Prostate Cancer Prevention: Concepts and Controversies

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Prostate Cancer PreventionConcepts and
Controversies

• J. Kellogg Parsons, M.D., M.H.S.
• Assistant Professor of Surgery
• Moores UCSD Comprehensive Cancer Center

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Population Trends in Prostate Cancer

• Incidence has stabilized.
• Death rate is decreasing.
• Goal decrease incidence

Cancer Prevention, 2008
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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

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General Concepts of Disease Prevention
Primary Prevention
Secondary Prevention
Risk Factors
Advanced Disease
Disease
Progression
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Prevention Studies Ideal Structure
Pre-clinical Studies
Hypotheses
Epi Studies
Phase I/II

• PCPT
• SELECT

Phase III
Clinical Practice?
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Prevention Studies Reality
Pre-clinical Studies
Hypotheses
Epi Studies
Phase I/II
Phase III
Clinical Practice?
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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.

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PCPT Key FindingsOverall Prevalence
24.8 reduction
24.4
18.4
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PCPT Key Findings
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PCPT Key FindingsHigh Grade (Gleason 7)
Prevalence
25.0 increase
5.1
6.4
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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?

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PCPT Updated Analyses

• Two important points
• Finasteride DOES NOT increase the risk of
  high-grade cancer.
• The sexual side effects of finasteride are
  minimal.

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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

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Bias Adjusted Incidence in PCPT
Risk reductions for finasteride Prostate cancer
30 High-grade 27
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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
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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
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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
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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

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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

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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

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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

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Selenium
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Selenium and Prostate Cancer
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A Brief Word on Statins
23 REDUCED RISK FOR HIGH-GRADE OR ADVANCED
DISEASE
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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!
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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
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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.

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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

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Tomatoes and Prostate CancerMeta-analysis of
Published Studies
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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

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The Mens Eating and Living (MEAL) Study
Urology, 2008
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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
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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.

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MEAL STUDY
2 lost to follow-up 1 opted for treatment
2 lost to follow-up
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MEAL STUDY VEGETABLE INTAKE
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MEAL STUDY Non-VEGETABLE INTAKE
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MEAL STUDY Plasma Carotenoids
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MEAL Study Active Surveillance
NEXT STEP TO DETERMINE IF THIS INTERVENTION WILL
PREVENT DISEASE PROGRESSION
BJU Int, 2008
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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

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Soy Meta-Analysis of Epidemiological Studies
30 Reduction in Prostate Cancer Risk
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Soy

• Phase II studies show promise for high soy diets
  for biochemical recurrence
• Studies are ongoing

• Urology 64 510, 2004
• Prostate 59 141, 2004

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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

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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

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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?

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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

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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