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.     

Dietary fat and prostate cancer: current status

Efforts to elucidate the causes of prostate cancer have met with little success to date. All that is known with certainty is that the incidence increases exponentially with age, varies by geography and by race or ethnicity, and is higher among men whose father or brother had the disease. Because the incidence changes in migrants and their offspring, exogenous factors certainly contribute to the risk of prostate cancer. Early epidemiologic studies implicated dietary fat as a likely causal factor for this cancer. However, scientific support for such an association has diminished in recent years as more epidemiologic evidence has accrued. Accordingly, we reviewed the relevant English language literature on this topic, including epidemiologic and animal studies, as well as current concepts regarding the involvement of fat in carcinogenesis to re-examine the fat-prostate cancer hypothesis. We conclude that dietary fat may indeed be related to prostate cancer risk, although the specific fat components that are responsible are not yet clear. Given the diverse effects of fatty acids on cellular biology and chemistry, it seems likely that the relationship is complex, involving the interplay of fat with other dietary factors, such as antioxidant vitamins and minerals, or with genetic factors that influence susceptibility. Some suggestions for further research are offered.     

The insulin-like growth factor system in cancer prevention: potential of dietary intervention strategies.

The insulin-like growth factor (IGF) system is related to proliferation and tumor growth, and high levels of circulating IGF-I are thought to be a risk factor for several types of cancer. This review summarizes the epidemiologic evidence for an association between circulating IGF-I and cancer risk as well as the experimental evidence for a causal relation between the endocrine IGF system and tumor growth. The potential for dietary intervention to alter the IGF system and thereby cancer risk is supported by several lines of evidence. Postulated mechanisms of action are as follows: (a) reduction of levels of circulating IGF-I, which will decrease activation of the IGF-I receptor and subsequent signaling pathways; (b) increasing local IGF binding proteins, which may have IGF-dependent effects through obstruction of IGF interaction with local IGF-I receptor as well as IGF-independent effects; and (c) interference with estrogens and estrogen receptor action, which may have direct (and possibly synergistic) effects on IGF signaling. An overview is given of the epidemiologic studies on dietary determinants of circulating IGF-I. Examples of dietary factors, such as dairy protein, lycopene, and phytoestrogens, are used to illustrate the potential mode of action of dietary interventions that may act on the IGF system. In conclusion, the IGF system has every potential to serve as an intermediate for cancer (chemo)prevention studies. On the short term, more research initiatives aimed at the effects of specific food components or dietary strategies on the IGF system both in animal models and in humans are warranted.     

The role of nutrition in cancer development and prevention

Nutrition has long been suspected to play an important role in cancer etiology. The biologic properties of nutrients make them prime candidates to aid in cancer prevention. Indeed, early epidemiologic cancer studies seemed to confirm the relevance of diet. These studies, however, were plagued by recall bias and confounding and may have thus been misleading. The results from large, prospective cohorts do not support a strong relation between nutrition and cancer. Given the difficulties in precisely assessing habitual diet, modest associations may exist, which may be impossible to capture when relying on self-reported dietary information. Energy balance, reflected in a low body weight and high level of physical activity, has been more convincingly related to lower cancer rates. The potential importance of more extreme dietary regimens and of nutrition during earlier periods of life remains to be explored. Finally, epigenetic research is likely to contribute to the understanding of nutritional regulation of gene expression.     

Mediterranean diet, antioxidants and cancer: the need for randomized trials.

In nutritional epidemiology the traditional approach has been to assess single nutrients or food items. Now, a growing interest exists in dietary patterns. The study of dietary patterns with a whole-diet approach represents a needed and complementary methodology. Among a priori defined patterns, the highly palatable traditional Mediterranean diet has many options to be the first choice in the dietary prevention of cancer. However, sound epidemiologic evidence about its ability to prevent the most frequent cancers is scarce. In conjunction with large and well-designed cohort studies, randomized trials using a whole-diet approach and not a simple antioxidant supplement are needed in Mediterranean countries.     

Micronutrients and cancer chemoprevention

Accumulating evidence suggests that a number of micronutrients may decrease the incidence of cancer of epithelial cell origin. These include vitamins A, C and E, beta-carotene and selenium. Few lines of research, apart from means to reduce cigarette smoking or heavy alcohol consumption, are as promising in terms of substantially decreasing human cancer incidence as studies of such micronutrients as dietary inhibitors of cancer. In this paper, we review the mechanisms by which these micronutrients may act to inhibit carcinogenesis, as well as the current animal and epidemiologic evidence supporting their role as chemopreventive agents. With respect to areas of future study, valuable information can be obtained from basic research as well as observational analytic epidemiologic studies utilizing dietary questionnaires which are more specifically focused and have been more rigorously evaluated than those previously employed. Another promising avenue of epidemiologic research is prospective studies of cancer incidence in relation to biochemical parameters in stored blood samples collected at baseline. The most reliable way to test directly whether a micronutrient prevents the development of human cancer is a large, randomized placebo-controlled trial among individuals with no previous history of the disease. The timely conduct of such trials is particularly important, since regular intake of nutritional supplements is already widespread in the United States, despite the lack of reliable evidence as to their benefits.     

Progress in understanding breast cancer: Epidemiological and biological interactions

Summary Little progress has been made recently in our understanding of the epidemiology of breast cancer. While results from epidemiologic studies regarding reproductive factors remain fairly reproducible from one study to another, other associations such as that between breast cancer risk and dietary fat intake, although biologically plausible, are not consistently found in direct study of humans, while yet other associations, which appear less plausible biologically, become stronger (such as the increased risk associated with modest levels of alcohol consumption). In this paper we attempt to review the epidemiology and biology of breast cancer jointly and describe possible mechanisms of breast cancer induction, the cellular composition of the breast, the epidemiology of breast cancer, and salient biological features, and attempt to reconcile the biology and epidemiology. It becomes obvious that future progress depends on better biological thinking by epidemiologists, and vice-versa. Areas of further research are suggested and discussed, concluding that the ability to measure diet with greater precision could have an important role to play in clarifying our understanding of breast cancer.     

Chemoprevention of colorectal cancer: dietary and pharmacologic approaches

Colorectal cancer is a major cause of death in the United States, where it accounts for approximately 57,000 deaths per year. Thus, the prevention of this disease would have a significant impact on public health. Chemoprevention is defined as the use of natural or pharmacologic agents to disrupt the process of carcinogenesis. Substances explored as chemopreventive agents in colorectal cancer include: (1) the nonsteroidal anti-inflammatory drugs (NSAIDS), which may inhibit the evolution and formation of adenomas by their inhibition of cyclooxygenase and decrease of prostaglandin synthesis; (2) antioxidants, such as vitamin E or C, which may modulate carcinogenic substances; and (3) folate and calcium, which may interfere with tumor cell growth and replication. Dietary intervention can be accomplished by decreasing fat intake and increasing fiber consumption, both of which have been linked to a lower incidence of colon cancer in multiple epidemiologic studies. This field is continuing to evolve. Hopefully, ongoing research efforts will offer a better understanding of the role of these and other substances in chemoprevention. This article summarizes the available data regarding dietary and pharmacologic approaches to colorectal cancer chemoprevention.     

Can the consumption of tomatoes or lycopene reduce cancer risk?

Lycopene, a natural antioxidant found predominantly in tomato products, is attracting attention as a cancer prevention agent. Serum and dietary lycopene levels have been found to be inversely related to the incidence of several types of cancer, including prostate cancer. Although the antioxidant properties of lycopene are thought to be primarily responsible for its apparent beneficial effects, other mechanisms may also be involved. We outline the possible mechanisms of action of lycopene and review the current findings of in vitro and in vivo studies in cancer prevention and to some extent treatment. We examine the epidemiologic evidence regarding consumption of tomato and tomato products with the risk of cancer at various sites. Data suggest lycopene may account for or contribute to chemoprevention, but this hypothesis requires further study. Numerous other potentially beneficial compounds are present in tomatoes and complex interactions among multiple components may contribute to the anticancer properties of tomatoes.     

Diet and breast cancer risk reduction

The association between diet and breast cancer risk has been investigated extensively and has led to some recommendations for prevention. Research suggests that maintaining a healthy weight may reduce the risk for breast cancer after menopause. Additionally, alcohol increases the risk for breast cancer even at moderate levels of intake, and women who drink alcohol also should take sufficient folate, which can mitigate this excess risk. Interesting questions for future research include the role of soy products, red meat, energy balance, and vitamin D, with particular attention to timing of exposure in early life. Breast cancer is a heterogeneous disease, and dietary factors may differentially affect certain breast cancer subtypes; future studies should therefore attempt to characterize associations according to tumor characteristics.     

Future possibilities in the prevention of breast cancer: Fat and fiber and breast cancer research

The potential for a reduction in dietary fat or for an increase in dietary fiber to reduce breast cancer risk has been debated for some years. It is argued here that available research data, even though extensive, leave open hypotheses ranging from little or no potential to major public health potential for breast cancer prevention by means of these dietary maneuvers. Some elements of a research strategy for testing these and other dietary breast cancer prevention hypotheses are described.     

Diet and cancer prevention

Research from several sources provides strong evidence that vegetables, fruits, and whole grains, dietary fibre, certain micronutrients, some fatty acids and physical activity protect against some cancers. In contrast, other factors, such as obesity, alcohol, some fatty acids and food preparation methods may increase risks. Unravelling the multitude of plausible mechanisms for the effects of dietary factors on cancer risk will likely necessitate that nutrition research moves beyond traditional epidemiological and metabolic studies. Nutritional sciences must build on recent advances in molecular biology and genetics to move the discipline from being largely 'observational' to focusing on 'cause and effect'. Such basic research is fundamental to cancer prevention strategies that incorporate effective dietary interventions for target populations.     

Review of epidemiologic studies of dietary acrylamide intake and the risk of cancer

Conjectured associations between dietary acrylamide intake and cancer have been evaluated in more than 15 epidemiologic studies examining almost every major cancer site. We have critically reviewed the epidemiologic studies of estimated dietary acrylamide exposure and cancer. As substantially greater acrylamide exposure occurs through tobacco smoke than dietary exposure, we present the results separately for never smokers or adjusted statistically for smoking status, where possible. After an extensive examination of the published literature, we found no consistent or credible evidence that dietary acrylamide increases the risk of any type of cancer in humans, either overall or among nonsmokers. In particular, the collective evidence suggests that a high level of dietary acrylamide intake is not a risk factor for breast, endometrial, or ovarian cancers, which have generated particular interest because of a conjectured hormonal mechanism of acrylamide. Moreover, the absence of a positive association between smoking and ovarian and endometrial cancers suggests that any association of these cancers with the much lower, more sporadic dietary acrylamide intake is unlikely. In conclusion, epidemiologic studies of dietary acrylamide intake have failed to demonstrate an increased risk of cancer. In fact, the sporadically and slightly increased and decreased risk ratios reported in more than two dozen papers examined in this review strongly suggest the pattern one would expect to find for a true null association over the course of a series of trials. Therefore, continued epidemiologic investigation of acrylamide and cancer risk appears to be a misguided research priority.     

Dietary fiber and cancer prevention.

A large body of literature suggests that eating a variety of foods containing high fiber has a protective effect against colon cancer. Evidence also indicates that a high fiber-containing diet may be protective against breast, ovary, endometrial, and gastrointestinal cancer. The focus of this review is the epidemiologic data for an inverse association between a high-fiber diet and risk for the previously mentioned cancers. Epidemiologic studies are categorized as international, within country, metabolic, time trend, case control, and cohort. Since 1980, 32 studies have assessed the role of fiber-containing foods in relation to colon cancer. Among these studies, 25 showed an inverse association. Of the seven case-control studies, which evaluated the relationship between the fiber-rich diet and breast cancer, six demonstrated an inverse association. For cancers of the esophagus, mouth, pharynx, stomach, rectum, endometrium, and ovary, there are only a limited number of studies, most showing a protective effect from eating a diet high in fiber-containing foods. The epidemiologic studies reviewed previously focus on dietary patterns in which fiber-rich foods usually occur as a complex mixture with other foods and food components, thus making it difficult to assess at this time if the protection is clearly from fiber per se or some other dietary component, such as low fat. For cancer prevention, the emphasis for dietary recommendation should be on a dietary pattern rather than on an isolated dietary fiber supplement.     

Apigenin and cancer chemoprevention: progress, potential and promise (review)

Cancer is one of the major public health burdens in the United States and in other developed countries, causing approximately 7 million deaths every year worldwide. Cancer rates vary dramatically in different regions and populations around the globe, especially between developing and developed nations. Changes in cancer prevalence patterns occur within regions as their populations age or become progressively urbanized. Migration has also contributed to such variations as changes in dietary habits influence cancer rates. These epidemiologic findings strongly suggest that cancer rates are influenced by environmental factors including diet, which is largely preventable. Approaches to prevent cancer include overlapping strategies viz. chemoprevention or dietary cancer prevention. Chemoprevention aims at prevention or reversal of the initiation phase of carcinogenesis or arrest at progression of carcinogenesis through the administration of naturally occurring constituents or pharmacological agents. Cancer prevention through diet may be largely achievable by increased consumption of fruits and vegetables. Considerable attention has been devoted to identifying plant-derived dietary agents which could be developed as promising chemopreventives. One such agent is apigenin. A naturally occurring plant flavone (4', 5, 7,-trihydroxyflavone) abundantly present in common fruits and vegetables including parsley, onions, oranges, tea, chamomile, wheat sprouts and some seasonings. Apigenin has been shown to possess remarkable anti-inflammatory, antioxidant and anti-carcinogenic properties. In the last few years, significant progress has been made in studying the biological effects of apigenin at cellular and molecular levels. This review examines the cancer chemopreventive effects of apigenin in an organ-specificity format, evaluating its limitations and its considerable potential for development as a cancer chemopreventive agent.     

Implications of phytoestrogen intake for breast cancer

Phytoestrogens are a group of plant-derived substances that are structurally or functionally similar to estradiol. Interest in phytoestrogens has been fueled by epidemiologic data that suggest a decreased risk of breast cancer in women from countries with high phytoestrogen consumption. Women with a history of breast cancer may seek out these "natural" hormones in the belief that they are safe or perhaps even protective against recurrence. Interpretation of research studies regarding phytoestrogen intake and breast cancer risk is hampered by differences in dietary measurement, lack of standardization of supplemental sources, differences in metabolism amongst individuals, and the retrospective nature of much of the research in this area. Data regarding the role of phytoestrogens in breast cancer prevention is conflicting, but suggest early exposure in childhood or early adolescence may be protective. In several placebo-controlled randomized trials among breast cancer survivors, soy has not been found to decrease menopausal symptoms. There is very little human data on the role of phytoestrogens in preventing breast cancer recurrence, but the few studies conducted do not support a protective role. There is in vivo animal data suggesting the phytoestrogen genistein may interfere with the inhibitive effects of tamoxifen on breast cancer cell growth.     

Head and neck cancer: a case for inhibition by isothiocyanates and indoles from cruciferous vegetables.

Chemical carcinogens derived from cigarettes and other tobacco products, as well as betel quid, paan, and alcohol consumption, are commonly associated with head and neck cancer risk. This is a particularly debilitating cancer, with a high recurrence rate and long-term treatment comorbidities affecting health and lifestyle. Controlling tobacco access or use may be an ideal prevention strategy but may also be challenging or undesired. Individuals, however, may be able to reduce their risk through simple and focused dietary change. Results from epidemiologic studies, basic research, and clinical investigations suggest that a diet rich in cruciferous vegetables may increase carcinogen metabolism, induce apoptosis, and reduce the risk of developing a primary head and neck tumor. This review briefly summarizes head and neck cancer nutritional epidemiology, and then describes the biochemical and epidemiologic literature describing the effects of crucifer consumption on head and neck carcinogenesis. To translate these findings, the strengths and limitations of specific intervention models are discussed, including differences in target populations and the choice of a food-based or pill-based approach for intervention. Addressing these factors in a future intervention may define a low-cost and non-toxic approach to reduce the burden of head and neck cancer.     

Expanding Cancer Prevention Education to National and International Audiences: The National Cancer Institute's Principles and Practice of Cancer Prevention and Control Annual Summer Course

The Summer Curriculum in Cancer Prevention has been sponsored by the National Cancer Institute's Cancer Prevention Fellowship Program for over two decades. This curriculum includes a 4-week course entitled “Principles and Practice of Cancer Prevention and Control.” The ultimate goal of this course is to present the most current cancer prevention research to a diverse workforce of researchers and practitioners eager to address the current challenges in this field. The course covers the current status of cancer prevention research and practice, ranging from epidemiology and clinical practice, and from basic to behavioral science research. It is comprised of lectures grouped into nine modules representing broad and specific topics relevant to cancer prevention. Course participants come from a broad cross-section of career stages, professions, and research interests, and are from across the USA and other countries. Over time and in response to feedback from participants, the course has developed to meet the needs and expectations of this diverse audience, and may serve as a model for those interested in cancer prevention education and training in other countries.     

HIV infection, aging, and immune function: implications for cancer risk and prevention

PURPOSE OF REVIEW: Combination antiretroviral therapy (ART) has turned HIV infection into a complex chronic disease. This article documents cancer risk among HIV-infected persons, reviews immune system effects of HIV infection in relation to cancer risk, discusses implications for cancer prevention, and suggests future research directions. RECENT FINDINGS: There has been a shift in the cancer spectrum from AIDS-defining cancers (ADC) to non-ADC, although the burden of ADC remains high. Although a high prevalence of non-HIV cancer risk factors among HIV-infected persons contributes to cancer risk, substantial evidence has accumulated in favor of an independent association between HIV-induced immunodeficiency and elevated risk of many specific cancer types, most of viral cause, although further work is needed to disentangle immunodeficiency and smoking effects for lung cancer, and immunodeficiency and hepatitis virus effects for liver cancer. Relationships between cancer risk and two other immune system hallmarks of HIV infection, chronic inflammation, and immune dysfunction/senescence, remain poorly understood. SUMMARY: Early, sustained ART is a crucial component of cancer prevention. Continued epidemiologic monitoring is needed to detect possible effects on cancer risk of specific ART classes or medications, long-term exposure to systemic inflammation or immune dysfunction, or earlier or more effective ART.