Effects of a Combination of Beta Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease
Gilbert S. Omenn, M.D., Ph.D., Gary E. Goodman, M.D., M.S., Mark D. Thornquist, Ph.D., John Balmes, M.D., Mark R. Cullen, M.D., Andrew Glass, M.D., James P. Keogh, M.D., Frank L. Meyskens, M.D., Barbara Valanis, Dr.P.H., James H. Williams, M.D., Scott Barnhart, M.D., M.P.H., and Samuel Hammar, M.D.
Background Lung cancer and cardiovascular disease are majorcauses of death in the United States. It has been proposed thatcarotenoids and retinoids are agents that may prevent thesedisorders.
Methods We conducted a multicenter, randomized, double-blind,placebo-controlled primary prevention trial — the Beta-Caroteneand Retinol Efficacy Trial — involving a total of 18,314smokers, former smokers, and workers exposed to asbestos. Theeffects of a combination of 30 mg of beta carotene per day and25,000 IU of retinol (vitamin A) in the form of retinyl palmitateper 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 diagnosedduring the 73,135 person-years of follow-up (mean length offollow-up, 4.0 years). The active-treatment group had a relativerisk 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 risksof other types of cancer. In the active-treatment group, therelative risk of death from any cause was 1.17 (95 percent confidenceinterval, 1.03 to 1.33); of death from lung cancer, 1.46 (95percent confidence interval, 1.07 to 2.00); and of death fromcardiovascular disease, 1.26 (95 percent confidence interval,0.99 to 1.61). On the basis of these findings, the randomizedtrial was stopped 21 months earlier than planned; follow-upwill continue for another 5 years.
Conclusions After an average of four years of supplementation,the combination of beta carotene and vitamin A had no benefitand may have had an adverse effect on the incidence of lungcancer and on the risk of death from lung cancer, cardiovasculardisease, and any cause in smokers and workers exposed to asbestos.
Lung cancer is the leading cause of death from cancer in theUnited States, accounting for approximately 29 percent of deathsfrom cancer and 6 percent of all deaths.1 New approaches areessential to prevent lung cancer in persons who have smokedcigarettes or who have had occupational exposure to asbestos.Twenty-nine percent of men and 25 percent of women who are 45to 64 years of age currently smoke,2 and at least 40 percentof men and 20 percent of women in this age group are formersmokers.3 An estimated 4000 to 6000 deaths from lung cancerper year are attributed to exposure to asbestos.4,5
On the basis of epidemiologic observations and laboratory studies,beta carotene and vitamin A have attracted wide interest asagents that may prevent lung cancer.6,7,8,9 The Beta-Caroteneand Retinol Efficacy Trial (CARET) is one of several recenttrials to assess the chemopreventive efficacy and safety ofbeta carotene and related agents.10,11,12,13
This report presents interim efficacy results of the CARET study,which coincided with the announcement of the steering committee'sdecision on January 11, 1996, to stop the trial's active intervention.Follow-up for additional end points is expected to continuefor another five years.
Methods
Study Design
The study's strategy, design, detailed methods, eligibility,pilot-study findings, and recruitment information have beenpublished elsewhere.9,14,15,16 Briefly, CARET was organizedin 1983 and began randomization in Seattle in 1985 in two pilotstudies: one enrolled 816 men with substantial occupationalexposure to asbestos, who were randomly assigned in a 1:1 ratioto receive either a combination of 15 mg of beta carotene perday and 25,000 IU of retinol per day (active treatment) or placebo;the second enrolled 1029 men and women with extensive historiesof cigarette smoking, to receive 30 mg of beta carotene perday, 25,000 IU of retinol per day, both vitamins, or neithervitamin (two-by-two design). The trial was expanded to includeadditional study centers in 1988 and 1991, and all subjectswere randomly assigned in a 1:1 ratio to either active treatmentor placebo. The pilot groups receiving active agents were consolidatedin 1988 into a single group receiving a standard daily regimenof 30 mg of beta carotene plus 25,000 IU of retinol in the formof retinyl palmitate. Thus, in the pilot study with the cohortof smokers, three subjects were assigned to active treatmentfor every subject assigned to placebo; therefore, the ratesrather than numbers of end points must be compared between activeand placebo groups. The design14 called for active interventionuntil late 1997 (110,000 person-years), with reporting of resultsin 1998.
Eligibility, Recruitment, and Randomization
Workers exposed to asbestos were men 45 to 74 years of age inthe pilot study and 45 to 69 years of age in the later periodof recruitment. To be eligible for the study the subjects hadto have first been exposed to asbestos on the job 15 years beforerandomization, and either have had a chest x-ray film positivefor asbestos-related lung disease or have worked in specifiedhigh-risk trades — as plumbers and pipe fitters, steamfitters,shipyard boilermakers, nonshipyard boilermakers, shipyard electricians,ship scalers, insulators, plasterboard workers, or sheet-metalworkers — for 5 years. The asbestos pilot study had norequirements regarding smoking15; subsequently, subjects wererequired to be current smokers or to have smoked within theprevious 15 years. For the population of smokers, women andmen were recruited from health insurance rolls and managed-careorganizations if they were 50 to 69 years of age, had at least20 pack-years of cigarette smoking, and either were currentlysmoking or had quit smoking within the previous six years. Theparticipants agreed to limit their supplemental intake of vitaminA to less than 5500 IU per day and to take no supplemental betacarotene. A total of 4060 workers exposed to asbestos and 14,254heavy smokers (44 percent of whom were women) were randomized.We provided detailed information for informed consent at recruitmentand regularly thereafter, including a letter to each participantdescribing the results of the 1994 Alpha-Tocopherol, Beta CaroteneCancer Prevention Study (ATBC).10
Active agents and placebos were purchased from Hoffmann–LaRocheand formulated by Tishcon Corporation. Both formulations weregiven as capsules. Beta carotene beadlets were combined withretinyl palmitate in a single capsule and dispensed in bottles,which were weighed and their contents checked. We assessed thesubjects' compliance by weighing the returned bottles to estimatethe number of capsules remaining (in 85 percent of the assessments)or by relying on the subjects' own estimates (15 percent). Bloodwas collected annually from the original pilot participantsand every two years from the other participants.
Subjects who stopped receiving study vitamins for any reasonother than death were defined as inactive participants and werestill followed for end points and counted in the analyses.
Data Collection and Monitoring of Safety and End Points
Each year active participants visited a study center once andwere telephoned twice, at four-month intervals. Inactive participantswere telephoned semiannually. Over 97 percent of scheduled contactswere completed. As of December 15, 1995, ascertainment of vitalstatus was more than 98 percent complete.
Symptoms and signs and newly diagnosed medical conditions weremonitored closely by questionnaire at all contacts and in limitedphysical examinations during study-center visits; laboratoryvalues for liver function and serum analytes were monitoredannually in participants randomized in the pilot studies (foruse in adjusting estimates of relative risk with the case–cohortapproach).17 The 13 monitored symptoms were graded accordingto the CARET symptom-assessment scale.16 An independent safetyand end-points monitoring committee met semiannually to reviewin blinded fashion data coded according to intervention group.When the results of the ATBC Cancer Prevention trial10 becameavailable, the committee reviewed the results of the first interimanalysis and requested that the blinding be ended. Subsequently,the committee reviewed data unblinded.
Ascertainment and Evaluation of End Points
All initial reports of cancers and deaths from each study centerwere submitted to the coordinating center and entered into atracking system. Participants and all study staff members involvedin the ascertainment and evaluation of end points and assignmentof final diagnoses remained unaware of the participants' treatmentassignment throughout the trial. Clinical records and, for tumorsinvolving the lung, pathology specimens were obtained for independentreview by the end-points review committee, composed of two oncologists,two internists, and a pathologist. An end point was consideredconfirmed when the end-point review process was completed. ThroughDecember 15, 1995, a total of 2420 end points had been reported:1446 cancers (in 1353 participants) and 974 deaths. Of the initialreports of lung cancer for which the end-point–reviewprocess was completed, 90 percent were confirmed; most of theremainder were found to be metastases and recurrences.
Statistical Analysis
The primary analysis, based on the intention to treat, was designedto test for differences between treatment groups in the incidenceof lung cancer with a weighted log-rank statistic stratifiedaccording to the risk group (workers exposed to asbestos orheavy smokers), time of recruitment (pilot study or subsequentperiod), and study center (six centers).14 Parameter estimatesand the results of statistical tests were similar with and withoutthe weighting; we present here the unweighted results. Estimatesof relative risk and confidence intervals were obtained fromstratified Cox regression models with the same strata as thelog-rank statistics. The cumulative incidence of end pointswas plotted through 5 1/2 years of follow-up because of thesmall number of participants beyond that time and involved 354participants with new cases of lung cancer, 829 deaths, and67,449 person-years of follow-up. Follow-up for all participantsbegan at randomization.
The prespecified monitoring policy for stopping the trial earlybecause of a benefit or adverse effect of the study vitaminswas based on O'Brien–Fleming boundaries18 applied to theweighted number of confirmed lung-cancer end points, the primaryend point. The critical P values were those of 0.0006 or lowerfor the first interim analysis in 1994 and those of 0.007 orlower for the second interim analysis in 1995. Results are basedon active intervention through December 15, 1995, at which timethe 18,314 participants had accumulated 73,135 person-yearsof follow-up (mean, 4.0 years; median, 3.7).
Results
Characteristics of the Participants
The two randomized groups were well matched, with a high-riskprofile for lung cancer and cardiovascular disease in both thesmokers and the workers exposed to asbestos (Table 1). All smokerswere encouraged and assisted, if willing, to stop smoking, andall former smokers were encouraged to maintain that status.Among current smokers, there was a net smoking-cessation rateof 5 percent per year.
Table 1. Risk Factors among the Participants at Base Line.
Through December 15, 1995, 15 percent of the workers exposedto asbestos who were assigned to active treatment became inactiveparticipants, as compared with 14 percent of those assignedto placebo. The respective values in the group of heavy smokerswere 20 percent and 19 percent. Among the active participants,the mean rates of capsule consumption were 93 percent throughfive years of follow-up, with no significant differences betweentreatment groups. The percentage of participants who took non–study-relatedsupplemental beta carotene or vitamin A in doses of more than5500 IU per day was low (2 percent and 1 percent, respectively).After five years of study supplementation, the median serumbeta carotene concentration in the active-treatment group was2100 ng per milliliter, as compared with 170 ng per milliliterin the placebo group; serum retinol levels were about 10 percenthigher than those in the placebo group (P<0.01). Except forslight skin yellowing in some of those receiving beta carotene(0.3 percent had yellowing of grade 3 or higher on the CARETsymptom-assessment scale),16 there were no differences of clinicalimportance between groups in any of the 13 monitored symptomsand signs, in tests of liver function, or in newly diagnosedconditions.
Incidence of Lung Cancer
The incidence of lung cancer was the primary end point. ThroughDecember 15, 1995, 388 participants — 2 percent of thetotal — were reported to have new cases of lung cancer(5.4 per 1000 person-years). In the case of 286, the end pointswere confirmed, whereas in the case of 102, further review bythe end-points committee was pending. Among the 388, 254 haddied. Five participants had two primary lung cancers each. The388 participants represent 79 percent of the 490 participantsprojected in our statistical design to have lung cancer by theend of the intervention. The 73,135 person-years of follow-upaccrued correspond to 66 percent of the total of 110,000 person-yearsprojected.14
The active-treatment group had a relative risk of lung cancerof 1.28 (95 percent confidence interval, 1.04 to 1.57; P = 0.02),as compared with the placebo group (Table 2). This result includesrelative risks of 1.40 (95 percent confidence interval, 0.95to 2.07) for workers exposed to asbestos, 1.42 (95 percent confidenceinterval, 1.07 to 1.87) for heavy smokers who were smoking atthe time of randomization, and 0.80 (95 percent confidence interval,0.48 to 1.31) for heavy smokers who were no longer smoking atthe time of randomization. There was no statistical evidenceof heterogeneity of the relative risk among these subgroups.Figure 1 shows the cumulative incidence of lung cancer afterrandomization; the incidence in the active-treatment and placebogroups was virtually identical for the first 18 months. Therewas no statistically significant effect of the interventionon survival after the diagnosis of lung cancer (relative riskof survival after diagnosis of lung cancer in the active-treatmentgroup as compared with the placebo group, 1.05; 95 percent confidenceinterval, 0.80 to 1.37).
Figure 1. Kaplan–Meier Curves of the Cumulative Incidence of Lung Cancer among Participants Receiving Active Treatment and Those Receiving Placebo.
Data are shown only through 5 1/2 years of follow-up because of the small numbers of participants beyond that time.
Incidence of Other Cancers
Active treatment had no statistically significant effect onthe risk of mesothelioma. There were 23 cases: 14 in the active-treatmentgroup and 9 in the placebo group. The remaining 1030 new casesof cancer (including the 300 prostate cancers, the second mostcommon cancer in this population) were distributed nearly evenlybetween the two treatment groups.
Mortality Rates
As shown in Table 2 and Figure 2, the mortality rate was 17percent higher in the active-treatment group than in the placebogroup (P = 0.02). Among the population of heavy smokers, therelative risk was not significantly different between thosewho were smoking at the time of randomization and those whowere no longer smoking at that time (relative risk, 1.15 vs.1.06).
Figure 2. Kaplan–Meier Curves of the Cumulative Incidence of Death from All Causes and Confirmed Cardiovascular Causes among Participants Receiving Active Treatment and Those Receiving Placebo.
Data are shown only through 5 1/2 years of follow-up because of the small numbers of participants beyond that time.
Analysis according to the cause of death (confirmed causes only;n = 764) showed that in the active-treatment group, as comparedwith the placebo group, the relative risk of death from anycause was 1.18 (95 percent confidence interval, 1.02 to 1.37);of death from lung cancer, 1.46 (95 percent confidence interval,1.07 to 2.00); and of death from cardiovascular causes (codes390 to 459 and 798 of the International Classification of Diseases,9th Revision, Clinical Modification), 1.26 (95 percent confidenceinterval, 0.99 to 1.61). As shown in Figure 2, there was nosignificant difference between treatment groups in the incidenceof death from all causes during the first 24 months. A reviewof all causes of death revealed no additional statisticallysignificant differences between the treatment groups.
Discussion
CARET was initiated in 1983 to test the hypothesis that betacarotene and vitamin A, through complementary antioxidant anddifferentiation-promoting actions and possibly through immunologicprotective effects, could reduce the incidence of lung cancerin high-risk populations. The trial met high standards for accrual,efficiency, quality assurance, and ascertainment of end points.There have been no side effects attributable to the interventionregimen. The participants have shown a high level of commitmentto the trial.
The results of the trial are troubling. There was no supportfor a beneficial effect of beta carotene or vitamin A, in spiteof the large advantages inferred from observational epidemiologiccomparisons of extreme quintiles or quartiles of dietary intakeof fruits and vegetables or of dietary intake or serum levelsof beta carotene or vitamin A.19,20 With 73,135 person-yearsof follow-up, the active-treatment group had a 28 percent higherincidence of lung cancer than the placebo group, and the overallmortality rate and the rate of death from cardiovascular causeswere higher by 17 percent and 26 percent, respectively.
These results confirm and extend the unexpected results reportedfor beta carotene in the ATBC Cancer Prevention Study in Finland.10We cannot distinguish the effects of beta carotene from thoseof vitamin A, since the two agents were administered in combination,under the hypothesis that they might have a favorable effectthrough complementary molecular actions.9
The second interim analysis led our safety and end-points monitoringcommittee and steering committee to recognize the extremelylimited prospect of a favorable overall effect, as well as thepossibility of true adverse effects. The decision to stop theintervention was made by the steering committee on January 11,1996. It is possible that the excess mortality in the active-treatmentgroup may have vanished or become statistically insignificantwith completion of the intended intervention period plus severalyears of follow-up; such reversals of findings have occurredboth in the course of a single large, randomized trial21,22and in subsequent randomized trials of the same agent or classof agents.23,24,25 However, it was impossible to ignore theresults of the ATBC Cancer Prevention Study10 in deciding whetherto stop the active-intervention phase.
We have no explanation for the possible adverse associationsthat we have observed to date. There was no evidence of systemictoxicity in any organ from the vitamin A or, except for theexpected skin yellowing, the beta carotene. The regimen didnot produce clinically important hypertriglyceridemia.26 Weconsidered continuing the trial with the retinyl palmitate alone;however, the need to rerandomize, the extended follow-up required,and the uncertainty about the involvement of the vitamin A madethis plan infeasible.
In this trial, beta carotene treatment raised the median serumbeta carotene levels to 12 times the base-line levels and theplacebo group's median values. Such levels may conceivably betoxic or at least cause serious disequilibrium with other compoundsimportant to redox relations or other cellular mechanisms. Betacarotene has been postulated to have a pro-oxidant effect undercertain nonphysiologic conditions.27,28 One study reported thatthe administration of beta carotene drastically lowered vitaminE levels,29 but we30 and three other groups10,31,32 have foundno such effect. In preliminary analyses of serum beta carotenelevels during active treatment, we could find no support forthe hypothesis that subjects with the highest serum levels ofbeta carotene were at greater risk for lung cancer or deathfrom cardiovascular causes, cancer, or any cause.
The results of our study and the ATBC Cancer Prevention Study10in populations at high risk for lung cancer and cardiovasculardisease and the finding of the Physicians' Health Study11 ofno benefit or harm after 12 years of beta carotene treatmentclearly do not support the widely accepted conclusion drawnfrom observational epidemiologic studies that beta caroteneis a primary component responsible for the association of lowerrisks of cancer and death from cardiovascular causes with highintakes of fruits and vegetables.19,33 Such studies typicallycompare extreme subgroups for such dietary features, ignoringor only crudely adjusting for many other potentially relevantvariables, such as the intake of red meat, physical activity,life situations, and other behavior.20 The dietary associationsseemed well matched to serum beta carotene measurements; asin other observational analyses, in our study base-line serumbeta carotene levels were inversely correlated with the subsequentincidence of lung cancer in both groups. However, randomizedprevention trials are needed to test the hypothesis that increasedbeta carotene intake can be protective.
The results of four large-scale chemoprevention trials of betacarotene and related agents can be summarized. The ATBC CancerPrevention Study10 tested daily supplementation with 20 mg ofbeta carotene and 50 mg of alpha-tocopherol (two-by-two factorialdesign) in 29,133 male smokers. The Physicians' Health Study11tested supplementation with 50 mg of beta carotene on alternatedays in 22,071 male physicians, 50 percent of whom had neversmoked, 39 percent of whom were former smokers, and 11 percentof whom were currently smoking. We tested daily supplementationwith a combination of 30 mg of beta carotene and 25,000 IU ofretinyl palmitate. Finally, a study conducted in Linxian, China,34assessed the value of daily supplementation with a combinationof 15 mg of beta carotene, 50 µg of selenium, and 30 mgof alpha-tocopherol as compared with three other combinationsof vitamins and minerals in a complex factorial design in 29,584adults presumed to be vitamin- and mineral-deficient —a very different population from those examined in the otherstudies. In the ATBC Cancer Prevention Study, 876 new casesof lung cancer were diagnosed, yielding a relative risk of lungcancer of 1.18 among subjects who received beta carotene (withor without alpha-tocopherol), as compared with those who didnot. In the Physicians' Health Study, 170 new cases of lungcancer were diagnosed, for a relative risk of lung cancer of0.93 among men taking beta carotene, as compared with thosewho received placebo. In our study, there were 388 new casesof lung cancer, yielding a relative risk of such cancer of 1.28among the subjects who received beta carotene and retinyl palmitate,as compared with those who received placebo. The Linxian studydid not report the incidence of lung cancer. Among the subjectswho received beta carotene, the relative risk of death fromany cause was 1.08 in the ATBC Cancer Prevention Study (3570deaths), 1.01 in the Physicians' Health Study (1947 deaths),1.17 in our trial (974 deaths), and 0.91 in the Linxian study(2127 deaths).
Reversing or overcoming lifelong metabolic or exogenous riskfactors may require 5 to 10 years or more to account for thelatent periods of cancers. Favorable effects may be particularlydifficult to achieve in the face of a continuing carcinogenicand atherogenic assault in smokers; alternatively, antioxidantsand antiproliferative agents might act on the constituents ofcigarette smoke. Long-term follow-up both during and after activetreatment with potential chemopreventive agents is essentialif we are to have any hope of observing long-term benefits andevaluating long-term risks. During the postintervention follow-upof our study subjects, as end points continue to accrue, wewill conduct laboratory analyses and analyze various subgroups,particularly former smokers.
Our findings provide important new information with respectto public policy and public health. When these results are combinedwith those from the ATBC Cancer Prevention Study10 and the Physicians'Health Study,11 they make it clear that there can be littleenthusiasm about the efficacy or safety of supplemental betacarotene or vitamin A in efforts to reduce the burdens of canceror heart disease in certain populations. However, we still recommendthe dietary intake of fruits and vegetables.
Other agents that prevent lung cancer and coronary heart diseasemust be identified and subjected to rigorous trials of safetyand efficacy. Meanwhile, to reduce the risk of these diseaseswe must rely primarily on three approaches: smoking cessation,prevention of smoking, and avoidance of occupational and environmentalexposure to carcinogenic substances.
Supported by grants (U01 CA63673, U01 CA63674, U01 CA47989,U01 CA48200, U01 CA48203, U01 CA48196, and U01 CA52596) fromthe National Cancer Institute.
We are indebted to the study subjects, staff members, and investigators;to the members of the safety and end-points monitoring committeeover the past several years (Anthony Miller, Robert Bruce, JulieBuring, Frank Iber, and O. Dale Williams); and to our colleagueswho provided data from the Physicians' Health Study.
* Other contributing authors were Carl Andrew Brodkin, M.D. (Universityof Washington, Seattle), Martin G. Cherniack, M.D. (Yale University,New Haven, Conn.), James E. Grizzle, Ph.D. (Fred HutchinsonCancer Research Center, Seattle), Marjorie Perloff, M.D. (NationalCancer Institute, Bethesda, Md.), and Linda Rosenstock, M.D.,M.P.H. (University of Washington, Seattle).
Source Information
From the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle (G.S.O., G.E.G., M.D.T., S.B.); the Departments of Environmental Health and Medicine, University of Washington, Seattle (G.S.O., G.E.G., S.B., S.H.); the Swedish Hospital Tumor Institute, Seattle (G.E.G.); the Department of Medicine, University of California at San Francisco, San Francisco (J.B.); the Department of Medicine, Yale University, New Haven, Conn. (M.R.C.); Kaiser Permanente Center for Health Research, Portland, Oreg. (A.G., B.V.); the Department of Medicine, University of Maryland, Baltimore (J.P.K.); and the Department of Medicine and Cancer Center, University of California at Irvine, Orange (F.L.M., J.H.W.).
Address reprint requests to Dr. Omenn at the Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, 1124 Columbia–MP859, Seattle, WA 98104.
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Antioxidant Vitamins, Cancer, and Cardiovascular Disease
Doering W., Pietrzik K., DeGrand D., Krinsky N. I., Peacocke M., Russell R. M., Hennekens C. H., Buring J. E., Peto R., Omenn G. S., Kushi L. H., Mink P. J., Folsom A. R., Greenberg E. R., Sporn M. B.
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335:1065-1069, Oct 3, 1996.
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(2009). Cancer Prevention Research: Back to the Future. Cancer Prevention Research
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Kelly, K., Kittelson, J., Franklin, W. A., Kennedy, T. C., Klein, C. E., Keith, R. L., Dempsey, E. C., Lewis, M., Jackson, M. K., Hirsch, F. R., Bunn, P. A., Miller, Y. E.
(2009). A Randomized Phase II Chemoprevention Trial of 13-CIS Retinoic Acid with Or without {alpha} Tocopherol or Observation in Subjects at High Risk for Lung Cancer. Cancer Prevention Research
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(2009). Chemoprevention of Lung Cancer. Proc Am Thorac Soc
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Gaziano, J. M., Glynn, R. J., Christen, W. G., Kurth, T., Belanger, C., MacFadyen, J., Bubes, V., Manson, J. E., Sesso, H. D., Buring, J. E.
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