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Cancer Prevention Clinical Trials in America Peter Greenwald, M.D., Dr. P.H. Division of Cancer Prevention National Cancer Institute PowerPoint PPT Presentation


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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

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Cancer Prevention Clinical Trials in America Peter Greenwald, M.D., Dr. P.H. Division of Cancer Prevention National Cancer Institute

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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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Lung Cancer PreventionPhase IIb Trial of Anethole Dithiolethioneon Bronchial Dysplasia (# sites/grade)

Current/Former Smokers with Bronchial Dysplasia

N=112

Anethole Dithiolethione

25 mg TID

Placebo

Repeat Bronchoscopy at 6 months

Results:  New lesions

No regression of old lesions

Lam et al., 2002


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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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Breast Cancer PreventionRisk Factors for Breast Cancer

  • Weight Gain as an adult/obesity

  • Estrogen & Progestin use

  • Alcohol use

Lubet,2000


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Breast Cancer PreventionOutline

  • Lifestyle Risk Factors

  • Prevention Trials

  • Biomarker End-point/ER Negative Priority


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Breast Cancer PreventionBreast Cancer Prevention Trial (BCPT)Recruitment

13,388

Tamoxifen

Placebo


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Breast Cancer PreventionBreast Cancer Prevention Trial (BCPT)Events Among Participants


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Breast Cancer PreventionMultiple Outcomes of Raloxifene

Evaluation (MORE) TrialRecruitment

Postmenopausal Women

With Osteoporosis

(n=7,705)

Raloxifene

120 mg/d

(n=2,572)

Raloxifene

60 mg/d

(n=2,557)

Placebo

(n=2,576)

3-Year Intervention

Primary Endpoint: Fractures

Secondary Endpoint: Breast Cancer

Cummings et al., 1999


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Breast Cancer PreventionMORE TrialResults: Invasive Breast Cancer

Relative Risk

(Confidence Interval)

Placebo

Raloxifene

27

3.6

13

0.9

0.24 (0.13-0.44)

Breast Cancer

Rate per 1,000 Women-Years

Cummings et al., 1999


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Breast Cancer PreventionStudy of Tamoxifen and Raloxifene

(STAR) TrialRecruitment

Risk-Eligible

Postmenopausal Women

(n=19,000)

Tamoxifen

20 mg/d

X 5 years

Raloxifene

60 mg/d

X 5 years

NSABP, 1999


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N

N

N

CH3

CH3

NC

CN

CH3

CH3

O

O

O

O

CH2

Breast Cancer PreventionThird Generation Aromatase Inhibitors/Inactivators

N

N

Nonsteroidal Inhibitors

N

NC

CN

Letrozole

Anastrozole

Androgen substrate

Steroidal Inactivator

Exemestane

Androstenedione


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Breast Cancer PreventionATAC (‘ARIMIDEX’, TAMOXIFEN, ALONE OR IN COMBINATION) Trial

Results: Contralateral

Breast Cancer

14*

33

28

Postmenopausal women with invasive breast cancer Stage I & II

Surgery  radiotherapy  chemotherapy

Anastrozole 1 mg/d+Tamoxifen Placebo

3125

Anastrozole Placebo+Tamoxifen 20 mg/d

3116

Anastrozole 1 mg/d+Tamoxifen 20 mg/d

3125

* 58%  compared to tamoxifen, p=0.007

ATAC trialists, 2002


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Breast Cancer PreventionOutline

  • Lifestyle Risk Factors

  • Prevention Trials

  • Biomarker End-point/ER Negative Priority


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Breast Cancer PreventionBreast Biomarker Modulation Trial

High Risk Women

N = 100

BRCA 1, 2 Testing

Pre-treatment Biopsy

Bexarotene (Targretin)

200 mg/d x 4 wks

Placebo

Post-treatment Biopsy

End-points: Biomarker modulation, proliferation, apoptosis,

retinoid regulated genes; BRCA mutation status

Brown, Elledge et al,

Texas Cancer Genetics Consortium, 2002


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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

Lubet,2000


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ProstateCancer Prevention


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Prostate Cancer PreventionFinasterideMechanism of Action


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Prostate Cancer PreventionPCPT Schema

Men 55+ yr

PSA ≤ 3 ng/ml

N=18,882

Randomization

Follow-up every 3 months

for 7 years

Finasteride

Placebo

End of Study Biopsy

End of Study Biopsy


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N = 4368

N = 4692

Not graded: Finasteride n=46, Placebo n=79

Prostate Cancer PreventionProstate Cancers Detected


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N = 4368

N = 4692

Prostate Cancer PreventionGleason ScoreTotal Number of Cancers

1147

1200

Finasteride

1100

Placebo

1000

900

803

776

800

700

600

Number of Cancers

457

500

400

280

237

300

200

55

100

20

0

Total Cancers

2 - 4

5 - 6

7 - 10

Gleason

Score

Not graded: Finasteride n=46, Placebo n=79


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Simulated needle biopsies in 3-dimensional reconstruction of radical prostatectomy specimen


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PSA

PSA

Placebo

PSA

Finasteride

PSA


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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 RiskHealth Professional Follow-up Study

181 Prostate Cancers Among 33,737 Cohort Members

Quintile of Selenium Level1 2 3 4 5

Median Selenium

Levels, ppm 0.66 0.76 0.82 0.88 1.14

Multivariant Odds Ratio

for 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 PreventionPlasma 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

68 Presurgical

prostate cancer patients

SeMet 200 g/d

2-3 weeks

Observation

  • Results:

    •  Prostate tissue Selenium levels

    • Pre & Post-study PSA unchanged

Sabichi et al, SWOG, 2002


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Pre-Prostatectomy Model

  • Selenium/VitaminE

  • Sulindac sulfone

  • Celecoxib

  • Genistein/Soy isoflavones

  • Toremifene

  • Hectorol

  • Lycopene

  • Bicalutamide + DFMO


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