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© 2002 American Society for Clinical Oncology
Cancer Prevention Clinical TrialsByFrom the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD. Address reprint requests to Peter Greenwald, MD, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, 6130 Executive Blvd, Rm 2040, MSC 2580, Bethesda, MD 20892-7309; email: pg37g{at}nih.gov
ABSTRACT: Prevention of cancer through interventions based on sound scientific research remains an important strategy of oncology research at the National Cancer Institute (NCI). Reducing the burden of cancer in the United States is focused on clinical investigations in medical settings and public health intervention research on cancer risk factors regarding lifestyle and diet. Chemoprevention research at the NCI has progressed systematically to identify potential agents that reduce cancer risk and to develop public health strategies that take advantage of basic research results. In addition, advances in our understanding of molecular targets and pathways and our use of new and emerging technologies have become important tools for oncology research. Priority areas for chemoprevention research, identified from experimental and clinical research, are investigated in clinical trials to determine their ability to reduce cancer risk in selected populations or in the general population. Priority areas discussed in this review are the relationship of the arachidonic acid pathway to carcinogenesis, lung cancer prevention in former smokers, breast cancer prevention, and prostate cancer prevention. In addition, two lifestyle factors that have potential to influence cancer risk—obesity and functionally enhanced foods—are discussed in the context of their link between clinical and public health-related research.
CANCER PREVENTION clinical trials are an integral part of oncology research at the National Cancer Institute (NCI). The focus of cancer prevention research supported by the NCI has two broad but related directions, clinical investigations in a medical setting and intervention research in the public health arena in areas such as tobacco control and prudent diet. Disease prevention research offers opportunities to reduce the cancer burden through aggressive programs that identify those at highest risk for disease and through scientifically sound prevention strategies that result from experimental and clinical research findings. The ultimate goal, central to the NCI’s mission, is population-wide application of proven interventions that are based on hypotheses and methods developed through basic biomedical research. The NCI’s Division of Cancer Prevention (DCP) has been at the forefront of cancer prevention research for more than two decades. In the 1980s, the DCP began a systematic review of potential chemopreventive agents and implemented clinical studies to identify agents for testing in clinical trials. Phase I (safety and pharmacokinetics), phase II (biomarker and preliminary efficacy), and phase III (large, randomized, controlled) clinical trials currently are investigating more than 60 potential chemopreventive agents. Priority chemoprevention research areas, discussed below, include the relationship of the arachidonic acid pathway to carcinogenesis, lung cancer prevention in former smokers, breast cancer prevention, and prostate cancer prevention. In addition, the discussion highlights obesity and functionally enhanced foods—only two of the many lifestyle factors that have the potential to influence cancer risk—and underscores the links between clinical and public health-related research.
The Arachidonic Acid Pathway Arachidonic acid (AA) metabolism is an attractive target for cancer prevention research, because increases in the level of expression of AA are characteristic of tissue damage, inflammatory responses, and carcinogenesis.1,2 In vivo, AA—a component of constitutive fatty acids in cell membranes—is synthesized by desaturation and elongation of linoleic acid. For humans, consumption of animals that feed on plants containing linoleic acid is a significant dietary source of AA. Also, AA may be formed directly in humans from linoleic acid supplied by foods such as soybeans, peanuts, margarine, and salad dressing.3 Metabolism of AA can occur through one of three distinct pathways, each with significant consequences in the initiation, promotion, and inhibition of carcinogenesis.4 These pathways, shown in Fig 1, are (A) AA conversion by cyclo-oxygenases (COXs) to prostaglandins and thromboxanes, (B) AA conversion by lipoxygenases (LOXs) to leukotrienes (LTs) and hydroxyeicosatetraenoic (HETE) acids (each LOX enzyme [eg, 5-LOX, 12-LOX, 15-LOX] catalyzes the formation of the corresponding hydroxyeicosanoid [eg, 5-HETE, 12-HETE, 15-S-HETE]), and (C) AA-stimulated production of sphingomyelinase, the enzyme that converts sphingomyelin to ceramide, a mediator of apoptosis.4 Chemoprevention studies on the inhibition of AA metabolism have focused on each of these pathways using various types of agents, including glycyrrhetinic acid, N-acetylcysteine, nonsteroidal anti-inflammatory drugs (NSAIDs), and polyphenols.5
The COX enzymes, which may be either continuously expressed (COX-1) or induced by inflammatory processes (COX-2), have been associated with cancer at various sites, including the colon, gastrointestinal tract, lung, and skin.6 Increased prostaglandin and thromboxane production in tumor cells has been linked to increased angiogenesis and proliferation and decreased differentiation and apoptosis.7,8 Epidemiologic, experimental, and intervention research on inhibition of COX-1 and COX-2 by NSAIDs indicates that NSAIDS may prevent tumor growth and increase differentiation and apoptosis through this mechanism.9,10 For example, in patients with familial adenomatous polyposis, celecoxib (a COX-2 inhibitor) significantly reduced the number of colorectal polyps by 28% and the polyp burden (sum of polyp diameters) by almost 31% after 6 months of treatment, compared with patients administered placebo.11 Celecoxib currently is being investigated in DCP-sponsored phase II chemoprevention trials for Barrett’s esophagus and cancers of the bladder, colon, mouth, prostate, and skin.12 The NSAID sulindac and its derivatives have become a focus of chemoprevention research, because they have demonstrated anticancer effects—through COX-1, COX-2, and LOX inhibition and other mechanisms—in more than 50 different tumor cell lines, as well as in animal models of human mammary, prostate, lung, and pancreatic carcinomas.13 The LOX pathway in AA metabolism is a promising target for chemoprevention research; LOX inhibition has been shown to reduce tumor cell growth more effectively than COX inhibition.14 LOXs have been associated with various cancer cell types, including breast, colon, prostate, pancreas, and non–small-cell lung cancers.14-16 For example, levels of 5-LOX mRNA are significantly higher in malignant prostate tissue than in benign tissue, and 5-HETE is increased dramatically in both hormone-responsive and hormone-nonresponsive human prostate cancer cells.15 5-LOX inhibition by nordihydroguaiaretic acid reverses the production of 5-HETE and causes an increase in apoptosis in lung, breast, and prostate cancer cells.14,17 12-LOX seems to be involved in both the growth and angiogenesis of prostate cancer cells; inhibition with baicalein, a selective 12-LOX inhibitor, reduces the levels of 12-HETE and induces apoptosis.18 In contrast, apoptosis by upregulation of 15-LOX has been reported in human colorectal cancer cells19 and in esophageal carcinomas that were treated with NSAIDs.20 The mechanisms for NSAID-induced apoptosis via the LOX pathway are not yet understood. LTs are important products of AA metabolism via the 5-LOX pathway. For instance, leukotriene B4 (LTB4) is a potent inflammatory mediator and the object of chemoprevention studies on esophageal adenocarcinoma.21 LTB4 and reactive oxygen species, which are both factors in inflammation, have been associated with genetic and epigenetic changes in esophageal cells that result in genetic instability, decreased apoptosis, and hyperproliferation.21 Peroxisome proliferator-activated receptors (PPARs)—nuclear receptors that function as ligand-activated transcription factors and are associated with lipid, glucose, and energy homeostasis—can be activated by fatty acids and eicosanoids such as LTs and prostaglandins.22 For example, PPARs bind with high affinity various dietary fatty acids—particularly long-chain, polyunsaturated fatty acids—that have been reported to lower the incidence of cancer in experimental animals.23 Studies in rats report that PPAR-gamma ligands inhibit mammary tumor growth,23 and that PPAR-gamma and PPAR-alpha ligands reduce cell proliferation in colonic mucosa after exposure to exogenous carcinogens.24 In addition, PPAR-gamma agonists inhibit proliferation and induce differentiation in breast, colon, and bladder carcinoma cell lines.25 However, studies in MIN mice—animals that are susceptible to intestinal neoplasia—report that activation of PPAR-gamma by synthetic PPAR-gamma agonists increased the frequency and size of colon tumors,26 suggesting that inhibition of carcinogenesis by modulation of PPARs may depend on the specific situation. In experimental studies, the NSAIDs sulindac and indomethacin activated PPAR-gamma and had antiproliferative effects in human oral squamous carcinoma cells and various fibroblasts cell lines.27,28 One clinical study is investigating whether PPAR-gamma ligands can affect rising prostate-specific antigen (PSA) values in early prostate cancer. Research on PPARs has led to the concept of developing selective PPAR modulators that have potential for cancer prevention. Current and future research is focusing on chemopreventive agents that can block the COX and LOX pathways in AA metabolism simultaneously, thus increasing ceramide production and apoptosis. Dual inhibitors—such as ML3000 and ER-34122, which are currently being investigated in phase II and III clinical trials on arthritis—have the advantages of reducing a wide range of inflammatory responses and alleviating the gastric toxicities characteristic of many individual COX or LOX inhibitors.29,30 It is possible that diet—including fatty acids, antioxidants, and even environmental contaminants of diet—may greatly influence the AA pathway. For example, mycotoxins are environmental contaminants that can be formed in some foodstuffs as a result of mold growth. Epidemiologic studies report that the mycotoxin fumonisin is associated with increased incidence of esophageal cancer in China and Africa, where contamination of corn has been documented.31,32 Experimental studies in rats indicate that fumonisin B1, a ceramide synthesis inhibitor, causes an increase in AA metabolism through COX and LOX pathways as well as increased inflammation, immune modulation, and protein kinase activation.33 Flavonoids such as curcumin, quercetin, and eugenol—which show antioxidant activity—have demonstrated COX inhibition,34 as well as dual COX and LOX inhibition34; this is accompanied by an increase in AA-stimulated sphingomyelinase production, which increases ceramide-induced apoptosis. In one study, curcumin inhibited the expression of COX-2 and the growth of colon cancer cells.35
Lung Cancer Prevention in Former Smokers A recent review of phase II prevention trials concluded that lung cancer was not prevented in smokers by alpha-tocopherol, beta-carotene, retinol, retinyl palmitate, N-acetylcysteine, or isotretinoin, although isotretinoin reduced squamous metaplasia in study participants who were successful in smoking cessation.36 Increased levels of proliferating cell nuclear antigen, a biomarker expressed in non–small-cell lung cancer, have been used to determine the chemopreventive efficacy of 13-cis-retinoic acid (13-cRA). In a study of former smokers, proliferating cell nuclear antigen levels were reduced by 13-cRA, indicating its potential as a chemopreventive agent in this population.39 One DCP-sponsored phase II chemoprevention trial is studying the use of 13-cRA, 9-cRA, and alpha-tocopherol among former smokers. Another phase II study among smokers and former smokers is investigating the inhaled corticosteroid budesonide, which has been used in asthma patients, to determine whether this agent can reduce bronchial dysplasia.
Breast Cancer Prevention However, clinical data indicate that tamoxifen increases the risk of endometrial cancer and thromboembolic disease.41 Thus, the chemopreventive potential of raloxifene, a selective estrogen receptor modulator anticipated to have lesser adverse side effects, was investigated for breast cancer as a secondary end point in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. MORE was designed to test whether raloxifene reduces the risk of fracture in postmenopausal women with osteoporosis.44 As of November 1999, MORE data demonstrated a 72% reduction in invasive breast cancer in women who received raloxifene. No increased risk of endometrial cancer was observed for raloxifene; increased risk of thromboembolic disease was similar to that for tamoxifen.44 A new trial, the Study of Tamoxifen and Raloxifene (STAR) trial, designed to compare the efficacies of raloxifene and tamoxifen for reducing breast cancer as a primary end point, has been initiated and is recruiting postmenopausal women. STAR is the first phase III chemoprevention trial using a pharmacologic standard of care (tamoxifen) as the control.43 Study designs and results for BCPT, International Breast Cancer Intervention Study, MORE, and STAR are summarized in Table 1. Both tamoxifen and raloxifene reduce risk only for estrogen receptor (ER)–positive breast cancer; ER-negative breast cancer risk is not affected.41,44
Although randomized, large-scale trials are the most powerful means of testing cancer-preventive agents, these trials require large study populations, extensive resources, and many years for completion. Identification of valid, intermediate-effect biomarkers that could serve as surrogate end point biomarkers (SEBs) for clinical disease would make it possible to design smaller, short-term prevention trials. Fabian et al,47 using breast fine-needle aspirations from high-risk and low-risk women, demonstrated that cytologic evidence of hyperplasia with atypia and abnormalities of several cellular biomarkers were more prevalent in high-risk women. Fine-needle aspiration cytology and biomarkers may be useful in identifying women who might benefit from breast cancer prevention trials and also as SEBs to monitor efficacy of potential preventive agents.48 An ongoing breast biomarker modulation trial in high-risk women treated with targretin—a retinoid that selectively activates retinoid X receptors—is comparing pretreatment and posttreatment biopsy specimens to determine changes in biomarkers, proliferation, apoptosis, and retinoid-regulated genes (P. Brown, personal communication, June 2002). Researchers also are investigating whether individual polymorphisms in metabolizing genes or genes associated with toxicity can be used to determine who might benefit most from tamoxifen or other preventive agents. The relationship of metabolic polymorphisms to breast cancer susceptibility has been the focus of several recent reviews.49-52 Research to develop agents effective against ER-negative breast cancer is a top priority. Promising candidate agents include inhibitors of epidermal growth factor receptor-tyrosine kinase, COX-2, and farnesyl transferase, retinoids, and PPAR-gamma agonists. The NCI currently is promoting studies to find useful animal models for facilitating discovery and development of such agents. Following leads from epidemiologic and experimental research that link diet and cancer risk, several food-derived chemopreventive agents for breast and prostate cancers are being investigated in NCI-sponsored studies (Table 2).
Prostate Cancer Prevention Secondary end point data from large-scale randomized controlled trials, supported by preclinical and epidemiologic data, suggest that vitamin E and selenium reduce prostate cancer risk.53 Analysis of data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study showed that 32% fewer cases of clinical prostate cancer (a secondary end point) were diagnosed among men who received vitamin E (dl-alpha-tocopheryl acetate).54 Also, secondary end point analysis of data from the Nutritional Prevention of Cancer Study,55 designed to test the effect of supplementation with selenium-enriched yeast on development of nonmelanoma skin cancer in patients with a history of skin cancer, demonstrated a significant 63% reduction in prostate cancer. In support, epidemiologic data from the Health Professionals Follow-Up Study showed an inverse association between the prediagnostic level of toenail selenium and risk for advanced prostate cancer (odds ratio 0.35, highest v lowest quintiles).56 Based on growing evidence that selenium and vitamin E may reduce prostate cancer risk, the Selenium and Vitamin E Cancer Prevention Trial (SELECT)—a phase III, randomized, double-blind, placebo-controlled, population-based trial—was initiated in 2001. SELECT is a study in 32,400 healthy men designed to test the efficacy of selenium (L-selenomethionine) and vitamin E (dl-alpha-tocopheryl acetate) alone and in combination for preventing prostate cancer.53 More than 9,700 men (white men > age 55, African-American men > age 50) with total PSA less than 4 ng/mL were enrolled between August 2001 and March 2002. The trial is projected to last 12 years, including 7 years of intervention plus follow-up, with a primary end point of biopsy-proven prostate cancer. Epidemiologic investigations of molecular/genetic markers have been included in the SELECT design.57 Prostatic intraepithelial neoplasia (PIN), believed to be a premalignant form of prostate cancer, seems to be common in relatively young men. PIN was identified in 9%, 20%, and 44% of men in their twenties, thirties, and forties, respectively; 10% of PIN cases in men in their forties was high-grade PIN, the form most strongly associated with invasive prostate cancer.58 Selenium supplementation (L-selenomethionine) is being tested in more than 460 men with high-grade PIN in a 3-year intervention; the primary end point is biopsy-proven prostate cancer, and several potential SEBs are being monitored. A short-term phase II trial of selenium supplementation in presurgical prostate cancer patients found a direct association between supplementation and prostate tissue selenium levels. In the early 1990s, data demonstrated that activity of 5-alpha-reductase, the enzyme that catalyzes conversion of testosterone to the metabolically more active dihydrotestosterone, was significantly lower in native Japanese men, who had among the lowest incidence of prostate cancer worldwide.59 These findings suggested that inhibiting 5-alpha-reductase may reduce prostate cancer risk. Currently, finasteride (a competitive inhibitor of 5-alpha-reductase) is being tested as a chemopreventive agent in the Prostate Cancer Prevention Trial (PCPT). The PCPT, which compares finasteride to placebo, is a population-based trial being conducted in more than 18,000 healthy men older than age 55 with a total PSA less than 3 ng/mL. All participants have an annual PSA measurement (plus biopsy if PSA is elevated) and digital rectal examination, as well as a biopsy after 7 years of intervention. The trial is designed to detect the primary end point of a 25% reduction in period prevalence of biopsy-proven cancer in 7 years with 90% power. PCPT is expected to be completed in 2004.60
Lifestyle factors such as tobacco and alcohol use, sun exposure, sexual behavior patterns, physical activity, obesity, and diet can influence cancer risk. Recognizing the roles that these factors may play in cancer development is essential for carrying out effective cancer prevention strategies, including clinical investigations. Obesity and functionally enhanced foods, discussed briefly here, serve as examples.
Obesity
Obesity has reached epidemic proportions in developed countries, including the United States.63,64 Data from the National Health and Nutrition Examination Survey (NHANES) II and the NHANES III indicate that obesity prevalence in adults in the United States increased from 14.5% to 22.5% between 1976 to 1980 and 1988 to 1994.65 Adult obesity continued to increase rapidly throughout the 1990s (Table 3).63 American children also are getting heavier. Between 1986 and 1998, the prevalence of overweight children (body mass index > the 95th percentile for age and sex) increased from
Obesity likely is a result of imprudent dietary practices (many high-fat foods, few vegetables and fruits, frequent snacks, large serving sizes) coupled with increasingly sedentary lifestyles. Between 1977 to 1978 and 1994 to 1996, snacking prevalence among young adults increased from 77% to 84%, kilocalories consumed per snacking occasion increased by 26%, and number of snacks per day increased by 14%.67 NHANES data indicate that daily energy intake of adults and adolescents in the United States increased by 100 to 300 kilocalories from 1976 to 1980 to 1988 to 1991.68 Many restaurants and fast food chains now are offering super-sized portions (containing a super-sized number of calories) at competitive prices to attract customers, contributing to the obesity problem.69,70
Functionally Enhanced Foods The acreage devoted to genetically modified crops in the United States is expanding rapidly, and food and feed products from modified crops, including soybeans, canola, corn, cotton, tomatoes, potatoes, and squash, are entering mainstream industries.71 For example, Roundup Ready soybeans (Monsanto Co, St Louis, MO), genetically modified to be resistant to the herbicide Roundup, were introduced in 1996; by 1999, they accounted for almost 40% of the soybean acreage in the Unites States.72 Modified crops with improved quality traits include tomatoes with extended shelf life and superior taste, color, and texture (eg, Flavr Savr tomato [Calgene Inc, Davis, CA]), soybeans with 80% or more oleic acid (monounsaturated), and soybeans with increased essential amino acid content.71 The typical soybean of the future is likely to be herbicide tolerant and insect protected and to contain both modified oil and protein. The soybean has demonstrated potential for cancer prevention. Epidemiologic data suggest that consumption of soy products is associated with reduced risk for breast,73 endometrial,74 and prostate cancers.75,76 Many soy-based foods are available to consumers, including tofu, soy milk, soy cheeses, frozen "yogurt," breakfast shakes, soy nuts, meat substitutes, and salad dressings.77 Recent evidence suggests that genistein may promote the growth of some estrogen-sensitive tumors and reduce the efficacy of tamoxifen, which emphasizes the need for additional studies to determine who will and will not benefit from dietary intervention strategies.78,79 Genetic engineering is opening up exciting opportunities for improving the nutritional characteristics of plant foods. A good example is the newly developed golden rice that contains beta-carotene (provitamin A) and iron. The rice carries three foreign genes that allow the grains to accumulate iron in a form that humans can absorb and four genes that give the grains the ability to produce beta-carotene, making the rice an excellent source of vitamin A.80 The recent availability of the entire rice genome sequence will allow the function of rice genes to be identified, with broad implications for future tailored rice engineering.81
Cancer prevention trials will continue to be carried out in the medical setting and the public health setting to test existing hypotheses and to develop new and refined hypotheses for testing in further trials. As cancer research continues, the guidance for cancer risk reduction provided to the public will be based on the best evidence available. Development and validation of SEBs for clinical cancer end points in prevention trials will be a major research focus. Realistically, it is likely that using panels of biomarkers to monitor chemopreventive effects will be more advantageous than using a single SEB. Expanded use of molecular technologies such as DNA microarrays and proteomics will help to identify molecular targets for chemopreventive agents and individuals at high risk for certain cancers. Research will continue on cancer vaccines, which initially may help the body reject tumors and prevent recurrence, and later be used for prevention in very high-risk individuals. Vaccines using tumor-associated antigens—present on tumor cells but essentially absent on normal cells—can elicit an immune response directed at tumor cells in cancer patients. Cancer vaccines are being studied for melanoma, lymphoma, and cancers of the breast, prostate, ovary, colon, rectum, and kidney. Recently, a vaccine against human papilloma virus type 16 was developed that is highly immunogenic and may ultimately help to prevent cervical cancer; human papilloma virus type 16 is a major risk factor for this disease.82 To accelerate future progress in cancer prevention research, cancer prevention must be built into the mainstream programs of major research institutions, efforts to attract researchers to this field must be intensified, and multidisciplinary, collaborative research approaches must be emphasized and encouraged.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
30 kg/m2) increases risk for certain cancers; evidence is strongest for postmenopausal breast, endometrial, colorectal, renal cell, and gallbladder cancers.
10% to 21.5% among African Americans, 21.8% among Hispanics, and 12.3% among non-Hispanic whites.
), GW7845, inhibits rat mammary carcinogenesis. Cancer Res 59: 5671-5673, 1999
