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2	Clinical Trial vs. Cohort Study
3	b Carotene and Lung Cancer
4	b Carotene and Lung Cancer: What Did We Know Prior to RCTs? b carotene is found in high concentrations in carrots and dark green leafy vegetables. b carotene is postulated to have anticancer effects—among the most efficient quenchers of singlet oxygen molecules. Observational epidemiologic studies: Individuals who consume high amounts of foods rich in b carotene or whose blood levels are high experience approx. 20-40% lower risk of developing cancer, including lung cancer. Because confounding could be likely in observational studies, RCTs are needed to determine whether b carotene prevents cancer. Dosage for optimal benefit was speculative.
5	b Carotene and Lung Cancer: What Did We Know Prior to RCTs?
6	b-Carotene: An Unusual Type of Lipid Antioxidant At higher oxygen levels, b carotene loses its antioxidant activity and shows an autocatalytic, pro-oxidant effect, particularly at relatively high concentrations. Similar oxygen-pressure-dependent behavior may be shown by other compounds containing many conjugated double bonds.
7	Characteristics of RCTs of b Carotene
8	Secondary Analysis of b carotene Trials of Lung Cancer 􀁺CARET RR = 0.80 for former smokers RR = 1.42 for current smokers 􀁺ATBC RR = 0.97 for 5-19 cigarettes/day RR = 1.25 for 20-29 cigarettes/day RR = 1.28 for more >29 cigarettes/day 􀁺PHS RR = 0.78 for nonsmokers RR = 1.00 for former smokers RR = 0.90 for current smokers
9	b Carotene and Lung Cancer: What Do We Know Now? No overall benefit of b carotene for smokers. Wide array of molecular responses identified that may account for adverse events in smokers. b carotene is not a very potent antioxidant and has various other actions. No anti-cancer effects of b carotene for well-nourished populations. Plausible that any chemopreventive action of b carotene supplementation is confined to poorly nourished individuals (Linxian). Individuals who eat high quantities of fruits and vegetables have lower risk of death from various chronic diseases.
10	"“Nutritional epidemiology is qualitatively" “Nutritional epidemiology is qualitatively incapable of identifying a dietary compound(s) that will be efficacious” F. Meyskens
11	"“As if we were..." “As if we were searching for a new therapeutic compound, we have expected high doses of a single nutrient to reproduce the beneficial effects of the complex nutrient mixtures found in whole foods. Perhaps this basic assumption is wrong.” T. Byers, CA Cancer J Clin, 1999
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13	Studies of Adenoma Recurrence
14	RCTs of Adenoma Recurrence
15	Strengths and Limitations of Adenoma Recurrence Studies: Is it the Right Model? Prospective nature Investigation of etiology of adenoma formation Detection bias minimized Relatively short-follow-up period needed for end point analysis Selectivity of population and limited generalizability Assessment of premalignant lesion rather than invasive cancer Investigating risk factors related to early events in carcinogenesis pathway Short duration in follow-up from exposure to end point
16	NSAIDs and Colorectal Neoplasia
17	Cohort Studies of NSAIDs and Colorectal Cancer
18	Colorectal Cancer and Adenomas Have High Incidence of COX-2 85% of cases positive at both the RNA and protein levels 40-50% of colorectal adenomas showed significant elevation of COX-2
19	Effect of Celecoxib in Familial Adenomatous Polyposis: Percent Change in Number of Polyps After Six Months of Treatment
20	Celecoxib/Selenium Trial Schema (Pre-December 20, 2004)
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22	Celecoxib/Selenium Trial Schema (Post-December 20, 2004)
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24	Safety of Chemoprevention Trials What evidence on toxicity of the agent should preclude the launching of a RCT? Previous trials might not have considered this adequately Phase II trial data on toxicity needed How much toxicity are we willing to tolerate? None? Minimal?
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27	Moving Forward…. Systematic development of chemopreventive agents is a long process, multi-factorial process All available evidence must be considered and any missing pieces must be disclosed or filled in Development of studies that will identify safe and efficacious agents that can be integrated into routine preventive medical practice As a research community, we need guidelines to inform that process in the most useful way Models have been proposed (i.e., Meysken’s algorithm). Such models will need to be validated using existing RCTs Next generation of RCTs will need to incorporate lessons learned so far
28	Lessons Learned Must test effects of nutritional supplements given in broader combinations, and in more modest doses, thereby simulating the micronutrient combinations in the matrix of whole foods We should critically appraise observational methodology as well as limitations of RCT design Trials should be designed to be long-term, testing nutrients over many years among people at average risk Must acknowledge agent’s anti-carcinogenic potential as well as disruption of normal homeostasis
29	Future Directions Do we continue searching for the “magic bullet”? Should we consider a pill as an alternative to lifestyle practices (i.e., diet, exercise, tobacco)? Do we continue to believe that a RCT is necessary before fully accepting a factor as protective? Some lifestyle factors are not amenable to double-blind RCTs. All agents must be suspected of adverse effects; don’t just focus on their potential benefits.