicine
 The National Comprehensive Cancer Network
 American Urological Association
 The R. Frank Jones Urological Society
 The American Cancer Society
 A thoughtful and broad approach to PSA is important
 The age for obtaining a baseline PSA has been lowered to 40 years
 There is no longer a single threshold PSA value that should prompt
prostate biopsy
 Decision to biopsy should be based:
 Primarily on PSA and DRE results
 Also take into account
 Free and total PSA
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 Patient age
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 PSA velocity
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 PSA density
Family history
Ethnicity
Prior biopsy history
Comorbidities
 Recent studies suggest that prostate screening leads to overdetection
and overtreatment of some patients
 Men should be informed of the risks and benefits of prostate cancer
screening before biopsy
 Certain men newly diagnosed with prostate cancer should be informed of
the option of active surveillance instead of immediate treatment
AUA: American Urological Association
Available at: http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf
Accessed May 2009.
Trial
Risk Group
Molecular
Target
Results
PCPT
Low
Type II 5AR
Updated 2008
SELECT
Low
Oxidative Stress
Reported 2008
REDUCE
Intermediate
Types I and II 5AR
Reported 2009
SWOG/Se
High
Se-mediated
effects
2010
Toremifene
High
Estrogen Receptor
2010
Andriole G. Urology. 2009;73(S5A):36-43.
NCT00030901; NCT00106691. Available at: www.clinicaltrials.gov. Accessed June 2009.
Primary endpoint: prevalence of prostate cancer during 7 years of study
Enrollment
N = 18,882 men > 55 years, normal DRE,
PSA < 3.0 ng/mL
Randomization
Placebo
Finasteride (5 mg daily)
Annual DRE, PSA
for 7 years
End of Study
Biopsy
Thompson I, et al. N Engl J Med. 2003;349:215-224.
End of Study
Biopsy
 Prostate cancer @ 7 years
 Placebo: 24.4%
 Finasteride: 18.4%
 24.8% reduction P < 0.001
 Tumors ~ Gleason Score 7–10
 Placebo: 237/1068 tumors (22%)
 Finasteride: 280/757 tumors (37%) P < 0.001
 May be due to sampling artifact and not drug-induced high grade
disease
 Safety
 Sexual side effects (gynecomastia, loss of libido, impotence,
decreased ejaculate) more common in finasteride-treated patients;
urinary symptoms more common in placebo-treated patients
Thompson I, et al. N Engl J Med. 2003;349:215-224.
 4 year, multicenter, international, randomized, double-blind,
placebo-controlled trial
 Dual 5-α reductase inhibitor dutasteride (0.5 mg/day) vs placebo
 Looking at patients with higher risk for prostate cancer (PSA 2.5-10
ng/mL for men 50-60 years; 3.0-10 ng/mL for men > 60 years)
 Single negative biopsy within 6 months of enrollment at baseline
 Primary endpoint: biopsy-detectable prostate cancer at 2 and 4
years of treatment
Andriole GL. Urology. 2009;73(S5A):36-43.
 Prostate cancer @ 4 years
 Placebo: 11.8%
 Dutasteride: 9.1%
 23% reduction P < 0.001
 Tumors ~ Gleason Score 7–10
 Placebo: 233/3406 (6.8%)
 Dutasteride: 220/3298 (6.7%) P = 0.81
 Safety
 Sexual side effects (gynecomastia, loss of libido, erectile dysfunction)
more common in dutasteride-treated patients
Andriole G, et al. American Urological Association Annual Meeting, Chicago, IL. April 28, 2009. LBA1.
 Man who is 55 years old or older
 Prostate volume > 40 mL
 Symptomatic: AUA score > 10 or so
 Risk factor for prostate cancer: AA, family history
 Elevated PSA with prior negative biopsy
 Male pattern baldness
 Wants to prevent prostate cancer
 Already on Alpha-Blocker
Thompson IM, et al. N Engl J Med. 2003;349:215-224.
Andriole GL, et al. Urology. 2004;64:537-543.
• Men with a prostate-specific antigen (PSA) score of 3.0 or
below who are screened regularly (or plan to get yearly PSA
tests) and currently show no signs of prostate cancer are
encouraged to talk with their doctor about the risks and
benefits of taking a 5-alpha reductase inhibitor (5-ARI) to
further prevent their likelihood of getting prostate cancer
• Men who are already taking a 5-ARI for other conditions
should talk with their doctor about continuing to use this
drug for the prevention of prostate cancer
Strength of evidence: The systematic review completed for this guideline identified 15
randomized clinical trials that met the inclusion criteria, nine of which reported prostate
cancer period-prevalence.
Kramer B, et al. J Clin Oncol. 2009;27:1502-1516.
ASCO: American Society of Clinical Oncology
SELECT Study Design
(Selenium and Vitamin E)
Pre-Randomization
Period
Calendar Year
2001 – 2004
(Planned 2001 – 2006)
Randomized
Calendar
Year
2001 - 2013
Vitamin E
+
Vitamin E
+
Placebo
+
Placebo
+
Selenium
Placebo
Selenium
Placebo
Follow - up
Prostate cancer, other cancer, death
Klein E. Ann NY Acad Sci. 2004;1031:234-241.
Selenium: 200 mcg/day; Vitamin E: 400 International Units/day
SELECT: Prostate Cancer Incidence
Placebo
Vitamin
E Selenium
Vitamin E + selenium
Hazard Ratios for Prostate Cancer
(compared with placebo)
Vitamin E: 1.13 (P = 0.06)
Selenium + Vitamin E: 1.05 (P = 0.52)
Selenium: 1.04 (P = 0.62)
Lippman S, et al. JAMA. 2009;301(1):39-51.
Data as of October 23, 2008; median follow-up 5.46 years
When to refer to a urologist:
 Significant risk based on “risk calculator”
 Abnormal PSA velocity (> 0.75 ng/mL/year)
 Abnormality detected on DRE
 Failure of medical management for BPH
 Patients with hematuria (> 3 RBCs/HPF)
BPH: benign prostatic hyperplasia; RBCs: red blood cells; HPF: high powered field
 Age, race/ethnicity, and family history are significant risk
factors for prostate cancer
 Prostate cancer screening
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Clinician and patient dialog regarding DRE, PSA
Thoughtful and broad approach to PSA
Discuss risks and benefits of testing in advance of tests
AUA now recommends a baseline PSA at 40 years of age for healthy, wellinformed men who wish to be tested
 Chemoprevention
 Promising results from PCPT and REDUCE with 5-alpha-reductase
inhibitors finasteride, dutasteride; significant reduction in prostate cancer
incidence at study endpoints (25 and 23%, respectively)
 ASCO/AUA practice guideline
 Selenium or vitamin E alone or in combination did not prevent prostate
cancer in the SELECT trial