Diet and cancer: the disconnect between epidemiology and randomized clinical trials

Dietary epidemiology has been highly successful in identifying the responsible agent in many diseases, including scurvy, pellagra, blindness, and spinal bifida. Case-control, cohort, and ecologic observational studies have consistently associated increased consumption of fruits and vegetables with a decreased risk for a wide variety of epithelial cancers and, in many cases, specific dietary components seem to decrease the risk for a wide array of epithelial cancers. Over time, there has been enthusiasm for one or another compounds, such as beta-carotene in the past and folate currently. Despite the success of translating similar epidemiologic observations to clinical benefit in other areas of medicine via the crucible of the randomized clinical trial, this strategy has not been nearly as successful for cancer. We propose that the inability of nutritional epidemiology to identify effective chemopreventive strategies is not just a problem of quantitation, but rather that the discipline is usually qualitatively incapable of identifying a dietary compound(s) that will be efficacious. One needs to consider the following basic questions in trying to understand why nutritional epidemiology has not been translated into progress in cancer prevention: Why do fruits and vegetable show a consistent protective effect against many epithelial cancers in epidemiologic studies? Once a specific dietary compound is identified as protective in observational studies, why do most subsequent observational studies confirm the effect? Why are dietary epidemiology observations frequently not confirmed by the randomized clinical trial? We call the identified problems "fishing with only one bait" and the "four-legged stool problem." The considerations identified in this analysis offer a number of possible solutions to puzzling findings: (a) Fruits and vegetables consistently show a protective effect against cancer in observational studies because they represent the entire "biological action package." (b) Dietary compounds show a protective effect in observational studies, but not in clinical trials, because this is an inevitable consequence of one compound being falsely identified as the active agent in a system in which multiple agents or multiple interacting regulatory molecules underlie the biological effect. The consequences are serious for trying to use epidemiology to identify effective nutritional compounds. The major conclusion has to be as follows: Supplementation with single dietary compounds is rarely going to be as effective as epidemiologic studies suggest; it is the biological action package that determines efficacy. Options for how we should move forward will be discussed. Dietary observational epidemiology is complex and involves many biases and confounders. We need to be more critical in the design of large randomized trials based on observational epidemiology or analysis. Rules of evidence are frequently ignored or misunderstood although the limitations of observational epidemiology are analogous to the problems associated with discovery-based research and biomarker identification. We need to be much more self-critical in the important and critical assessment of dietary compounds and their role in cancer prevention given the very high appeal for this approach both within the lay and scientific communities.