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Cancer Prevention Clinical Trials in America

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

•    cost/tax
•   Smoke-free environment
•   Youth
•   Cessation in adults
•   Anti-nicotine vaccine
Lung Cancer Prevention
Phase IIb Trial of Anethole Dithiolethione
on Bronchial Dysplasia (# sites/grade)
             Current/Former Smokers with
                 Bronchial Dysplasia
                        N=112


Anethole Dithiolethione              Placebo
      25 mg TID

             Repeat Bronchoscopy at 6 months

Results:  New lesions
         No regression of old lesions
                                               Lam et al., 2002
BREAST CANCER PREVENTION
 Breast Cancer Prevention
 Outline

• Lifestyle Risk Factors

• Prevention Trials

• Biomarker End-point/ER Negative Priority
 Breast Cancer Prevention
 Risk Factors for Breast Cancer

• Weight Gain as an adult/obesity
• Estrogen & Progestin use
• Alcohol use




                                    Lubet,2000
 Breast Cancer Prevention
 Outline

• Lifestyle Risk Factors

• Prevention Trials

• Biomarker End-point/ER Negative Priority
Breast Cancer Prevention
Breast Cancer Prevention Trial (BCPT)
Recruitment


                       13,388



          Tamoxifen             Placebo
Breast Cancer Prevention
Breast Cancer Prevention Trial (BCPT)
Events Among Participants
Breast Cancer Prevention
Multiple Outcomes of Raloxifene
Evaluation (MORE) Trial
Recruitment

                     Postmenopausal Women
                       With Osteoporosis
                           (n=7,705)




                           Raloxifene        Raloxifene
          Placebo
                            60 mg/d          120 mg/d
         (n=2,576)
                           (n=2,557)         (n=2,572)


                       3-Year Intervention

          Primary Endpoint: Fractures
          Secondary Endpoint: Breast Cancer


                                                     Cummings et al., 1999
Breast Cancer Prevention
MORE Trial
Results: Invasive Breast Cancer

                                                        Relative Risk
                              Placebo   Raloxifene   (Confidence Interval)


 Breast Cancer                  27         13         0.24 (0.13-0.44)

 Rate per 1,000 Women-Years     3.6        0.9




                                                             Cummings et al., 1999
Breast Cancer Prevention
Study of Tamoxifen and Raloxifene
(STAR) Trial
Recruitment

                            Risk-Eligible
                       Postmenopausal Women
                             (n=19,000)




          Tamoxifen                           Raloxifene
           20 mg/d                             60 mg/d
           X 5 years                          X 5 years




                                                           NSABP, 1999
              Breast Cancer Prevention
              Third Generation Aromatase Inhibitors/Inactivators
                                                         N       N
                      N       N
Nonsteroidal                                                 N
                          N
Inhibitors
                                               CH3                   CH3
              NC                        CN      NC CH
                                                     3       CH3 CN
                     Letrozole                     Anastrozole

                                                Androgen substrate
                                    O                                      O
Steroidal
Inactivator


                O                              O
                          CH2
                                  Exemestane       Androstenedione
                Breast Cancer Prevention
                ATAC (‘ARIMIDEX’, TAMOXIFEN, ALONE OR IN COMBINATION) Trial

                    Postmenopausal women with invasive breast cancer Stage I & II


                                 Surgery  radiotherapy  chemotherapy




                 Anastrozole 1 mg/d       Anastrozole Placebo       Anastrozole 1 mg/d
                         +                        +                          +
                 Tamoxifen Placebo         Tamoxifen 20 mg/d        Tamoxifen 20 mg/d
                       3125                     3116                     3125
Results:
Contralateral
Breast Cancer
                        14*                     33                         28



                             * 58%  compared to tamoxifen, p=0.007
                                                                         ATAC trialists, 2002
 Breast Cancer Prevention
 Outline

• Lifestyle Risk Factors

• Prevention Trials

• Biomarker End-point/ER Negative Priority
            Breast Cancer Prevention
       Breast Biomarker Modulation Trial

                      High Risk Women
                           N = 100
                                     BRCA 1, 2 Testing
                                     Pre-treatment Biopsy



    Bexarotene (Targretin)                           Placebo
      200 mg/d x 4 wks

Post-treatment Biopsy
End-points: Biomarker modulation, proliferation, apoptosis,
            retinoid regulated genes; BRCA mutation status


                                      Brown, Elledge et al,
                                      Texas Cancer Genetics Consortium, 2002
    Breast Cancer Prevention
    Agents 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
Prostate Cancer
  Prevention
Prostate Cancer Prevention
Finasteride
Mechanism of Action
Prostate Cancer Prevention
PCPT Schema
                     Men 55+ yr
                    PSA ≤ 3 ng/ml
                      N=18,882


                  Randomization


      Placebo       Follow-up       Finasteride
                  every 3 months
                    for 7 years

   End of Study                     End of Study
     Biopsy                           Biopsy
                           Prostate Cancer Prevention
                           Prostate Cancers Detected
                                    1147
                    1200                                        Finasteride N = 4368
                    1100
                                                                Placebo N = 4692
Number of Cancers




                    1000
                     900      803
                     800
                     700
                                                      571                576
                     600
                     500                        435
                     400
                                                                   368
                     300
                     200
                     100
                       0
                            Total Cancers   For Cause Cancers    End-of-Study
                                                                   Cancers
                             Prostate Cancer Prevention
                             Gleason Score
                             Total Number of Cancers
                      1200            1147
                                                                        Finasteride N = 4368
                      1100
                      1000                                              Placebo N = 4692
  Number of Cancers




                       900      803                               776
                       800
                       700
                       600
                       500                                  457
                       400
                                                                              280
                       300                                                          237
                       200
                       100                   20   55
                         0
                             Total Cancers    2-4            5-6               7 - 10
                                                  Gleason Score

Not graded: Finasteride n=46, Placebo n=79
Simulated needle biopsies in 3-dimensional
reconstruction of radical prostatectomy specimen
              PSA

Placebo       PSA




               PSA


Finasteride   PSA
Prostate Cancer Prevention
U.S. –Finland Lung Cancer
Intervention Trial
ATBC Study
Cumulative Lung Cancer Incidence
ATBC Study
Cancers According to Vitamin E
Treatment Status
Skin Cancer Prevention Trial
Design
Selenium (200 g) in Brewers Yeast vs. Placebo
Skin Cancer Prevention Trial
End Points
Selenium (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 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
  Prostate Cancer Prevention
  Plasma Selenium and Later Prostate Cancer
  Baltimore 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 E
Cancer Prevention Trial (SELECT)
Prostate Cancer Prevention
Selenomethionine and Prostate Cancer
Recruitment 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
Pre-Prostatectomy Model


 Selenium/VitaminE
 Sulindac sulfone
 Celecoxib
 Genistein/Soy isoflavones
 Toremifene
 Hectorol
 Lycopene
 Bicalutamide + DFMO

				
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