Prostate Cancer Prevention:Prostate Cancer Prevention:Concepts and ControversiesConcepts and Controversies

J. Kellogg Parsons, M.D., M.H.S.J. Kellogg Parsons, M.D., M.H.S.

Assistant Professor of SurgeryAssistant Professor of Surgery

Moores UCSD Comprehensive Cancer Moores UCSD Comprehensive Cancer CenterCenter

Cancer Prevention, 2008Cancer Prevention, 2008

• Incidence Incidence has has stabilized.stabilized.• Death rate Death rate is decreasing.is decreasing.• Goal: Goal: decrease decrease incidenceincidence

Population Trends in Prostate Population Trends in Prostate CancerCancer

Goals TodayGoals Today

• Review concepts of disease Review concepts of disease preventionprevention

• Review the Prostate Cancer Review the Prostate Cancer Prevention Trial (PCPT)Prevention Trial (PCPT)

• Review the Selenium and Vitamin E Review the Selenium and Vitamin E Cancer Prevention Trial (SELECT)Cancer Prevention Trial (SELECT)

• Review micronutrients and diet Review micronutrients and diet • Develop practical recommendations Develop practical recommendations for clinical practicefor clinical practice

General Concepts of Disease General Concepts of Disease PreventionPrevention

DiseasDiseasee

Advanced Advanced DiseaseDisease

ProgressionProgression

Risk Risk FactorFactor

ss

Primary Primary PreventionPrevention

Secondary Secondary PreventionPrevention

HypothesesHypotheses

Phase I/IIPhase I/II

Phase IIIPhase III

Clinical Practice?Clinical Practice?

Pre-Pre-clinical clinical StudiesStudies

Epi Epi StudiesStudies

Prevention Studies: Ideal Prevention Studies: Ideal StructureStructure

• PCPTPCPT• SELECTSELECT

HypothesesHypotheses

Phase I/IIPhase I/II

Phase IIIPhase III

Clinical Practice?Clinical Practice?

Pre-Pre-clinical clinical StudiesStudies

Epi Epi StudiesStudies

Prevention Studies: RealityPrevention Studies: Reality

PCPT: Key CharacteristicsPCPT: Key Characteristics

• 18, 882 men randomized18, 882 men randomized• ≥ ≥ 55 years 55 years • PSA ≤ 3.0 ng/mLPSA ≤ 3.0 ng/mL• Normal DRENormal DRE

• Finasteride vs. placeboFinasteride vs. placebo• Uniform PSA criteria for biopsyUniform PSA criteria for biopsy• End-of-study biopsy for all cancer-free End-of-study biopsy for all cancer-free menmen

• Duration:Duration: • 7 year design.7 year design.• Ended 15 months earlyEnded 15 months early..

PCPT Key Findings:PCPT Key Findings:Overall PrevalenceOverall Prevalence

0

5

10

15

20

25

Prostate Cancer Prevalence

Placebo

Finasteride24.4%24.4% 18.4%18.4%

24.8% 24.8% reductionreduction

PCPT: Key FindingsPCPT: Key Findings

PCPT Key Findings:PCPT Key Findings:High Grade (Gleason ≥7) High Grade (Gleason ≥7)

PrevalencePrevalence

0

1

2

3

4

5

6

7

High Grade Prevalence

Placebo

Finasteride

5.1%5.1% 6.4%6.4%

25.0% 25.0% increaseincrease

PCPT: Initial Key PointsPCPT: Initial Key Points

• Prostate cancer is highly prevalent.Prostate cancer is highly prevalent.• Nearly 1 in 4 men in placebo groupNearly 1 in 4 men in placebo group

• Finasteride decreases the overall risk Finasteride decreases the overall risk of prostate cancer.of prostate cancer.

• Finasteride possibly increases the Finasteride possibly increases the risk of high-grade prostate cancer.risk of high-grade prostate cancer.• Finasteride artifact? Finasteride artifact? • Selective inhibition of low grade Selective inhibition of low grade tumors? tumors?

• Altered hormonal mileiu? Altered hormonal mileiu? • Statistical anomaly?Statistical anomaly?

PCPT: Updated AnalysesPCPT: Updated Analyses

• Two important points:Two important points:

1)1) Finasteride DOES NOT increase the risk Finasteride DOES NOT increase the risk of high-grade cancer.of high-grade cancer.

2)2) The sexual side effects of finasteride The sexual side effects of finasteride are minimal. are minimal.

Why the Initial High-Grade Why the Initial High-Grade Finding?Finding?

• Finasteride increases the Finasteride increases the sensitivity:sensitivity:• of PSA for detecting cancerof PSA for detecting cancer• of a DRE for detecting cancerof a DRE for detecting cancer• of prostate biopsy for detecting of prostate biopsy for detecting high-grade cancerhigh-grade cancer

• These factors led to significant These factors led to significant BIAS in the initial analysesBIAS in the initial analyses

Bias Adjusted Incidence in PCPTBias Adjusted Incidence in PCPT

Risk reductions for finasterideRisk reductions for finasterideProstate cancer: 30%Prostate cancer: 30%

High-grade: 27%High-grade: 27%

PCPT: Sexual Side EffectsPCPT: Sexual Side Effects

• Intensive analysis using:Intensive analysis using:• Sexual Activity Scale score (100-point scale)Sexual Activity Scale score (100-point scale)• SF-36SF-36• Multiple other quality of life measuresMultiple other quality of life measures

• No clinically significant difference between placebo and finasterideNo clinically significant difference between placebo and finasteride (2.11 points at end-of-study) (2.11 points at end-of-study)

JNCI 99: 1025, 2007JNCI 99: 1025, 2007

Finasteride Then…Finasteride Then…

““Should finasteride now be recommended to men Should finasteride now be recommended to men in order to lower their risk of prostate in order to lower their risk of prostate cancer? Several disturbing findings…argue cancer? Several disturbing findings…argue that it should not.”that it should not.”

--Dr. Peter Scardino--Dr. Peter ScardinoNEJM 349: 297-9, 2003NEJM 349: 297-9, 2003

……And NowAnd Now

““Dr. Peter Scardino… originally Dr. Peter Scardino… originally thought finasteride was dangerous thought finasteride was dangerous but now recommends its use.”but now recommends its use.” NY NY Times, June 15, 2008Times, June 15, 2008

Finasteride has to be recognized as Finasteride has to be recognized as the first clearly demonstrated way the first clearly demonstrated way to prevent prostate cancer…Why to prevent prostate cancer…Why wouldn’twouldn’t every man take it? every man take it? ““New Take on a Prostate Drug, New Take on a Prostate Drug,

and a New Debate”and a New Debate”NY Times June 15, 2008NY Times June 15, 2008

The REDUCE TrialThe REDUCE Trial

• Dutasteride vs. placeboDutasteride vs. placebo• 8,000 men8,000 men• 50-75 years50-75 years• PSA 2.5 to 10 ng/ml PSA 2.5 to 10 ng/ml • 4-year duration4-year duration• Biopsies: cause, 2 year, and 4 Biopsies: cause, 2 year, and 4 yearyear

The Selenium and Vitamin E Prostate The Selenium and Vitamin E Prostate Cancer Prevention Trial (SELECT)Cancer Prevention Trial (SELECT)

• Largest cancer prevention trial ever Largest cancer prevention trial ever undertakenundertaken

• > 34,000 men enrolled (1823 at UCSD)> 34,000 men enrolled (1823 at UCSD)• Scheduled end date: 2013Scheduled end date: 2013• Participants randomized to:Participants randomized to:

• Vitamin E Vitamin E • Selenium Selenium • Both Both • PlaceboPlacebo

• Primary end point: Primary end point: incident prostate incident prostate cancercancer

Vitamin EVitamin E

• Alpha-tocopherol is Alpha-tocopherol is biologically active formbiologically active form

• Anti-oxidantAnti-oxidant• Inhibits NF-Kappa BetaInhibits NF-Kappa Beta• Modulates cellular Modulates cellular proliferationproliferation

• Induce apoptosisInduce apoptosis• Recommended (SELECT) Recommended (SELECT) dosedose• 400 IU once daily daily

• Risk of side effectsRisk of side effects• Minimal at this dose Minimal at this dose or lessor less

SeleniumSelenium

• Essential trace Essential trace nutrient found in nutrient found in plantsplants

• Inhibits cancer cell Inhibits cancer cell growthgrowth

• Induces apoptosisInduces apoptosis• Alters androgen Alters androgen receptor signalingreceptor signaling

• Recommended doseRecommended dose• L-selenomethionine L-selenomethionine 200 µg once daily200 µg once daily

• Risk of side effectsRisk of side effects• MinimalMinimal

SeleniumSelenium

Selenium and Prostate Cancer

A Brief Word on Statins…

23% REDUCED RISK FOR HIGH-23% REDUCED RISK FOR HIGH-GRADE OR ADVANCED DISEASEGRADE OR ADVANCED DISEASE

Diet-Based InterventionsDiet-Based Interventions

• General concept:General concept:• Altering diet in prostate Altering diet in prostate cancer patients may possibly cancer patients may possibly slow prostate cancer slow prostate cancer initiation and/or progression.initiation and/or progression.

• Can involve:Can involve:• Change in diet Change in diet • SupplementsSupplements

THIS IS THIS IS NOT NOT ““COMPLEMENTARY” OR COMPLEMENTARY” OR

“ALTERNATIVE” MEDICINE!“ALTERNATIVE” MEDICINE!

Diet and Prostate CancerDiet and Prostate Cancer

• Tomatoes Tomatoes • Crucifers (Broccoli, brussel Crucifers (Broccoli, brussel sprouts, cauliflower)sprouts, cauliflower)

• SoySoy• Fat and meatFat and meat• Omega-3 fatty acids Omega-3 fatty acids • Vitamin DVitamin D• Calcium and dairyCalcium and dairy

THERE ARE NO PHASE III THERE ARE NO PHASE III CLINICAL TRIALSCLINICAL TRIALS

Diet and Prostate CancerDiet and Prostate Cancer

• Pre-clinical evidence:Pre-clinical evidence:1-31-3

• Components of crucifers Components of crucifers (isothiocyanates) and tomatoes (isothiocyanates) and tomatoes (carotenoids):(carotenoids):1)1) Induce apoptosis of prostate cancer Induce apoptosis of prostate cancer cells cells

2)2) Inhibit carcinogenesisInhibit carcinogenesis3)3) Promote expression of Promote expression of cytoprotective enzymescytoprotective enzymes

4)4) Protect against oxidative DNA Protect against oxidative DNA damagedamage 1.1. Cancer ResCancer Res, 67: 836, 2007., 67: 836, 2007.

2.2. Cancer Epidemiol Biomarkers Cancer Epidemiol Biomarkers PrevPrev,10:949, 2001.,10:949, 2001.

3.3. J Natl Cancer InstJ Natl Cancer Inst, 93:1872, , 93:1872, 2001.2001.

Plant-based DietsPlant-based Diets

TomatoesTomatoes• Putative active agent: lycopenePutative active agent: lycopene

• Free radical scavengerFree radical scavenger• Induces apoptosisInduces apoptosis

• Epidemiological studies inconsistentEpidemiological studies inconsistent• Emerging consensus:Emerging consensus:

• Tomatoes moderately beneficialTomatoes moderately beneficial• Lycopene is notLycopene is not• Processed tomatoes okay--possibly even Processed tomatoes okay--possibly even better than rawbetter than raw

Tomatoes and Prostate CancerTomatoes and Prostate CancerMeta-analysis of Published StudiesMeta-analysis of Published Studies

Plant-based DietsPlant-based Diets

Cruciferous vegetablesCruciferous vegetables• BBroccoli (baby broccoli sprouts), roccoli (baby broccoli sprouts), brussel sprouts, cauliflower, kalebrussel sprouts, cauliflower, kale

• Putative agents: isothiocyanatesPutative agents: isothiocyanates• Induce expression of cytoprotective Induce expression of cytoprotective enzymesenzymes

• Inhibit carcinogenesisInhibit carcinogenesis• Free radical scavengersFree radical scavengers

• Epidemiological studies (PLCO, Epidemiological studies (PLCO, HPFS) show protective effectHPFS) show protective effect

The Men’s Eating and Living The Men’s Eating and Living (MEAL) Study (MEAL) Study

Urology, 2008Urology, 2008

The MEAL StudyThe MEAL Study

• Telephone-based dietary Telephone-based dietary counseling program.counseling program.• Based on social cognitive theory.Based on social cognitive theory.11

• Adapted from studies of breast Adapted from studies of breast cancer patients.cancer patients.• Has produced robust diet changes Has produced robust diet changes in 1500 patients for over 4 in 1500 patients for over 4 years years 2,32,3

1. Miller WR and Rollnick S, 2002 1. Miller WR and Rollnick S, 2002 2. 2. Cancer Epidemiol Biomarkers PrevCancer Epidemiol Biomarkers Prev1515:: 1886, 2006 1886, 2006 3. JAMA, 20073. JAMA, 2007

The MEAL StudyThe MEAL Study

• Counseling interventionCounseling intervention• Centralized from UCSD.Centralized from UCSD.• Each participant assigned a counselor.Each participant assigned a counselor.

• Build self-efficacy.Build self-efficacy.• 13 counseling sessions. 13 counseling sessions.

• 25-50 minutes.25-50 minutes.• Diet goal: 7 servings/day of Diet goal: 7 servings/day of vegetables.vegetables.

357 Patients Assessed for

Eligibility

74 Randomized

48 Assigned to Intervention

26 Assigned to Control

45 Completed Study†

24 Completed Study‡

†2 lost to follow-up2 lost to follow-up 1 opted for treatment1 opted for treatment

‡2 lost to follow-up2 lost to follow-up

MEAL STUDYMEAL STUDY

MEAL STUDY MEAL STUDY

VEGETABLE INTAKEVEGETABLE INTAKE

0

50

100

150

200

250

300

Total vegetables Crucifers Tomatoes Othervegetables

Diet interventionControl

MEAL STUDY MEAL STUDY Non-VEGETABLE INTAKENon-VEGETABLE INTAKE

MEAL STUDY MEAL STUDY Plasma CarotenoidsPlasma Carotenoids

0

5

10

15

20

25

30

35

40

Lutein Lycopene TotalCarotenoids

Diet interventionControl

MEAL Study MEAL Study Active SurveillanceActive Surveillance

BJU Int, 2008BJU Int, 2008

NEXT STEP: NEXT STEP: TO DETERMINE IF TO DETERMINE IF THIS INTERVENTION WILL THIS INTERVENTION WILL

PREVENT DISEASE PREVENT DISEASE PROGRESSIONPROGRESSION

Soy ProductsSoy Products

• Rich in isoflavones (genistein and Rich in isoflavones (genistein and daidzein) and phytoestrogensdaidzein) and phytoestrogens• Anti-oxidantsAnti-oxidants• Inhibit tumor cell proliferationInhibit tumor cell proliferation• Possible effect on telomerasePossible effect on telomerase• Estrogenic effects/alterations in androgen Estrogenic effects/alterations in androgen receptorreceptor

• Decrease prostate cancer risk in large Decrease prostate cancer risk in large epidemiological studiesepidemiological studies

Soy: Meta-Analysis of Epidemiological Studies

30% Reduction in30% Reduction inProstate Cancer RiskProstate Cancer Risk

SoySoy

• Phase II studies show promise Phase II studies show promise for high soy diets for for high soy diets for biochemical recurrencebiochemical recurrence

• Studies are ongoingStudies are ongoing

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

FishFish(Omega-3 fatty acids)(Omega-3 fatty acids)

• Decrease prostate Decrease prostate cancer risk in large cancer risk in large epidemiological epidemiological studiesstudies

• Omega-3 Omega-3 polyunsaturated fatty polyunsaturated fatty acidsacids• Alter cyclooxygenase Alter cyclooxygenase (COX-2) pathways(COX-2) pathways

• Inhibit tumor growthInhibit tumor growth• Induce apoptosisInduce apoptosis

• Phase II biomarker Phase II biomarker studies currently studies currently underwayunderway

Meat and Animal Products Meat and Animal Products

• IncreaseIncrease prostate cancer prostate cancer risk in large risk in large epidemiological studiesepidemiological studies

• Red meatRed meat• Cooked meats contain PhIP, Cooked meats contain PhIP, a potent mutagena potent mutagen

• Risk may be higher for Risk may be higher for processed meatsprocessed meats

• Dietary fatDietary fat• Increases risk of Increases risk of aggressive cancer and aggressive cancer and recurrence after treatmentrecurrence after treatment

• Weight loss >11 lbs = 40% Weight loss >11 lbs = 40% risk reduction in high-risk reduction in high-grade cancergrade cancer

A Brief Word on Pomegranate Juice…A Brief Word on Pomegranate Juice…

• Single trial of 46 patientsSingle trial of 46 patients• Increased PSA doubling time in patients Increased PSA doubling time in patients with biochemical recurrencewith biochemical recurrence

• Limited laboratory studiesLimited laboratory studies• No No epidemiological studiesepidemiological studies• Pro-apoptotic, anti-proliferative, and Pro-apoptotic, anti-proliferative, and anti-oxidant?anti-oxidant?

SummarySummaryWhat to tell your patientsWhat to tell your patients

• Finasteride prevents prostate cancerFinasteride prevents prostate cancer• NO increased risk of high-grade NO increased risk of high-grade diseasedisease

• Minimal sexual side effectsMinimal sexual side effects• SELECT Trial may show benefits for SELECT Trial may show benefits for Vitamin E and/or selenium, but no Vitamin E and/or selenium, but no definitive evidence yetdefinitive evidence yet

• Statins may potentially prevent Statins may potentially prevent aggressive prostate canceraggressive prostate cancer

SummarySummaryWhat to tell your patientsWhat to tell your patients

• Studies are ongoing—nothing definitive yet.Studies are ongoing—nothing definitive yet.• There is little downside to There is little downside to moderatemoderate changes in nutritional intakechanges in nutritional intake

• Vegetable intense dietVegetable intense diet• TomatoesTomatoes• BroccoliBroccoli

• SoySoy• FishFish• Decrease meat, fat, and animal Decrease meat, fat, and animal product intakeproduct intake