CARET was a randomized, double-blind, placebo-controlled trial of the cancer prevention efficacy and safety of a daily combination of 30 mg of ?-carotene and 25,000 IU of retinyl palmitate in 18,314 persons at high risk for lung cancer. We studied two high-risk populations: 4,060 men with extensive occupational exposure to asbestos, and 7,965 men and 6,289 women with at least 20 pack-years of cigarette smoking history. CARET began in 1985 with two pilot studies (Vanguard cohort) and expanded to six sites beginning in 1988 (Efficacy cohort). The design projected active intervention until 1997, encompassing 110,000 person-years of follow-up for the 18,314 randomized participants. The CARET intervention was halted in January 1996, 21 months ahead of schedule, with the twin conclusions for definitive evidence of no benefit and substantial evidence of a harmful effect of the intervention on both lung cancer incidence and total mortality. During the intervention phase of CARET, serum, plasma, whole blood, and lung tissue specimens were collected on participants. These biospecimens make up the CARET Biorepository. The overall results of CARET were presented at a special NCI press conference January 18, 1996, followed by a publication (NEJM 334:1150-5, 1996). Further details about lung cancer were published (JNCI 88:1550-9, 1996) soon after. Lung cancer incidence and cardiovascular disease mortality findings during the first six years of post-intervention follow-up were published in 2004 (JNCI 96:1743-50, 2004).
On June 30, 2005, CARET stopped active follow-up of participants. Passive follow-up to extend cancer and death outcomes through 2013 was conducted via linkages with select cancer registries and the National Death Index (NDI). CARET continues to support the extensive biological repository and ancillary studies that utilize the CARET samples and data.
Rationale for Study
Lung cancer is a highly lethal disease with an 80-90% mortality rate. In 2005, it was estimated that approximately 170,000 Americans would be diagnosed with lung cancer and 155,000 would die. In the United States, lung cancer is the most common cause of cancer death in men and women, exceeding the combined total for breast, prostate, and colon cancers. Lung cancer is also one of the few diseases with a well-defined etiology: inhalation of tobacco smoke. While tobacco use has become less common over the past 25 years, approximately 25% of the American public still currently use tobacco. Moreover, former smokers continue to be at elevated risk; and the majority of Americans who now develop lung cancer are former smokers. Thus, even if cigarette smoking could be eliminated as an environmental carcinogen, lung cancer would remain a problem for the foreseeable future.
Over the past 20 years there has been intense interest in cancer chemoprevention, the use of agents to prevent, arrest, or reverse the development of cancers. On the basis of epidemiological observations and in vivo animal studies, dietary micronutrients (including beta-carotene and vitamin A) were some of the first agents to attract wide interest as potential lung cancer prevention agents. The Beta-Carotene and Retinol Efficacy Trial (CARET) was one of several trials started in the early 1980s to assess the chemopreventive efficacy and safety of beta-carotene and vitamin A.
Study Design
Eligibility
Eligibility criteria for the two CARET exposure populations were as follows:
Asbestos-exposed participants (N = 4,060)
Men who, on entry to the study,
- were aged 45-69*
- were current smokers or quit within 15 years prior to enrollment*
- had their first exposure to asbestos on the job at least 15 years prior to enrollment
- had a chest X-ray positive for changes compatible with asbestos exposure according to International Labour Organization (ILO) criteria; or had been employed in a protocol-defined high-risk trade for at least 5 years, at least 10 years prior to enrollment
Heavy smoker participants (N = 14,254)
Men and women who, on entry to the study,
- were aged 50-69
- had a cigarette smoking history of 20 or more pack-years
- were current smokers or had quit within the previous 6 years
* For the asbestos pilot study there was no smoking eligibility requirement and the age criterion was 45-74 years. Among the asbestos-exposed participants enrolled during the pilot phase (N = 816), 16% were never smokers and 36% were former smokers who had quit more than 15 years prior to enrollment; 10% were between 70 and 74 years of age.
Recruitment
Six study centers performed participant recruitment under the direction of the Coordinating Center, located in Seattle, Washington. Study centers were located in Baltimore, Maryland; Irvine, California; Groton, Connecticut (referred to as the New Haven Study Center); Portland, Oregon; San Francisco, California; and Seattle, Washington. Recruitment began in 1985 in Seattle with two pilot studies (one for asbestos-exposed participants and the other for heavy smokers). Pilot recruitment ended in 1988, at which time the full-scale efficacy trial was initiated. Accrual was completed in September 1994. The Baltimore, New Haven, and San Francisco Study Centers recruited primarily asbestos-exposed participants. In August 1992, the CARET Steering Committee approved the recruitment at these three study centers of smoker-eligible spouses and other members of the asbestos-exposed participants' households who met the heavy smoker eligibility criteria for CARET. Seattle and Portland recruited a small number of asbestos-exposed participants, but their primary goals were for heavy smokers. Irvine recruited only heavy smokers. Participants randomized after July 1988 into CARET are referred to as the Efficacy cohort. The participants in the pilot studies were incorporated into CARET as the Vanguard cohort. The figure below shows the timing of adding study centers and their accrual goals (total accrual goal 17,510).
The initial contact with a potential participant was usually a mailing that included an introductory letter, an interest survey, and a study fact sheet. The interest survey included questions about the individual's age, sex, smoking status and smoking history, asbestos exposure, and potential interest in joining the study. The study center reviewed the returned interest surveys and screened out ineligibles. Study centers telephoned individuals who were not clearly ineligible. The purpose of the phone call was to review or clarify information on the interest survey, ask questions about the study exclusion criteria, and schedule an appointment for the First Visit for those who seemed to be eligible.
Intervention
Prior to randomization, interested and eligible participants were followed during a 3-month run-in period receiving placebo medication to determine their adherence to taking the study vitamins (as well as to establish their baseline levels of symptoms, signs, and liver function tests). Participants who took at least 50% of their placebo capsules were randomized to either active study vitamins or placebo.
The asbestos pilot study randomized participants to daily doses of either 1) 15 mg beta-carotene and 25,000 IU retinol or 2) placebos. The heavy smoker Pilot study consisted of four intervention arms: 1) 30 mg beta-carotene and 25,000 IU retinol; 2) 30 mg beta-carotene; 3) 25,000 IU retinol; and 4) placebos daily. In the full-scale trial, participants in both exposure populations were assigned to either 1) 30 mg beta-carotene and 25,000 IU retinyl palmitate or 2) placebos daily. Beginning in July 1988, pilot study participants were transitioned to the new protocol. As part of the full-scale trial, pilot study participants were referred to as the Vanguard cohort. The following figure shows the change in intervention arms for pilot study participants on the transition to the full-scale study.
As depicted in the figure, Vanguard participants who were on active arms during the pilot studies had their daily study vitamin dosage changed to 30 mg beta-carotene and 25,000 IU retinyl palmitate; those on placebos continued on placebos. Thus, heavy smoker Pilot participants have a 3:1 allocation to the CARET intervention arms. The form of vitamin A that participants received was changed from retinol to retinyl palmitate to allow the vitamin A and the beta-carotene to be administered in a single capsule.
Follow-Up
Throughout the intervention phase of the trial participants were followed with routine clinic visits and phone contacts. While the intervention was being administered, participants enrolled during the pilot phase were contacted more frequently than those enrolled during the full-scale trial. These Pilot/Vanguard participants were monitored more closely for indications of toxicity related to the study vitamins, because their longer time on study meant that any toxicity related to cumulative dose would have been most likely observed in them prior to those enrolled later in the larger (Efficacy) cohort.
The intervention was stopped in January 1996, and participants were invited to return to their study centers for a "transition" visit and final blood draw. For the remainder of active post-intervention follow-up (through 2005), participants were contacted annually by phone (1997-2000) or by mailed questionnaire (2000-2005). State cancer registry and National Death Index (NDI) linkages were conducted in 2015 to extend follow-up for endpoints. Death outcome information from the NDI linkage was complete through 2013; state cancer registry data were through 2012 for WA and CA, and through 2013 for CT.
Intervention phase, Pilot studies (1985 - 1988):
Visits Three times a year, four months after randomization and every four months thereafter
Phone contacts Three times a year, two months after randomization and every four months thereafter
Intervention phase, Pilot/Vanguard (1989 - 1995):
Visits Semiannually, on and six months after the anniversary dates of randomization to the pilot study
Phone contacts Semiannually, three and nine months after the anniversary dates of randomization to the pilot study
Intervention phase, Efficacy (1989 - 1995):
Visits Six months and 12 months after randomization, and annually thereafter on the anniversary dates of randomization
Phone contacts Three and nine months after randomization during the first year; and semiannually thereafter, four and eight months after the anniversary dates of randomization
Post-intervention, Transition phase (1996 - 1997):
Visits Once on the anniversary dates of randomization
Phone contacts Semiannually, four and eight months after the anniversary dates of randomization
Post-intervention, Phone Follow-up phase (1997 - 2000):
Phone contacts Annually on the anniversary dates of randomization
Post-intervention, Mail Follow-up phase (2000 - 2005):
Mailed questionnaire On the anniversary dates of randomization
Post-intervention, Passive Follow-up phase (2005 - 2013):
Registry linkages One-time linkage to the NDI and three state cancer registries: California Cancer Registry, Connecticut Tumor Registry, and Washington State Cancer Registry. Because of state regulatory restrictions, we were not able to access the cancer registries of Oregon or Maryland.
Data Collection
Cancer and death outcomes were captured on all participants throughout intervention and post-intervention phase follow-up. During the intervention phase of CARET, serum, plasma, whole blood, and lung tissue specimens were collected following a routine schedule. CARET collected extensive data that can be used in conjunction with the CARET Biorepository in studies of cancers and other diseases. Data collected included smoking history, medical conditions, family cancer history, dietary intake, occupational history of asbestos exposure, and demographics.
Primary Publications
- Omenn G, Goodman G, Thornquist M, Balmes J, Cullen M, Glass A, Keogh J, Meyskens F, Valanis B, Williams J, Barnhart S, Hammar S.
Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease.
(New England Journal of Medicine 334:1150-5, 1996) - Omenn G, Goodman G, Thornquist M, Balmes J, Cullen M, Glass A, Keogh J, Meyskens F, Valanis B, Williams J, Barnhart S, Cherniack M, Brodkin C, Hammar S.
Risk factors for lung cancer and for intervention effects in CARET, the beta-Carotene and Retinol Efficacy Trial.
(Journal of the National Cancer Institute 88:1550-9, 1996) - Goodman G, Thornquist M, Balmes J, Cullen M, Meyskens F, Omenn G, Valanis B, Williams J.
The beta-Carotene and Retinol Efficacy Trial: Incidence of Lung Cancer and Cardiovascular Disease Mortality During 6-Year Follow-up After Stopping Beta-Carotene and Retinol Supplements.
(Journal of the National Cancer Institute 96:1743-50, 2004)