cancer prevention clinical trials in america peter greenwald, m.d., dr. p.h. division of cancer...
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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• Anti-nicotine vaccine
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
BREAST CANCER PREVENTION
Breast Cancer Prevention
Outline
• Lifestyle Risk Factors
• Prevention Trials
• Biomarker End-point/ER Negative Priority
Lubet,2000
Breast Cancer PreventionRisk Factors for Breast Cancer
• Weight Gain as an adult/obesity• Estrogen & Progestin use • Alcohol use
Breast Cancer Prevention
Outline
• Lifestyle Risk Factors
• Prevention Trials
• Biomarker End-point/ER Negative Priority
13,388
Tamoxifen Placebo
Breast Cancer Prevention Breast Cancer Prevention Trial (BCPT)Recruitment
Breast Cancer Prevention Breast Cancer Prevention Trial (BCPT)Events Among Participants
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
Placebo RaloxifeneRelative Risk
(Confidence Interval)
Breast Cancer
Rate 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
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
Breast Cancer Prevention Third Generation Aromatase Inhibitors/Inactivators
AnastrozoleLetrozole
NC CN
AndrostenedioneO
O
Exemestane
Nonsteroidal Inhibitors
O
CH2
O
CNNCCH3 CH3
CH3 CH3
N
N N
Steroidal Inactivator
Androgen substrate
N N
N
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 & IIPostmenopausal women with invasive breast cancer Stage I & IIPostmenopausal women with invasive breast cancer Stage I & II
Surgery Surgery radiotherapy radiotherapy chemotherapy chemotherapySurgery 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
Breast Cancer Prevention
Outline
• Lifestyle Risk Factors
• Prevention Trials
• Biomarker End-point/ER Negative Priority
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
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
Prostate Cancer Prevention
Prostate Cancer Prevention
FinasterideMechanism of Action
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 Prevention
PCPT Schema
803
435368
1147
571 576
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
Total Cancers For Cause Cancers End-of-StudyCancers
Nu
mb
er
of
Ca
nc
ers
FinasteridePlacebo
Not graded: Finasteride n=46, Placebo n=79
N = 4368
N = 4692
Prostate Cancer Prevention
Prostate Cancers Detected
Not graded: Finasteride n=46, Placebo n=79
N = 4368
N = 4692
803
20
457
280
1147
55
776
237
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
Total Cancers 2 - 4 5 - 6 7 - 10
Gleason Score
Nu
mb
er o
f C
ance
rs
Finasteride
Placebo
Prostate Cancer Prevention
Gleason ScoreTotal Number of Cancers
Simulated needle biopsies in 3-dimensional reconstruction of radical prostatectomy specimen
PSA
PSA
PSA
PSA
Placebo
Finasteride
Prostate Cancer Prevention
U.S. –Finland Lung CancerIntervention Trial
ATBC StudyCumulative Lung Cancer Incidence
ATBC Study
Cancers According to Vitamin ETreatment Status
Skin Cancer Prevention Trial
DesignSelenium (200 g) in Brewers Yeast vs. Placebo
Skin Cancer Prevention Trial
End PointsSelenium (200 g) in Brewers Yeast vs. Placebo
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
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
Prostate Cancer Prevention
Selenium and Vitamin ECancer Prevention Trial (SELECT)
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
Pre-Prostatectomy Model
Selenium/VitaminESulindac sulfoneCelecoxib Genistein/Soy isoflavones Toremifene HectorolLycopeneBicalutamide + DFMO