Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.

BACKGROUND: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality. PURPOSE: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention. METHODS: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 alpha value, and all P values were derived from two-sided statistical tests. RESULTS: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations. CONCLUSIONS: CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29133 male smokers in Finland.

Changes in diet, weight, and serum lipid levels associated with olestra consumption.

BACKGROUND: Specially manufactured low-fat and nonfat foods have become increasingly available over the past 2 decades and controversy has surrounded the issue of whether these products have beneficial or adverse effects on the health and nutritional status of Americans. METHODS: This study examines the association of olestra consumption with changes in dietary intakes of energy, fat, and cholesterol and changes in weight and serum lipid concentrations. Data are from a cohort of 335 participants in the Olestra Post-Marketing Surveillance Study sentinel site in Marion County (Indianapolis, Ind). Diet, weight, and serum lipid levels were assessed before the market release of olestra and 1 year later, after olestra-containing foods were widely available. Olestra intake at the 1-year follow-up was categorized as none, low (>0 to 0.4 g/d), moderate (0.4 to 2.0 g/d), and heavy (>2.0 g/d). RESULTS: Participants in the heavy olestra consumption category significantly reduced dietary intake of percentage of energy from fat (2.7 percentage points, P for trend,.003) and saturated fat (1.1 percentage points, P for trend,.02). Consumers in the highest category of olestra consumption had statistically significantly reduced total serum cholesterol levels of -0.54 mmol/L (-21 mg/dL)compared with -0.14 mmol/L (-5 mg/dL) among olestra nonconsumers (P for trend,.03). CONCLUSIONS: These results indicate that introduction of a new fat substitute (olestra) in the US market was associated with healthful changes in dietary fat intake and serum cholesterol concentrations among consumers who chose to consume olestra-containing foods.

The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with cigarette smokers.

In preparation for a phase IV lung cancer chemoprevention trial, we conducted a pilot trial of beta-carotene and retinol in high-risk smokers. Eligibility criteria were ages of 50-69 years, a smoking history of at least 20 pack-years, and either being a current smoker or having quit within the past 6 years. Participants were recruited by mailing an interest survey to 29,928 age-selected members of King County Medical Blue Shield. We randomized 1,029 women and men to one of four intervention arms: placebo, retinol, 25,000 international units/day; beta-carotene, 30 mg/day; or retinol plus beta-carotene. Participants were followed for side effects and adherence every 2 months either by a telephone call or a clinic visit. Blood was sampled for retinoid, carotenoid, and liver function analyses annually. beta-carotene and retinol were well tolerated during the follow-up period, which had a median of 1.5 years and a maximum of 3.3 years. Yellowing of the skin was seen in both beta-carotene arms. No differences were seen among arms or over time in incidence or severity of the other 15 monitored symptoms and signs or in serum liver function tests. Adherence was good: 83% of participants remained active on study at 1 year and 75% at 2 years. Serum beta-carotene increased from a prerandomization median concentration of 170 to 2100 ng/ml after 4 months of supplementation, and retinyl palmitate median levels more than tripled.(ABSTRACT TRUNCATED AT 250 WORDS)

The Carotene and Retinol Efficacy Trial (CARET) to prevent lung cancer in high-risk populations: pilot study with asbestos-exposed workers.

Pilot studies are an essential component for major chemoprevention trials. Prior to initiating the multicenter Carotene and Retinol Efficacy Trial to assess the effectiveness of beta-carotene and retinol for preventing lung cancer, we conducted pilot studies in Seattle between 1985 and 1988 in two high risk populations: current and former heavy smokers and asbestos-exposed workers. The Asbestos Workers Pilot Study for the Carotene and Retinol Efficacy Trial demonstrated that recruitment of asbestos-exposed participants with relevant risk factors was feasible from identified sources. We documented negligible toxicity and high adherence with the protocol, schedule, and intervention. Results from the pilot led to extension of the placebo run-in period, changes in the eligibility criteria, improvements in recruitment strategies and scheduling, elimination of stratification by risk factors in randomization, modifications of study vitamin dosage and of side effects monitoring, and refinement of trial design parameters for Carotene and Retinol Efficacy Trial. The Smokers Pilot is reported in the accompanying article (G. E. Goodman et al., Cancer Epidemiol., Biomarkers & Prev., 2: 389-396, 1993).

Strategies for recruitment to a population-based lung cancer prevention trial: the CARET experience with heavy smokers. Beta-Carotene and Retinol Efficacy Trial.

The Beta-Carotene and Retinol Efficacy Trial tested the effect of the combination of beta-carotene (30 mg) and retinyl palmitate (25,000 units) daily on the incidence of lung cancer in high-risk individuals. In study centers located in Seattle, WA; Portland, OR; and Irvine, CA, we recruited current and recent ex-cigarette smokers, aged 50-69 years. Our primary method of recruitment was by mailing study information and eligibility questionnaires to age-selected health insurance subscribers. A total of 1,216,549 subscriber households were contacted, which resulted in 16,449 enrollments and 12,184 randomizations. Other methods of recruitment yielded 1421 enrollments and 1002 randomizations. Seventy-four % of those participants who enrolled in the 3-month placebo run-in were randomized. The major reasons for nonrandomization once subjects were enrolled were: becoming ineligible (13%), concern about or development of side effects attributed to the study vitamins (18%), loss of interest or being too busy (23%), and not showing up at the appointed time or not willing to come to the study center (23%). Here, we discuss the reasons for nonparticipation and for subjects leaving the trial prior to randomization and possible modifications of trial design and procedures to address these problems. This recruitment approach provided a constant flow of potentially eligible participants, screened out many ineligible and uninterested persons prior to the scheduling of a study center visit, and ensured randomization of committed participants. A major limitation of this study was that the pool of minorities that was reached was small.

Choices by rats between water and solutions of GABA or other amino acids.

Responses differed widely when rats were offered choices between water and solutions of GABA, its isomers alpha-aminobutyric acid (AABA) and alpha-aminoisobutyric acid (AIB), or of another 4-carbon amino acid, threonine. They preferred solutions of threonine and AABA starting at concentrations of about 30 mM; preference for threonine declined when its concentration was 330 mM or above. Rats never preferred GABA or AIB, but instead avoided these amino acids when concentrations were approximately 100 mM or above. Control rats showed strong preferences for drinking from a given location. Limited studies with humans showed variations in the concentrations at which they could detect GABA; the mean was about 0.06 mM, a concentration far below that at which rats began to avoid this amino acid. The ability of dietary GABA to depress food intake of rats (as shown in earlier studies) does not seem related to a uniquely high sensitivity to its gustatory qualities.

Early adopters of olestra-containing foods: who are they?

OBJECTIVE: To identify the characteristics of people consuming olestra-containing foods when first introduced at a test-marketing site. DESIGN: Data are from the Olestra Postmarketing Surveillance Study (OPMSS). After the introduction of olestra into a large test-marketing site, study participants received 3 follow-up telephone calls, at 3-month intervals, in which they were questioned about their diets during the previous month. SUBJECTS/SETTING: 1,007 adults in Indianapolis, Ind, who participated in a baseline clinic visit (before introduction of olestra into the food market) and completed at least 2 of 3 follow-up telephone calls (after the introduction of olestra into the market). STATISTICAL ANALYSES PERFORMED: Logistic regression was used to examine associations between olestra consumption and sociodemographic characteristics, health conditions, attitudes toward health and diet, and health-related behaviors. RESULTS: Olestra consumption on at least 1 of the follow-up telephone calls was reported by 41.5% of the study sample, and consumption on 2 or more telephone calls was reported by 20.0% of the sample. Factors associated with early adoption of olestra-containing foods included white ethnicity, higher education, overweight, absence of diabetes, attitudes indicative of diet and health concerns (e.g.; perceptions that there is a strong relationship between diet and disease), and a lower fat intake. APPLICATIONS/CONCLUSIONS: In spite of the controversy surrounding the introduction of olestra into the food market persons with attitudes indicative of diet and health concerns were likely to be early adopters of olestra-containing foods. Dietitians and other health care providers should inquire about intake levels of foods with fat substitutes and ensure that these foods are not being consumed in excessive amounts or being consumed instead of nutrient-dense foods that are naturally low in fat.

Participation and adherence among older men and women recruited to the Beta-Carotene and Retinol Efficacy trial (CARET).

We evaluated as functions of age and gender participation and adherence rates in older adults recruited to pilot studies for CARET, a multicenter chemoprevention trial. Eligible were men and women aged 50-69 who were current or recent former smokers, and men aged 45-74 with occupational exposure to asbestos. We found negligible differences by age in response to recruitment mailings, drop out during the enrollment process and after randomization, and adherence to taking the study capsules. Men had numerically lower drop-out and higher adherence rates than women, but differences were not statistically significant. These results should encourage researchers to recruit older men and women (at least up to age 69) to clinical trials.

Proportional hazards model for repeated measures with monotonic ordinal response.

In this paper we present a proportional hazards model to determine the effect of predictors on repeated measures data with ordinal response that is monotonic over time. The model can handle both categorical and continuous predictors. It naturally models the time spent in the response states. The assumption of proportional hazards can be partially assessed if replicates (individuals with identical covariate vectors) are available. Censoring can be incorporated into the model, although it does require additional modelling if the censoring is informative.

Research cost analyses to aid in decision making in the conduct of a large prevention trial, CARET. Carotene and Retinol Efficacy Trial.

Because of their larger study populations and longer durations, prevention trials typically are more costly than treatment trials. Thus it is important to analyze costs systematically to aid in making cost-effective decisions during the conduct of prevention trials as well as in the original design. Cost analysis must be tied to sample size estimation because costs depend on such factors as the total number of person-years of follow-up and the number of trial outcomes, which are not basic design parameters but are derived quantities resulting from sample size estimation. We illustrate the use of cost analysis to decide among options for future conduct of an ongoing prevention trial with three issues that have arisen during the Carotene and Retinol Efficacy Trial (CARET): the trade-off between extending the duration of the trial or increasing the number of participants, the effect on costs of delay in accrual, and the cost effectiveness of particular retention activities.

Weight-control behaviors among adults and adolescents: associations with dietary intake.

BACKGROUND: This study aimed to assess the prevalence of weight-control behaviors and their associations with overall dietary intake among adults and adolescents. METHODS: Participants included 3,832 adults and 459 adolescents from four regions of the United States. Cross-sectional data were collected on energy and nutrient intake, weight-control behaviors, body mass index (BMI), and sociodemographics. RESULTS: Current weight-control behaviors were reported by 52.7% of the study population (adult women, 56.7%; adult men, 50.3%; adolescent girls, 44.0%; adolescent boys, 36.8%). Weight-control behaviors were consistently and positively associated with socioeconomic status among adults, but not among adolescents. Among "dieters," unhealthy practices were reported by 22.7% of adult women, 21.3% of adult men, 30.4% of adolescent girls, and 18.5% of adolescent boys. Adults trying to control their weight reported healthier nutrient intakes than those not trying to control their weight, in particular when moderate weight-control methods were employed. Among adolescents, there were fewer differences across dieting status and these were not suggestive of healthier intakes among dieters than nondieters. CONCLUSIONS: Weight-control behaviors are reported by a large percentage of the population. Weight-control behaviors tend to be healthier among adults than among adolescents, in terms of the types of behaviors used and their impact on nutrient intakes. Obesity prevention interventions should emphasize the importance of using healthy weight-control practices.

Statistical design and monitoring of the Carotene and Retinol Efficacy Trial (CARET).

CARET is a chemoprevention trial of beta-carotene and vitamin A with lung cancer as the primary outcome. Participants at high risk for lung cancer are drawn from two populations: asbestos-exposed workers and heavy smokers. The intervention is a daily combination of 30 mg beta-carotene and 25,000 IU vitamin A as retinyl palmitate. Nearly 18,000 participants will be followed for a mean 6 years, yielding over 100,000 person-years of follow-up. We project that this sample size will have 80% power to detect a 23% decrease in the incidence of lung cancer cases. The purpose of this paper is to present the values of the key sample size parameters of CARET; our schemes for monitoring CARET for sample size adequacy, incidence of side effects, and efficacy of the study vitamins; an overview of the data collected; and plans for the primary, secondary, and ancillary analyses to be performed at the end of the trial. These approaches to the design, monitoring, and analysis of CARET are applicable for many other prevention trials.

Olestra consumption does not predict serum concentrations of carotenoids and fat-soluble vitamins in free-living humans: early results from the sentinel site of the olestra post-marketing surveillance study.

In 1996, the U.S. Food and Drug Administration approved olestra, a fat substitute, for use in snack foods. Previous studies had shown that olestra consumption could reduce absorption of carotenoids and fat-soluble vitamins. To determine the association between consumption of olestra-containing snack foods and serum concentrations of carotenoids and fat-soluble vitamins in a free-living population, we interviewed independent population-based cross-sectional samples of 1043 adults before olestra was available and 933 adults 9 mo after olestra snacks were introduced into the marketplace in Marion County, IN, the first major test market for olestra. A cohort composed of 403 adults from the first survey, oversampling those most frequently reporting olestra consumption during follow-up telephone interviews, completed a second survey. We assessed diet, lifestyle factors and olestra consumption, and collected blood for assays for the serum concentrations of six carotenoids, four fat-soluble vitamins and lipids. Nine months after the introduction of olestra into the marketplace, 15.5% of Marion County residents reported consuming an olestra-containing snack in the previous month, with a median frequency among consumers of 3.0 times per month. There were no significant associations or consistent trends for decreased serum carotenoids or fat-soluble vitamins associated with olestra consumption, although cohort members consuming >/=2 g/d of olestra had adjusted total serum carotenoids 15% lower compared with baseline. There were increases in serum vitamin K concentrations associated with olestra consumption (P = 0.03 in the cross section and P = 0.06 in the cohort). In summary, there was no statistically significant evidence in this free-living population of associations between olestra consumption and decreased serum concentrations of carotenoids and fat-soluble vitamins.

Demographic, dietary and lifestyle factors differentially explain variability in serum carotenoids and fat-soluble vitamins: baseline results from the sentinel site of the Olestra Post-Marketing Surveillance Study.

Biochemical measures of nutrients or other dietary constituents can be an important component of nutritional assessment and monitoring. However, accurate interpretation of the nutrient concentration is dependent on knowledge of the determinants of the body pool measured. The purpose of this study was to identify the determinants of serum carotenoid and fat-soluble vitamin concentrations in a large, community-based sample (n = 1042). Multiple linear regression analysis was used to examine effects of demographic characteristics (age, sex, race/ethnicity, education), health-related behavior (exercise, sun exposure, smoking, alcohol consumption), and intake (diet, supplements) on serum retinol, 25-hydroxyvitamin D, alpha-tocopherol, phylloquinone, and carotenoid concentrations. Age, sex, race/ethnicity, vitamin A intake, and alcohol consumption were found to be determinants of serum retinol concentration. Race/ethnicity, vitamin D intake, body mass index, smoking status, and sun exposure were determinants of serum 25-hydroxyvitamin D concentration. Determinants of serum alpha-tocopherol were age, sex, race/ethnicity, alpha-tocopherol intake, serum cholesterol, percentage of energy from fat (inversely related), supplement use, and body mass index. Age, sex, phylloquinone intake, serum triglycerides, and supplement use were determinants of serum phylloquinone concentration. Primary determinants of serum carotenoids were age, sex, race/ethnicity, carotenoid intake, serum cholesterol, alcohol consumption, body mass index, and smoking status. Overall, the demographic, dietary, and other lifestyle factors explained little of the variability in serum concentrations of retinol (R2 = 0.20), 25-hydroxyvitamin D (R2 = 0.24), and the carotenoids (R2 = 0.15-0.26); only modest amounts of the variability in serum phylloquinone concentration (R2 = 0.40); and more substantial amounts of the variability in serum alpha-tocopherol concentration (R2 = 0.62).

Development and validation of a food use checklist for evaluation of community nutrition interventions.

We developed a new dietary assessment instrument, the Food Behavior Checklist (FBC), which measures food use related to adopting lower-fat and higher-fiber diets. The FBC is a simplification of the 24-hour diet recall that consists of 19 simple yes/no questions about foods consumed during the previous day. To develop the FBC, an expert committee generated a list of foods based on our intervention program, and we used focus groups and random-digit dialing pretests to refine the format and clarify items. To validate the FBC, we compared responses of 96 women on the FBC to information collected during a professionally administered 24-hour diet recall. For most items, agreement between the FBC and 24-hour recall, based on the kappa statistic, was good to excellent. Agreement was poor for items requiring detailed knowledge about food composition (e.g. high-fiber cereal). There was a trend to over-report general food categories (e.g. luncheon meats) but not specific food items (e.g. ice cream). In an embedded randomized study, we found that a set of introductory items designed to serve as a memory retrieval cue did not improve agreement between the FBC and 24-hour recall. These data provide preliminary evidence supporting the use of short checklist questionnaires on the previous day's food use as a means to assess diet at the group or community level. This relatively inexpensive and rapid measure can be used to inform the design of public health nutrition programs and as an evaluation tool in intervention research.

Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.

BACKGROUND: Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. RESULTS: A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. CONCLUSIONS: After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.

Serum concentrations of retinol, alpha-tocopherol and the carotenoids are influenced by diet, race and obesity in a sample of healthy adolescents.

An important part of understanding the functions of vitamin A, vitamin E and the carotenoids in nutritional status assessment, health promotion and disease prevention is knowledge of factors that influence their distribution in human tissues. Our objective was to examine serum concentrations of these nutrients and compounds in a sample of 285 healthy participants, 12-17 y old, from three U. S. cities. Pearson correlations between diet measured with a food frequency questionnaire and serum nutrient concentrations among these adolescents (adjusted for total serum cholesterol, age, sex, race and body mass index) were as follows: retinol, 0.23; alpha-tocopherol, 0.16; alpha-carotene, 0.31; beta-carotene, 0.15; beta-cryptoxanthin, 0.38; lycopene, 0.08; and lutein + zeaxanthin, 0.25. Multivariate linear regression modeled associations of demographic, dietary and physiologic variables with serum concentrations of these nutrients. African-American participants had significantly lower concentrations of serum retinol (P < 0.001), alpha-tocopherol (P < 0.01) and alpha-carotene (P < 0.02), but higher concentrations of lutein + zeaxanthin (P = 0.001) compared with Caucasians. Obese participants had serum nutrient concentrations that were 2-10% (P < 0.05) lower than normal weight participants. Dietary intake was a significant predictor of all serum analytes (P < 0.01) except lycopene. These models explained 20% of the variability in serum retinol, 28% of the variability in serum alpha-tocopherol, and 14-24% of the variability in serum carotenoids.

Severe gastrointestinal bleeding after hematopoietic cell transplantation, 1987-1997: incidence, causes, and outcome.

OBJECTIVE: Severe GI bleeding after hematopoietic cell transplantation is commonly due to lesions that are unusual in nontransplant patients. The frequency of GI bleeding appears to have decreased over the last decade, but the reasons have not been readily apparent. We sought to determine the incidence of severe bleeding during two time periods, to describe the causes and outcomes of bleeding, and to analyze the reasons behind an apparent decline in severe bleeding over the decade covered. METHODS: During 1986-1987 and 1996-1997, we followed all patients with and without severe bleeding at our institution, a marrow transplant center. RESULTS: Over this decade, the incidence of severe bleeding declined from 50/467 (10.7%) to 15/635 (2.4%) (p < 0.0001). Overall mortality from intestinal bleeding declined from 3.6% to 0.9% (p = 0.002), but mortality in those with bleeding remained high (34% vs 40%). The onset (day 42 vs 47) and platelet counts (35,994 vs 37,600/microl) were similar, but the sites and causes of bleeding were different. During 1986-1987, 27/50 patients bled from multiple GI sites, viral and fungal ulcers, or graft-versus-host disease (GVHD). Over the decade, bleeding from GVHD had decreased 80% (p < 0.0001), and bleeding from viral (p < 0.0001) and fungal (p = 0.023) ulcers almost disappeared. CONCLUSIONS: The incidence of severe GI bleeding has declined significantly over the last decade because of prevention of viral and fungal infections and severe acute GVHD. However, severe bleeding after transplant remains a highly morbid event, particularly among patients with GVHD.