cancer prevention clinical trials in america peter greenwald, m.d., dr. p.h
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Cancer Prevention Clinical Trials in America Peter Greenwald, M.D., Dr. P.H. Division of Cancer Prevention National Cancer Institute NIH, DHHS. Lung Cancer Prevention Public Health Approaches. cost/tax Smoke-free environment Youth Cessation in adults - PowerPoint PPT PresentationTRANSCRIPT
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Cancer Prevention Clinical Trials in
America
Peter Greenwald, M.D., Dr. P.H.Division of Cancer Prevention
National Cancer Institute
NIH, DHHS
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Lung Cancer PreventionPublic Health Approaches
cost/tax• Smoke-free environment• Youth• Cessation in adults• Anti-nicotine vaccine
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Current/Former Smokers with Bronchial Dysplasia
N=112
Anethole Dithiolethione25 mg TID
Results: New lesions No regression of old lesions
Lung Cancer PreventionPhase IIb Trial of Anethole Dithiolethioneon Bronchial Dysplasia (# sites/grade)
Lam et al., 2002
Placebo
Repeat Bronchoscopy at 6 months
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BREAST CANCER PREVENTION
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Breast Cancer PreventionOutline
• Lifestyle Risk Factors
• Prevention Trials
• Biomarker End-point/ER Negative Priority
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Lubet,2000
Breast Cancer PreventionRisk Factors for Breast Cancer
• Weight Gain as an adult/obesity• Estrogen & Progestin use • Alcohol use
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Breast Cancer PreventionOutline
• Lifestyle Risk Factors
• Prevention Trials
• Biomarker End-point/ER Negative Priority
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13,388
Tamoxifen Placebo
Breast Cancer Prevention Breast Cancer Prevention Trial (BCPT)Recruitment
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Breast Cancer Prevention Breast Cancer Prevention Trial (BCPT)Events Among Participants
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Postmenopausal WomenWith Osteoporosis
(n=7,705)
Placebo(n=2,576)
Raloxifene60 mg/d
(n=2,557)
Raloxifene120 mg/d(n=2,572)
3-Year Intervention
Primary Endpoint: FracturesSecondary Endpoint: Breast Cancer
Cummings et al., 1999
Breast Cancer Prevention Multiple Outcomes of Raloxifene Evaluation (MORE) TrialRecruitment
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Placebo RaloxifeneRelative Risk
(Confidence Interval)
Breast CancerRate per 1,000 Women-Years
27
3.6
13
0.9
0.24 (0.13-0.44)
Cummings et al., 1999
Breast Cancer Prevention MORE TrialResults: Invasive Breast Cancer
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Risk-EligiblePostmenopausal Women
(n=19,000)
Tamoxifen20 mg/d
X 5 years
Raloxifene60 mg/d
X 5 years
NSABP, 1999
Breast Cancer Prevention Study of Tamoxifen and Raloxifene (STAR) TrialRecruitment
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Breast Cancer Prevention Third Generation Aromatase Inhibitors/Inactivators
AnastrozoleLetrozole
NC CN
AndrostenedioneO
O
Exemestane
Nonsteroidal Inhibitors
OCH2
O
CNNCCH3 CH3
CH3 CH3
N
N N
Steroidal Inactivator
Androgen substrate
N N
N
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1414** 3333 2828Results:Results: Contralateral Contralateral Breast CancerBreast Cancer
Postmenopausal women with invasive breast cancer Stage I & IIPostmenopausal women with invasive breast cancer Stage I & II
Surgery Surgery radiotherapy radiotherapy chemotherapy chemotherapy
AnastrozoleAnastrozole 1 mg/d 1 mg/d++
TamoxifenTamoxifen Placebo Placebo31253125
AnastrozoleAnastrozole Placebo Placebo++
TamoxifenTamoxifen 20 mg/d 20 mg/d31163116
AnastrozoleAnastrozole 1 mg/d 1 mg/d++
TamoxifenTamoxifen 20 mg/d 20 mg/d31253125
Breast Cancer Prevention ATAC (‘ARIMIDEX’, TAMOXIFEN, ALONE OR IN COMBINATION) Trial
* 58% * 58% compared to tamoxifen, p=0.007 compared to tamoxifen, p=0.007ATAC trialists, 2002ATAC trialists, 2002
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Breast Cancer PreventionOutline
• Lifestyle Risk Factors
• Prevention Trials
• Biomarker End-point/ER Negative Priority
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Brown, Elledge et al, Texas Cancer Genetics Consortium, 2002
Breast Cancer PreventionBreast Biomarker Modulation Trial
Bexarotene (Targretin) 200 mg/d x 4 wks
Placebo
High Risk Women N = 100
BRCA 1, 2 TestingPre-treatment Biopsy
Post-treatment BiopsyEnd-points: Biomarker modulation, proliferation, apoptosis, retinoid regulated genes; BRCA mutation status
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Lubet,2000
Breast Cancer PreventionAgents With Promise Against ER Negative Tumors
• Tyrosine Kinase Inhibitors– Specific (EGFR family)– Non-specific (Genistein)
• Bexarotene & retinoid-like compounds• COX-2 Inhibitors• Farnesyl transferase inhibitors • Statins• Doublets
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Prostate Cancer Prevention
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Prostate Cancer PreventionFinasterideMechanism of Action
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Follow-up every 3 months
for 7 years
End of Study Biopsy
End of Study Biopsy
Men 55+ yr
PSA ≤ 3 ng/ml
N=18,882
Placebo Finasteride
Randomization
Prostate Cancer PreventionPCPT Schema
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803
435368
1147
571 576
0100200300400500600700800900
100011001200
Total Cancers For Cause Cancers End-of-StudyCancers
Num
ber
of C
ance
rs
FinasteridePlacebo
Not graded: Finasteride n=46, Placebo n=79
N = 4368N = 4692
Prostate Cancer PreventionProstate Cancers Detected
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Not graded: Finasteride n=46, Placebo n=79
N = 4368N = 4692
803
20
457
280
1147
55
776
237
0100200300400500600700800900
100011001200
Total Cancers 2 - 4 5 - 6 7 - 10Gleason Score
Num
ber o
f Can
cers
FinasteridePlacebo
Prostate Cancer PreventionGleason ScoreTotal Number of Cancers
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Simulated needle biopsies in 3-dimensional reconstruction of radical prostatectomy specimen
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PSA
PSA
PSA
PSA
Placebo
Finasteride
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Prostate Cancer PreventionU.S. –Finland Lung CancerIntervention Trial
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ATBC StudyCumulative Lung Cancer Incidence
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ATBC StudyCancers According to Vitamin ETreatment Status
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Skin Cancer Prevention TrialDesignSelenium (200 g) in Brewers Yeast vs. Placebo
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Skin Cancer Prevention TrialEnd PointsSelenium (200 g) in Brewers Yeast vs. Placebo
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Prostate Cancer Prevention Selenium Level in Toenails and Risk Health Professional Follow-up Study
181 Prostate Cancers Among 33,737 Cohort Members
Quintile of Selenium Level 1 2 3 4 5 Median SeleniumLevels, ppm 0.66 0.76 0.82 0.88 1.14
Multivariant Odds Ratiofor Prostate cancer 1.00 0.59 0.35 0.76 0.35
p trend = 0.03
Yoshizawa et al., 1998
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Prostate Cancer Prevention Plasma Selenium and Later Prostate CancerBaltimore Longitudinal Study of Aging
Quartile of Selenium Level 1 2 3 4
Se (µg/dl) (8.2-10.7) (10.8-11.8) (11.9-13.2) (13.3-18.2)
Cases (%) 20 (39) 9 (17) 10 (19) 13 (25) Controls (%) 18 (19) 28 (29) 26 (27) 24 (25)Odds Ratio 1.00 0.15 0.21 0.24
Brooks et al., 2001
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Prostate Cancer PreventionSelenium and Vitamin ECancer Prevention Trial (SELECT)
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Prostate Cancer PreventionSelenomethionine and Prostate CancerRecruitment of Presurgical Patients
SeMet 200 g/d
68 Presurgicalprostate cancer patients
Results: Prostate tissue Selenium levels• Pre & Post-study PSA unchanged
Observation
Sabichi et al, SWOG, 2002
2-3 weeks
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Pre-Prostatectomy Model
Selenium/VitaminESulindac sulfoneCelecoxib Genistein/Soy isoflavones Toremifene HectorolLycopeneBicalutamide + DFMO