Contents 1 Allocating Cancer-Directed Expenditures: Tensions Between Prevention, Early Detection and Treatment is Unnecessary.... 1 Bruce E. Hillner and Thomas J. Smith 1.1 Introduction.... 1 1.2 Our Life Expectancy and Cancer Success Stories... 2 1.3 No Cure in Sight: Costs of Drugs, Gadgets, Genomics and Technology... 2 1.4 Bending the Cancer Cost Curve... 5 1.5 Conclusion... 8 References.... 8 2 Lessons Learned from Prevention Programs: Different Endpoints Should Be Used in Secondary and Tertiary Prevention... 11 Franz Porzsolt 2.1 Introduction.... 11 2.2 Methods.... 12 2.3 Results.... 13 2.3.1 Traditional Outcomes of Treatment and of Prevention Programs.... 13 2.3.2 Proposal for the Evaluation of Prevention Programs... 15 2.4 Discussion... 16 2.4.1 The Risk of Interpretation in Prevention Programs... 16 2.4.2 The Resulting Need for Evaluation of Preventive Medicine... 17 2.4.3 Recommendations for Future Preventive Research... 18 References.... 18 v
vi Contents 3 Biomarkers for Early Detection and as Surrogate Endpoints in Cancer Prevention Trials: Issues and Opportunities... 21 Barbara K. Dunn, Karin Jegalian, and Peter Greenwald Abbreviations... 21 3.1 Biomarkers: What They Are and How They Are Applied... 23 3.1.1 Screening Biomarkers for Early Detection... 23 3.1.2 Biomarkers as Surrogate Endpoints in Cancer Prevention Trials.... 26 3.2 Breast Precancer and Cancer Prevention... 28 3.2.1 Ductal Carcinoma In situ... 30 3.2.2 Tissue Stroma and Mammographic Density.... 31 3.2.3 Biomarkers, ER-Positive Breast Cancer, and Breast Cancer Prevention Trials.... 31 3.2.4 Biomarkers and Estrogen Receptor-Negative Breast Cancers... 33 3.2.5 Access to Breast Tissue for Biomarker Evaluation.... 33 3.2.6 Biomarkers in Phase 2 Chemoprevention Trials.... 34 3.3 Prostate Cancer Prevention... 35 3.3.1 PSA Screening and Early Detection of Prostate Cancer.... 35 3.3.2 Phase 3 Prostate Cancer Prevention Trials... 35 3.3.3 Discovery of New Biomarkers for Early Detection of Prostate Cancer.... 36 3.4 Colorectal Cancer Prevention... 37 3.5 Lung Cancer Prevention................................... 38 3.5.1 Molecular Markers for Early Detection and Prognosis... 39 3.5.2 Treating Nicotine Addiction... 40 3.5.3 Fluorescence Bronchoscopy... 40 3.6 Conclusions.... 40 References.... 40 4 Targeting Polyamines and Inflammation for Cancer Prevention.... 49 Naveen Babbar and Eugene W. Gerner 4.1 Introduction.... 50 4.2 Polyamines, Inflammation, and Cancer... 50 4.2.1 Polyamine Metabolism... 50 4.2.2 Polyamines and Cancer.... 52 4.3 Roles of Inflammation and Polyamines in Prostate Cancer... 53 4.3.1 Polyamines and Prostate Cancer.... 53 4.3.2 Polyamines, Inflammation, and Prostate Cancer... 53 4.3.3 Targeting Polyamines and Inflammation in Prostate Cancer... 54 4.4 Roles of Inflammation and Polyamines in Colon Cancer.... 55 4.4.1 Polyamines and Colon Cancer... 55 4.4.2 Polyamines, Inflammation, and Colon Cancer.................. 56 4.4.3 Targeting Polyamines and Inflammation in Colon Cancer... 56
Contents vii 4.5 Roles of Inflammation and Polyamines in Other Cancers... 59 4.6 Conclusions.... 60 References.... 60 5 Thinking About the Role (Largely Ignored) of Heavy Metals in Cancer Prevention: Hexavalent Chromium and Melanoma as a Case in Point.... 65 Frank L. Meyskens and Sun Yang 5.1 Background... 65 5.1.1 The Evolution of the Idea.................................. 65 5.1.2 Substances That Bind Melanin... 66 5.2 Major Risk Factors for Cutaneous Melanoma... 67 5.2.1 Epidemiology... 67 5.3 Metals... 69 5.3.1 Chemistry and Genetic Damage... 69 5.3.2 Chromium Chemistry... 69 5.3.3 Upregulation of Metallothioneins (MTs)... 70 5.3.4 Some Preliminary Experimental Data.... 70 5.4 Future Prospects... 72 References.... 72 6 Hepatitis B Virus and Cancer Prevention.... 75 Mei-Hwei Chang 6.1 Infection and Cancer... 75 6.2 Disease Burden of Liver Cancer... 77 6.3 Hepatitis B Virus Infection and Hepatocellular Carcinoma... 77 6.4 Cancer Prevention Against Hepatocellular Carcinoma... 78 6.5 Hepatitis B Vaccination Program... 79 6.6 Effective Reduction of Chronic HBV Infection by Universal Hepatitis B Immunization....................... 79 6.7 The Effect on Liver Cancer Prevention by Vaccination... 80 6.8 Problems and Strategies of Successful HCC Prevention by Hepatitis B Vaccination... 81 6.9 Implications and Future Prospects... 81 References.... 82 7 Chemoprevention of Hepatocellular Carcinoma in Chronic Hepatitis C... 85 Timothy R. Morgan 7.1 Hepatitis C.... 85 7.2 Hepatocellular Carcinoma.... 86 7.3 Prevention of Hepatocellular Carcinoma... 87 7.3.1 Curative Treatment... 87
viii Contents 7.3.2 Treatments That Suppress Hepatitis C Virus... 88 7.3.3 Noncurative Chemoprevention... 88 7.3.4 Prospective Randomized Trials: Carotenoids and Phytochemicals... 88 7.3.5 Secondary Chemoprevention of HCC.... 89 7.3.6 Nonrandomized, Uncontrolled and/or Retrospective Clinical Trials.... 90 7.3.7 Epidemiologic Studies... 91 7.3.8 Drugs Used to Treat Hepatocellular Carcinoma... 92 7.3.9 Prevention of Hepatocellular Carcinoma in Cell Lines and Animal Models.... 92 7.3.10 Phase II Trial of S-Adenosylmethionine in Hepatitis C Cirrhosis.... 94 7.4 Conclusions.... 97 References.... 97 8 Nutritional Aspects of Primary Prostate Cancer Prevention... 101 Hans-Peter Schmid, Claus Fischer, Daniel S. Engeler, Marcelo L. Bendhack, and Bernd J. Schmitz-Dräger 8.1 Introduction.... 101 8.2 Dietary/Nutritional Factors... 102 8.2.1 Dietary Fat.... 102 8.2.2 Obesity... 102 8.2.3 Micronutrients.... 102 8.2.4 Vitamins... 103 8.2.5 Minerals... 103 8.2.6 Phytoestrogens... 104 8.2.7 Diabetes Mellitus... 104 8.3 American Cancer Society (ACS) Guideline... 105 8.3.1 A: Try to Maintain a Healthy Weight......................... 105 8.3.2 B: Take Regular Physical Exercise... 105 8.3.3 C: Maintain a Healthy Diet with a Focus on Fruit and Vegetables.... 105 8.3.4 D: Reduce Alcohol Intake.... 105 8.4 Conclusions.... 106 References.... 106 9 Prostate Cancer Prevention with 5 Alpha-Reductase Inhibitors... 109 Dipen J. Parekh 9.1 Rationale for the Chemoprevention of Prostate Cancer........... 109 9.2 The Prostate Cancer Prevention Trial... 110 9.3 Pathologic Characteristics of the Cancers in the Prostate Cancer Prevention Trial.... 110
Contents ix 9.4 Finasteride Increases Sensitivity of Prostate-Specific Antigen, Digital Rectal Examination and Biopsy Detection for Prostate Cancer.... 111 9.4.1 Decreased Prostate Volume with Finasteride Increases Cancer Detection.... 112 9.5 Side Effects of Finasteride... 113 9.6 Conclusion... 113 References.... 113 10 Hormone Replacement Therapy and Breast Cancer.... 115 Anthony Howell and Gareth D. Evans 10.1 Background... 115 10.2 HRT Use in Women Diagnosed with Breast Cancer... 116 10.2.1 Observational Studies... 116 10.2.2 Randomised Trials... 117 10.2.3 Effects of Withdrawal of HRT in Women with Breast Cancer... 117 10.3 HRT and Risk of Breast Cancer... 118 10.3.1 Observational Studies... 118 10.3.2 Randomised Studies... 118 10.3.3 Withdrawal of HRT in Women Without Breast Cancer... 119 10.3.4 Summary... 119 10.4 HRT After Oophorectomy in Women Less Than 50 Years of Age... 119 10.4.1 Observational Studies... 120 10.5 Coronary Heart Disease... 120 10.6 Potential Biological Explanations.... 121 10.7 Conclusions.... 122 References.... 122 11 Physical Activity and Breast Cancer: Review of the Epidemiologic Evidence and Biologic Mechanisms.... 125 Christine M. Friedenreich 11.1 Epidemiologic Evidence... 126 11.1.1 Background... 126 11.1.2 Methodologic Issues in Studies of Physical Activity and Cancer... 126 11.1.3 Overall Associations Between Physical Activity and Breast Cancer Risk.... 126 11.1.4 Type, Dose, and Timing of Activity... 126 11.1.5 Population Subgroups... 128 11.1.6 Summary of Epidemiologic Findings... 131 11.2 Biologic Mechanisms... 132 11.2.1 Adiposity.... 132 11.2.2 Sex Hormones.... 132
x Contents 11.2.3 Insulin-Related Factors... 134 11.2.4 Adipokines and Inflammation.... 134 11.2.5 Other Mechanisms... 135 11.3 Conclusion... 135 References.... 136 12 Prevention of Breast Cancer by Newer SERMs in the Future... 141 Trevor Powles 12.1 Introduction.... 141 12.2 Arzoxifene.... 142 12.3 Lasofoxifene............................................ 142 12.4 Discussion... 143 12.5 Conclusions.... 144 References.... 144 13 Chemoprevention of Hormone Receptor-Negative Breast Cancer: New Approaches Needed... 147 Iván P. Uray and Powel H. Brown 13.1 Introduction.... 148 13.2 Endocrine Preventive Agents... 148 13.3 Selective Estrogen Receptor Modulators... 148 13.4 Aromatase Inhibitors.... 151 13.5 New Strategies to Prevent Hormone-Independent Breast Cancer... 152 13.5.1 PARP Inhibitors... 152 13.6 Cell Growth Inhibitors... 153 13.6.1 Statins... 153 13.6.2 Metformin... 153 13.6.3 Retinoids... 154 13.6.4 PPAR Agonists... 156 13.6.5 COX-2 Inhibitors... 156 13.6.6 Tyrosine Kinase Inhibitors... 157 13.6.7 The IGF System... 158 13.6.8 Conclusions and Future Directions.... 158 References.... 159
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