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Prostate Cancer Prevention: Concepts and Controversies

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Review the Prostate Cancer Prevention Trial (PCPT) ... Finasteride decreases the overall risk of prostate cancer. ... of prostate biopsy for detecting high ... – PowerPoint PPT presentation

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Title: Prostate Cancer Prevention: Concepts and Controversies


1
Prostate Cancer PreventionConcepts and
Controversies
  • J. Kellogg Parsons, M.D., M.H.S.
  • Assistant Professor of Surgery
  • Moores UCSD Comprehensive Cancer Center

2
Population Trends in Prostate Cancer
  • Incidence has stabilized.
  • Death rate is decreasing.
  • Goal decrease incidence

Cancer Prevention, 2008
3
(No Transcript)
4
Goals Today
  • Review concepts of disease prevention
  • Review the Prostate Cancer Prevention Trial
    (PCPT)
  • Review the Selenium and Vitamin E Cancer
    Prevention Trial (SELECT)
  • Review micronutrients and diet
  • Develop practical recommendations for clinical
    practice

5
(No Transcript)
6
General Concepts of Disease Prevention
Primary Prevention
Secondary Prevention
Risk Factors
Advanced Disease
Disease
Progression
7
Prevention Studies Ideal Structure
Pre-clinical Studies
Hypotheses
Epi Studies
Phase I/II
  • PCPT
  • SELECT

Phase III
Clinical Practice?
8
Prevention Studies Reality
Pre-clinical Studies
Hypotheses
Epi Studies
Phase I/II
Phase III
Clinical Practice?
9
(No Transcript)
10
PCPT Key Characteristics
  • 18, 882 men randomized
  • 55 years
  • PSA 3.0 ng/mL
  • Normal DRE
  • Finasteride vs. placebo
  • Uniform PSA criteria for biopsy
  • End-of-study biopsy for all cancer-free men
  • Duration
  • 7 year design.
  • Ended 15 months early.

11
PCPT Key FindingsOverall Prevalence
24.8 reduction
24.4
18.4
12
PCPT Key Findings
13
PCPT Key FindingsHigh Grade (Gleason 7)
Prevalence
25.0 increase
5.1
6.4
14
PCPT Initial Key Points
  • Prostate cancer is highly prevalent.
  • Nearly 1 in 4 men in placebo group
  • Finasteride decreases the overall risk of
    prostate cancer.
  • Finasteride possibly increases the risk of
    high-grade prostate cancer.
  • Finasteride artifact?
  • Selective inhibition of low grade tumors?
  • Altered hormonal mileiu?
  • Statistical anomaly?

15
(No Transcript)
16
PCPT Updated Analyses
  • Two important points
  • Finasteride DOES NOT increase the risk of
    high-grade cancer.
  • The sexual side effects of finasteride are
    minimal.

17
Why the Initial High-Grade Finding?
  • Finasteride increases the sensitivity
  • of PSA for detecting cancer
  • of a DRE for detecting cancer
  • of prostate biopsy for detecting high-grade
    cancer
  • These factors led to significant BIAS in the
    initial analyses

18
Bias Adjusted Incidence in PCPT
Risk reductions for finasteride Prostate cancer
30 High-grade 27
19
PCPT Sexual Side Effects
  • Intensive analysis using
  • Sexual Activity Scale score (100-point scale)
  • SF-36
  • Multiple other quality of life measures
  • No clinically significant difference between
    placebo and finasteride (2.11 points at
    end-of-study)

JNCI 99 1025, 2007
20
Finasteride Then
  • Should finasteride now be recommended to men in
    order to lower their risk of prostate cancer?
    Several disturbing findingsargue that it should
    not.
  • --Dr. Peter Scardino

NEJM 349 297-9, 2003
21
And Now
Dr. Peter Scardino originally thought
finasteride was dangerous but now recommends its
use. NY Times, June 15, 2008
Finasteride has to be recognized as the first
clearly demonstrated way to prevent prostate
cancerWhy wouldnt every man take it?
New Take on a Prostate Drug, and a New
Debate NY Times June 15, 2008
22
The REDUCE Trial
  • Dutasteride vs. placebo
  • 8,000 men
  • 50-75 years
  • PSA 2.5 to 10 ng/ml
  • 4-year duration
  • Biopsies cause, 2 year, and 4 year

23
The Selenium and Vitamin E Prostate Cancer
Prevention Trial (SELECT)
  • Largest cancer prevention trial ever undertaken
  • 34,000 men enrolled (1823 at UCSD)
  • Scheduled end date 2013
  • Participants randomized to
  • Vitamin E
  • Selenium
  • Both
  • Placebo
  • Primary end point incident prostate cancer

24
Vitamin E
  • Alpha-tocopherol is biologically active form
  • Anti-oxidant
  • Inhibits NF-Kappa Beta
  • Modulates cellular proliferation
  • Induce apoptosis
  • Recommended (SELECT) dose
  • 400 IU once daily
  • Risk of side effects
  • Minimal at this dose or less

25
Selenium
  • Essential trace nutrient found in plants
  • Inhibits cancer cell growth
  • Induces apoptosis
  • Alters androgen receptor signaling
  • Recommended dose
  • L-selenomethionine 200 µg once daily
  • Risk of side effects
  • Minimal

26
Selenium
27
Selenium and Prostate Cancer
28
A Brief Word on Statins
23 REDUCED RISK FOR HIGH-GRADE OR ADVANCED
DISEASE
29
Diet-Based Interventions
  • General concept
  • Altering diet in prostate cancer patients may
    possibly slow prostate cancer initiation and/or
    progression.
  • Can involve
  • Change in diet
  • Supplements

THIS IS NOT COMPLEMENTARY OR ALTERNATIVE
MEDICINE!
30
Diet and Prostate Cancer
  • Tomatoes
  • Crucifers (Broccoli, brussel sprouts,
    cauliflower)
  • Soy
  • Fat and meat
  • Omega-3 fatty acids
  • Vitamin D
  • Calcium and dairy

THERE ARE NO PHASE III CLINICAL TRIALS
31
Diet and Prostate Cancer
  • Pre-clinical evidence1-3
  • Components of crucifers (isothiocyanates) and
    tomatoes (carotenoids)
  • Induce apoptosis of prostate cancer cells
  • Inhibit carcinogenesis
  • Promote expression of cytoprotective enzymes
  • Protect against oxidative DNA damage
  • Cancer Res, 67 836, 2007.
  • Cancer Epidemiol Biomarkers Prev,10949, 2001.
  • J Natl Cancer Inst, 931872, 2001.

32
Plant-based Diets
  • Tomatoes
  • Putative active agent lycopene
  • Free radical scavenger
  • Induces apoptosis
  • Epidemiological studies inconsistent
  • Emerging consensus
  • Tomatoes moderately beneficial
  • Lycopene is not
  • Processed tomatoes okay--possibly even better
    than raw

33
Tomatoes and Prostate CancerMeta-analysis of
Published Studies
34
Plant-based Diets
  • Cruciferous vegetables
  • Broccoli (baby broccoli sprouts), brussel
    sprouts, cauliflower, kale
  • Putative agents isothiocyanates
  • Induce expression of cytoprotective enzymes
  • Inhibit carcinogenesis
  • Free radical scavengers
  • Epidemiological studies (PLCO, HPFS) show
    protective effect

35
The Mens Eating and Living (MEAL) Study
Urology, 2008
36
The MEAL Study
  • Telephone-based dietary counseling program.
  • Based on social cognitive theory.1
  • Adapted from studies of breast cancer patients.
  • Has produced robust diet changes in 1500 patients
    for over 4 years 2,3

1. Miller WR and Rollnick S, 2002 2. Cancer
Epidemiol Biomarkers Prev 15 1886, 2006 3.
JAMA, 2007
37
The MEAL Study
  • Counseling intervention
  • Centralized from UCSD.
  • Each participant assigned a counselor.
  • Build self-efficacy.
  • 13 counseling sessions.
  • 25-50 minutes.
  • Diet goal 7 servings/day of vegetables.

38
MEAL STUDY
2 lost to follow-up 1 opted for treatment
2 lost to follow-up
39
MEAL STUDY VEGETABLE INTAKE
40
MEAL STUDY Non-VEGETABLE INTAKE
41
MEAL STUDY Plasma Carotenoids
42
MEAL Study Active Surveillance
NEXT STEP TO DETERMINE IF THIS INTERVENTION WILL
PREVENT DISEASE PROGRESSION
BJU Int, 2008
43
Soy Products
  • Rich in isoflavones (genistein and daidzein) and
    phytoestrogens
  • Anti-oxidants
  • Inhibit tumor cell proliferation
  • Possible effect on telomerase
  • Estrogenic effects/alterations in androgen
    receptor
  • Decrease prostate cancer risk in large
    epidemiological studies

44
Soy Meta-Analysis of Epidemiological Studies
30 Reduction in Prostate Cancer Risk
45
Soy
  • Phase II studies show promise for high soy diets
    for biochemical recurrence
  • Studies are ongoing
  • Urology 64 510, 2004
  • Prostate 59 141, 2004

46
Fish(Omega-3 fatty acids)
  • Decrease prostate cancer risk in large
    epidemiological studies
  • Omega-3 polyunsaturated fatty acids
  • Alter cyclooxygenase (COX-2) pathways
  • Inhibit tumor growth
  • Induce apoptosis
  • Phase II biomarker studies currently underway

47
Meat and Animal Products
  • Increase prostate cancer risk in large
    epidemiological studies
  • Red meat
  • Cooked meats contain PhIP, a potent mutagen
  • Risk may be higher for processed meats
  • Dietary fat
  • Increases risk of aggressive cancer and
    recurrence after treatment
  • Weight loss 11 lbs 40 risk reduction in
    high-grade cancer

48
A Brief Word on Pomegranate Juice
  • Single trial of 46 patients
  • Increased PSA doubling time in patients with
    biochemical recurrence
  • Limited laboratory studies
  • No epidemiological studies
  • Pro-apoptotic, anti-proliferative, and
    anti-oxidant?

49
SummaryWhat to tell your patients
  • Finasteride prevents prostate cancer
  • NO increased risk of high-grade disease
  • Minimal sexual side effects
  • SELECT Trial may show benefits for Vitamin E
    and/or selenium, but no definitive evidence yet
  • Statins may potentially prevent aggressive
    prostate cancer

50
SummaryWhat to tell your patients
  • Studies are ongoingnothing definitive yet.
  • There is little downside to moderate changes in
    nutritional intake
  • Vegetable intense diet
  • Tomatoes
  • Broccoli
  • Soy
  • Fish
  • Decrease meat, fat, and animal product intake
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