What Are the Future Needs Within the Epidemiological Domain That Relate to Lycopene? Dr. Alan Kristal, Fred Hutchinson Cancer Research Center Dr. Kristal provided a review of the published observational research; described the limitations and future research directions of lycopene exposure measurements, prostate cancer epidemiology, and genetic variability; and critiqued past and ongoing human trials studies with intermediate biomarker endpoints. He concluded that the results from the strongest epidemiologic studies (i.e., prospective studies with cooked tomatoes, dietary lycopene, or serum lycopene) appear mixed. Many of the studies are too small to detect modest effects, and the associations may be restricted to population subgroups. The most relevant lycopene exposure measurement is probably prostate tissue lycopene concentration, but only serum and diet can be measured in epidemiologic studies. Consumption of lycopene and high-lycopene foods appears to correlate poorly with serum lycopene. Single-dose lycopene feeding studies do not reflect long-term intake, and inferences from single-dose studies may not be accurate as to the lycopene that is or is not bioavailable. Thus, the best measure of prostate tissue lycopene exposure is likely to be multiple serum lycopene measures collected over time. The more that is learned about prostate cancer, the more difficult it maybe to study the disease. Prostate-specific antigen (PSA) is not a sensitive screening test for prostate cancer; some men with prostate cancer have “normal” PSA. In addition, PSA screening guidelines may mask the association between lycopene and cancer risk. Contemporary epidemiologic studies of prostate cancer require detailed information on screening history, stage, and grade. The Surveillance, Epidemiology, and End Results (SEER) cancer registries may obscure grade classifications by grouping Gleason scores as 2–4, 5–7, and 8–10. A Gleason score of 7 is common and clinically high grade. Key questions that need to be answered include: Do the effects of lycopene vary with genetic characteristics? For example, lycopene may have a substantial chemopreventative effect only among men with a high susceptibility to oxidative DNA damage. Research in this area is currently speculative and it would require large sample sizes to investigate the question fully. Another question to consider: Has the misinterpretation of widely quoted pilot studies for clinical trials mislead both scientists and the public? Clinical trials studies should meet the same critical standards as epidemiologic studies. For example, an experimental study without a control arm would not be informative about the intervention effect. Small clinical trials with intermediate biomarker endpoints require validation of endpoints and rigorous design and execution. In addition, a decision to begin a prevention clinical trial requires much more scientific data. In summary, Dr. Kristal concluded that: 1) epidemiologic studies are mixed but not generally supportive, and human clinical trials to date are not informative; 2) definitive epidemiological studies will require a better assessment of lycopene exposure, a better characterization of prostate cancer, and larger sample sizes; and 3) definitive clinical trials will require validation of intermediate endpoints and rigorous design and execution. There is considerable room for improvement in epidemiologic studies, particularly with respect to exposure assessments, control for effect modification (e.g., gene interactions), and confounding (e.g., PSA). Discussion A participant noted that data in animals and humans suggest that there is a maximal lycopene uptake into mucosal cells from a single meal. Lycopene and other carotenoids generally remain long enough for an additional amount to come in from a second meal. There also is a limited amount of lycopene that can move from the mucosal cells into lymph at any one time, which is also dependent on the amount of fat consumed. Thus, although there appears to be a maximal dose level in tissues, there may be continued residual uptake from additional meals because of delays in absorption, recirculation and metabolism. One participant hypothesized that, with multiple doses, there could be more accumulation of lycopene in tissues that may not be reflected in the plasma. Dr. Kristal agreed that, if the serum reaches a plateau, there still might be accumulation in tissues. Little research has been done on this topic. Another participant commented that although there is a need for placebo controls, particularly in biomarker studies, it would be more difficult with food-based interventions than with supplements. Dr. Kristal explained that he is less concerned with the issue of placebo than with having a “meaningful comparison group” from which to make some inference. A placebo is optimal, but it is difficult with food studies. A participant asked what is meant by a “validated” biomarker for clinical trials in prostate cancer. Currently, it is not clear whether even biopsy-proven prostate cancer is a predictor of morbidity or mortality. Gleason grade or stage could be as close to a validated biomarker as is possible at this time. Dr. Kristal stated that the biomarker should have “face validity” and make sense. Meaningful endpoints should be identified. The use of intermediate biomarkers is an extremely complicated issue. A participant asked if surrogate cells might provide some clues (e.g,. buccal cavity cells or exfoliated cells). Dr. Kristal replied that an exfoliated cell could be a better measure of lycopene in prostate or other tissue than serum. This is an interesting point that should be investigated further. 2/05 NIH Meeting Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.