Cancer incidence in the Love Canal area.

Data from the New York Cancer Registry show no evidence for higher cancer rates associated with residence near the Love Canal toxic waste burial site in comparison with the entire state outside of New York City. Rates of liver cancer, lymphoma, and leukemia, which were selected for special attention, were not consistently elevated. Among the other cancers studied, a higher rate was noted only for respiratory cancer, but it was not consistent across age groups and appeared to be related to a high rate for the entire city of Niagara Falls. There was no evidence that the lung cancer rate was associated with the toxic wastes buried at the dump site.

Dietary fiber, vegetables, and colon cancer: critical review and meta-analyses of the epidemiologic evidence.

Whether colon cancer risk can be modified by a diet rich in vegetables, grains, and fruit, and, if so, whether the protective factor is dietary fiber or other biologically active components correlated with a high-fiber diet are questions of active research interest. Because studies on diet are susceptible to bias from a number of sources, in this review we evaluated the adequacy of study methodology as well as study results to clarify how much protection, if any, is conferred by a high-fiber diet. The review consisted of an aggregate assessment of the strength of evidence from 37 observational epidemiologic studies as well as meta-analyses of data from 16 of the 23 case-control studies. Both types of analyses revealed that the majority of studies gave support for a protective effect associated with fiber-rich diets; an estimated combined odds ratio (OR) of 0.57 (95% confidence interval = 0.50, 0.64) was obtained when the highest and lowest quantiles of intake were compared. Risk estimates based on vegetable consumption (OR = 0.48) were only slightly more convincing than those based on an estimate of fiber intake (OR = 0.58), but the data do not permit discrimination between effects due to fiber and nonfiber effects due to vegetables.

Cancer prevention and control: from research through applications.

As the understanding of the magnitude and social impact of cancer has advanced, three major forces have shaped the current state of the art in cancer prevention and control: the maturation of organization approaches to solving the cancer problem; the accumulation of scientific evidence that justified and illuminated the concept of cancer as a controllable disease; and, most recently, the development of a systematic cancer control research process that provides efficiency and clearer direction to the planning of a national cancer control program. The National Cancer Institute, recognizing the need for goal setting and scientific accountability in the conduct of cancer control research, has established quantified mortality reduction objectives for the year 2000 related to smoking cessation, diet changes, early detection, and state-of-the-art treatment. The cancer control research process and these objectives will guide the allocation of cancer control resources toward the application of effective health promotion strategies.

Sarcomas of soft tissues after Vietnam service.

Vietnam service and military service experiences of 281 men with sarcomas of soft tissues were compared in this epidemiologic study to a control group of men derived from driver's license files and matched on 5-year period of birth and ZIP code of residence. No direct association was found for service in Vietnam (odds ratio, 0.53; confidence limits, 0.21-1.31) or for any military service (odds ratio, 0.53; confidence limits, 0.37-0.76). A multivariate matched logistic regression analysis showed similar results for Vietnam service while controlling for military service. Results also were similar when the 130 cases who had died were compared to a second control group derived from death certificates. Finally, no significant associations were found for "Agent Orange" or other variables that might be related to herbicide exposure.

Socioeconomic factors and cancer incidence among blacks and whites.

Findings from previous studies suggest that differences in socioeconomic status may be responsible for some, if not all, of the elevated incidence of cancer among blacks as compared with whites. Using incidence data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program, we tested this hypothesis by correlating black and white cancer incidence rates in three US metropolitan areas between 1978 and 1982 with data from the 1980 census on socioeconomic status within individual census tracts. The study analyzed data on the incidence of cancer at all sites combined (greater than 100 cancer sites) and at seven major sites separately. As in other studies, income and educational levels served as surrogates for socioeconomic status. The present study also used census-tract data on population density as a surrogate factor. Each of these measures of socioeconomic status was analyzed independently. Before correlation with census-tract data, age-adjusted data on cancer incidence showed statistically significant elevated risks among blacks for cancer at all sites combined and at four of the seven separate sites; whites showed an elevated risk for cancer at two sites. Cancer at only one site, the colon, showed no significant association with race. When age-adjusted incidence data were correlated with socioeconomic status, the comparative black-white risks changed: Whites showed an elevated risk of cancer at all sites combined and at three of the seven separate sites; blacks maintained their elevated risk at three sites. These findings suggest that the disproportionate distribution of blacks at lower socioeconomic levels accounts for much of the excess cancer burden among blacks. They also suggest that for both blacks and whites unidentified racial factors, which may be either cultural or genetic and which are not closely linked to socioeconomic status, may play a role in the incidence of some cancers.

Relationship of hair dye use, benign breast disease, and breast cancer.

An epidemiologic case-control study of 118 breast cancer patients and 233 controls was conducted to test the hypothesis that hair dyes are related to breast cancer. Matched controls were selected by "random digit dialing," and all epidemiologic data were collected by telephone interviews. No overall association was detected. On a prospective basis, the interaction between hair dye exposure and six variables known to be risk factors for breast cancer then were examined: previous benign breast disease (BBD), "ever" versus "never" pregnant, age at first pregnancy, menopause induced by operation, age at menarche, and education. A statistically significant increased risk of breast cancer was found for women with a history of BBD and exposure to hair dyes as compared to women with BBD but no hair dye exposure: The relative risk (RR) was 4.5, and the 95% confidence intervals (C) were 1.20 and 15.78. A total of 24 women (19 patients and 5 controls) reported a history of BBD and hair dye use. Further analysis revealed a significant association between hair dye use and breast cancer among women 40-49 years of age (RR = 3.33; 95% CI: 1.1 and 10.85) and a highly significant (P = 0.0008) dose-response relationship among women who used hair dyes for changing their natural color as opposed to covering gray hair. The numbers of patients and controls included in this study were small and several hypotheses were tested. Additional epidemiologic studies are needed before firm conclusions can be reached concerning the nature of these associations.

Angiosarcoma of the liver: an epidemiologic survey.

Diagnosed from 1970 through 1975, the annual incidence rate for angiosarcoma of the liver among residents of New York State (excluding New York City) was 0.25 per million. A case-control study indicated that direct exposure to arsenic, vinyl chloride (VC), and thorium dioxide was a significantly important factor in the etiology of this disorder (P less than 0.02). Direct exposure to these chemicals could not be demonstrated for 19 (73%) of the 26 study patients. The fact that 5 of these patients lived nearer to VC fabrication or polymerization plants than did their matched controls lent some support to the hypothesis that indirect modes of exposure, not specifically related to occupation, might be important in the etiology of this disorder.

Dietary beta carotene and lung cancer risk in U.S. nonsmokers.

BACKGROUND: Approximately 15% of all lung cancer deaths in the United States (about 22,350 deaths annually) may not be directly attributable to active cigarette smoking. Consumption of beta carotene, which is derived almost exclusively from intake of fruits and vegetables, has been associated with a reduced risk of lung cancer in smokers. However, studies examining this association in nonsmokers, particularly nonsmoking men, are limited. PURPOSE: The purpose of this study was to examine whether dietary factors including beta carotene and retinol are associated with a reduced risk for lung cancer in nonsmoking men and women. METHODS: A population-based, matched case-control study of lung cancer in nonsmokers was conducted in New York State from 1982 to 1985. Dietary interviews were completed for 413 individually matched case-control pairs of subjects. To determine whether the relationship between dietary intake from specific food groups and lung cancer differed by type of interview, smoking history, sex, age, or histologic type, we examined data on the case-control pairs from each subgroup separately. The intake of beta carotene and retinol was calculated as the weighted sum of the monthly frequencies of consumption of food items containing these nutrients, where the weights correspond to the nutrient content of a typical portion of the food items. RESULTS: Consumption of greens (P for trend < .01), fresh fruits (P for trend < .01), and cheese (P for trend < .05) was associated with a significant dose-dependent reduction in risk for lung cancer, whereas consumption of whole milk (P for trend < .01) was associated with a significant dose-dependent increase in risk. Use of vitamin E supplements was also protective (odds ratio = 0.55; 95% confidence interval [CI] = 0.35-0.85). Increased consumption of the following food groups was associated with a reduction in risk among females: vegetables (P for trend < .025), raw fruits and vegetables (P for trend < .005), and dairy products (P for trend < .025). In males, increased consumption of raw fruits and vegetables was associated with a reduced risk for lung cancer (P for trend < .005). Dietary beta carotene (OR = 0.70; 95% CI = 0.50-0.99), but not retinol (OR = 0.98; 95% CI = 0.82-1.17), was significantly associated with risk reduction. CONCLUSIONS: This is the largest study to date of dietary factors and lung cancer in nonsmokers; results suggest that dietary beta carotene, raw fruits and vegetables, and vitamin E supplements reduce the risk of lung cancer in nonsmoking men and women.

Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance.

BACKGROUND: Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. PURPOSE: We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. METHODS: A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. RESULTS: No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.

Cancer in United States Jews.

The published studies of cancer of United States Jews are reviewed. Despite the lack of religious designation on death certificates, case reports, and census returns, a number of indirect methods for measuring the problem have been devised, which produce fairly consistent findings. In general, for American Jews, these show deficits in cancer mortality, among males, for the buccal cavity and pharynx and prostate and, among females, for the breast, uterine cervix and corpus, and bladder. Excesses in mortality, noted for both sexes, are esophagus, stomach, colon, pancreas, lymphomas, and leukemia and, in females, the lung and the ovary. The standardized mortality ratios for cancer of selected sites for Russian-born residents of upstate New York, 1969 through 1971, are presented as an indirect measure of the problem in the United States Jews. Statistically significant excesses were found in males for stomach and colon, with a striking deficit in cancer of the buccal cavity and pharynx. Among females, excesses were noted for stomach, pancreas, and lung with a sharp deficit in the uterine cervix. On the basis of the religious affiliation of the cemetery of burial, estimates of the Jewish and non-Jewish components of the 800 deaths in Russian-born residents were determined. Expected deaths in these two subgroups by sex, for each cancer site, were then calculated by use of the site-specific proportionate mortality of upstate New York for these years. This revealed a significant excess among Jewish males for colon cancer, with a deficit in lung cancer, while among the non-Jewish male components stomach cancer mortality was the only site significantly in excess. Among Jewish females, stomach and lung cancers were in excess, with a deficit in cancers of the breast and cervix uteri. In non-Jewish Russian-born females, the only site significantly in excess was stomach, with breast cancer showing a deficit.

Keynote address: cancer prevention.

Life-style factors that have a major impact on cancer risk are smoking, alcohol consumption, and diet. Current evidence suggests that dietary fat is an etiologic factor for colorectal and postmenopausal breast cancer and that foods high in dietary fiber may be beneficial against colorectal cancer. Clinical prevention trials, augmented by molecular and biological marker studies, will provide new knowledge for diet modification and chemoprevention. These studies are likely to influence the scope of oncology and public health practices of the future.

Role of biology and prevention in aerodigestive tract cancers.

Primary prevention aimed at smoking control and chemoprevention for high-risk persons or patients at risk for a second cancer provide strong potential for cancer prevention and control of aerodigestive cancers. The National Cancer Institute (NCI) has a major effort to build this area of research. The Third Upper Aerodigestive Tract Cancer Task Force Workshop, held in 1989 under the auspices of the National Cancer Institute's Organ System Program, reviewed the opportunities for chemoprevention research on aerodigestive epithelial cancers such as the regulation of growth and differentiation in normal and malignant cells. The chemoprevention program's drug development effort is evaluating several promising candidate agents for future clinical testing and the NCI clinical intervention program is supporting several trials of selected chemoprevention agents with demonstrated potential for inhibiting cancers of the lung, bronchus, oral cavity, and esophagus. Of special interest to this program is the assessment of beta-carotene, retinol and related synthetic retinoids, and several vitamin and mineral combinations under study in high-risk international populations. Chemoprevention in the medical setting is a major focus of NCI's Community Oncology Program (CCOP), a network designed not only to increase accrual of patients to trials but also to speed adoption of state-of-the-art therapies. Public health strategies are directed toward control of exposure to tobacco. The focal point for these activities is NCI's Smoking, Tobacco, and Cancer Program (STCP). STCP smoking cessation efforts are targeted at specific populations that are at greater risk for developing cancer including youth, minority and ethnic groups, women, smokeless tobacco users, and heavy smokers. Two of the world's largest controlled intervention trials conducted by the STCP are underway: the Community Intervention Trial for Smoking Cessation (COMMITT), which focuses on 6.5 million heavy smokers in 11 pairs of matched communities in North America, and the American Stop Smoking Intervention Study (ASSIST), a coalition model designed to reach millions of Americans through existing health promoting systems.

Genetic and cellular changes in colorectal cancer: proposed targets of chemopreventive agents.

Progress in development of a genetic model for colorectal tumorigenesis and human chemoprevention research may allow the mechanism-based identification of targets and chemopreventive agents that will protect against colorectal cancer. For example, numerous mutagenic events can occur throughout colorectal carcinogenesis, including loss of heterozygosity in tumor suppressor genes such as APC, MCC, DCC, and p53, as well as in oncogenes such as K-ras. Chemopreventive agents that inhibit mutagenic activity such as N-acetyl-l-cysteine, oltipraz, and nonsteroidal anti-inflammatory drugs may protect against these mutations. Also, agents such as perillyl alcohol and lovastatin that interfere with protein isoprenylation and, hence, inhibit oncogene activation may protect against aberrant K-ras expression. Hyperproliferation in normal mucosa, leading to growth and progression of neoplasia, are also aspects of colorectal carcinogenesis that can be controlled by chemopreventive agents. Calcium is a chemopreventive agent for which there is both clinical and experimental evidence of inhibition of cell proliferation in colon mucosa. Other examples of antiproliferative agents with potential chemopreventive efficacy in colon are 2-difluoromethylornithine, dehydroepiandrosterone, and selenium. Differentiating agents such as retinoids and deltanoids also may slow proliferation and progression. Antioxidants have potential for interfering with both mutagenicity and proliferation (e.g., by preventing oxidative activation of carcinogens and scavenging activated oxygen species generated during inflammation). The same mechanistic principles apply to identification of dietary chemopreventive intervention for colorectal carcinogenesis. For example, lowering dietary fat and increasing dietary fiber lead to lower colorectal mucosal proliferation, and cruciferous vegetables contain agents such as indoles and dithiolthiones that have shown antimutagenic activity.

Perspectives on surrogate end points in the development of drugs that reduce the risk of cancer.

This paper proposes a scientific basis and possible strategy for applying surrogate end points in chemopreventive drug development. The potential surrogate end points for cancer incidence described are both phenotypic (at the tissue, cellular, and molecular levels) and genotypic biomarkers. To establish chemopreventive efficacy in randomized, placebo-controlled clinical trials, it is expected that in most cases it will be critical to ensure that virtually all of the biomarker lesions are prevented or that the lesions prevented are those with the potential to progress. This would require that both the phenotype and genotype of the target tissue in agent-treated subjects, especially in any new or remaining precancers, are equivalent to or show less progression than those of placebo-treated subjects. In the National Cancer Institute chemoprevention program, histological modulation of a precancer (intraepithelial neoplasia) has thus far been the primary phenotypic surrogate end point in chemoprevention trials. Additionally, we give high priority to biomarkers measuring specific and general genotypic changes correlating to the carcinogenesis progression model for the targeted cancer (e.g., progressive genomic instability as measured by loss of heterozygosity or amplification at a specific microsatellite loci). Other potential surrogate end points that may occur earlier in carcinogenesis are being analyzed in these precancers and in nearby normal appearing tissues. These biomarkers include proliferation and differentiation indices, specific gene and general chromosome damage, cell growth regulatory molecules, and biochemical activities (e.g., enzyme inhibition). Serum biomarkers also may be monitored (e.g., prostate-specific antigen) because of their accessibility. Potentially chemopreventive drug effects of the test agent also may be measured (e.g., tissue and serum estrogen levels in studies of steroid aromatase inhibitors). These initial studies are expected to expand the list of validated surrogate end points for future use. Continued discussion and research among the National Cancer Institute, the Food and Drug Administration, industry, and academia are needed to ensure that surrogate end point-based chemoprevention indications are feasible.

Neurofibromatosis and other disorders among children with CNS tumors and their families.

We conducted a population-based case-control study with 338 patients, less than 15 years of age, diagnosed with a primary tumor of the central nervous system from January 1968 through December 1977 in 53 New York State counties. The study also included 676 controls selected from the birth certificate files of the New York State Department of Health. We collected information on neurofibromatosis and congenital anomalies in study subjects, their siblings and parents by telephone interview with the mother of each case and control. We obtained supplemental information on neurofibromatosis in the patients and their families from hospital medical records. This study confirmed the strong association of neurofibromatosis with risk of CNS tumors. Thirteen cases and no controls had neurofibromatosis. Two fathers and 3 mothers of cases had neurofibromatosis. Five cases had siblings with neurofibromatosis. None of the first-degree relatives of controls had neurofibromatosis. We observed a relative risk of 4.49 for history of seizures. Seizures are often among the presenting symptoms for CNS tumors. We observed no difference between cases and controls in the occurrence of congenital anomalies. There was a nonsignificant excess of congenital anomalies among siblings of cases compared with controls. This decreased to 1.13 when adjusted for number of siblings.

Cancer chemoprevention: progress and promise.

Cancer chemoprevention is the use of agents to inhibit, delay or reverse carcinogenesis. The focus of chemoprevention research in the next millennium will include defining the genotypic and phenotypic (functional and histological) changes during carcinogenesis, the cancer risk conferred by these changes, their modulation in preclinical experimentation and randomised clinical trials by chemopreventive drugs, dietary agents and regimens and treatments resulting from early detection. The key elements of this research effort will be basic and translational risk evaluation programmes; chemopreventive and dietary agent drug discovery and development; development of transgenic animal models; required safety and pharmacology studies; well-designed phase I, II and III chemoprevention studies; and much expanded early detection programmes. The large number of chemoprevention research programmes now ongoing ensures that the promise of chemoprevention will continue to be realised in the next decade.

Cancer chemoprevention: progress and promise.

Cancer chemoprevention is the use of agents to inhibit, delay or reverse carcinogenesis. The focus of chemoprevention research in the next millennium will include defining the genotypic and phenotypic (functional and histological) changes during carcinogenesis, the cancer risk conferred by these changes, their modulation in preclinical experimentation and randomised clinical trials by chemopreventive drugs, dietary agents and regimens and treatments resulting from early detection. The key elements of this research effort will be basic and translational risk evaluation programmes; chemopreventive and dietary agent drug discovery and development; development of transgenic animal models; required safety and pharmacology studies; well-designed phase I, II and III chemoprevention studies; and much expanded early detection programmes. The large number of chemoprevention research programmes now ongoing ensures that the promise of chemoprevention will continue to be realised in the next decade.

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.

Issues in the early termination of the aspirin component of the Physicians' Health Study. Data Monitoring Board of the Physicians' Health Study.

The Physicians' Health Study is a randomized, double-blind, placebo-controlled prevention trial of 22,071 US physicians, using a factorial design to evaluate the role of aspirin in the prevention of cardiovascular mortality and beta carotene in the reduction of cancer incidence. After approximately 5 years of follow-up, the aspirin component was terminated, 3 years ahead of schedule. Several factors were considered in the decision to terminate, including a cardiovascular mortality rate markedly lower than expected in both aspirin and placebo subjects, precluding the evaluation of the primary aspirin hypothesis, and a highly significant (P < .00001) and impressive (44%) reduction in the risk of first myocardial infarction in the aspirin group. Issues in the decision to terminate are described in this report.

Endometrial cancer after menopausal use of estrogens.

The incidence of endometrial cancer has increased rapidly during recent years, paralleling the increased postmenopausal use of estrogens. The relation of endometrial cancer to disease conditions in which estrogens are elevated and three case-control epidemiologic studies suggest the likelihood of a cause-and-effect relation between estrogen use and endometrial cancer. These studies and New York State Cancer Registry data further suggest that the incidence will continue to rise in coming years. A thorough reevaluation of the medical indications for estrogen replacement therapy is urgently needed. Women with long-term exposure to estrogens should have periodic cancer screening examinations.