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Epidemiology and Prevention |
Departments of Epidemiology [S. T. M., B. C., T. Z.], Surgery/Otolaryngology [C. F.], and Medicine/Medical Oncology [D. C.], Yale University School of Medicine, New Haven, Connecticut 06520; Departments of Otolaryngology [W. J. G.] and Psychiatry and Behavioral Science [M. B., G. S-P.], University of Miami, Miami, Florida 33136; St. Francis Hospital, Department of Hematology/Oncology, Hartford, Connecticut 06105 [B. G. F.]; University of Pennsylvania, Philadelphia, Pennsylvania 19104 [K. B.]; and Children’s Hospital and Medical Center, Cincinnati, Ohio 45229 [J. B.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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With advances in early detection, nearly one-half of these patients present early with stage I or II disease. Although treatment given at this stage is relatively successful, failure remains common, and is manifested primarily by local recurrences and second primary cancers, the latter of which generally occur in other sites within the head and neck, or in the esophagus or lung. The expected incidence of second primaries varies by site of the initial cancer (2, 3, 4) , and by current tobacco habits (5) , but a reasonable estimate is that 4% of stage I/II patients will develop second primary cancers yearly (6) . These second primary cancers are a consequence of field cancerization of the upper aerodigestive tract, usually associated with chronic exposure to tobacco and alcohol. Second cancers of the head and neck are the leading cause of death in patients diagnosed with early-stage head and neck cancers (7) . Prevention of second cancers is a model for chemoprevention of epithelial carcinogenesis and has great clinical relevance.
Several agents are known to induce regression of precancerous lesions of the oral cavity, particularly ß-carotene and various retinoids. As reviewed elsewhere (8) , at least three randomized and six nonrandomized trials of ß-carotene and seven of various retinoids have reported significant chemopreventive efficacy in oral precancerous lesions. Retinoids have also been evaluated as potential chemopreventive agents in head and neck cancer, with one trial reporting significant benefit with regard to second primary tumors (9) but two others reporting a lack of benefit (10 , 11) .
Because ß-carotene has been demonstrated to have efficacy in the regression of oral precancerous lesions and lacks the side effects typically seen with higher-dose retinoids, we initiated a trial to evaluate ß-carotene in the prevention of second head and neck cancers. The primary objective of this randomized, double-blinded, placebo-controlled trial was to determine whether supplemental ß-carotene (50 mg/day) reduces failure attributable to second primary tumors (head and neck, esophagus, and lung) and local recurrences in patients curatively treated for early-stage cancers of the head and neck. A secondary objective was to evaluate the effect of this intervention on overall mortality.
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SUBJECTS AND METHODS |
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TopABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Patients were recruited from two sites, one based at Yale University
that recruited from the entire state of Connecticut, and the second
based at the University of Miami that recruited from 14 hospitals in
south Florida. In Connecticut, patients were identified using the Yale
Cancer Center’s Rapid Case Ascertainment Shared Resource, which allows
for population-based identification of patients with newly diagnosed
malignancies. Patients were identified by reviewing pathology reports
at all 35 of the state’s general acute care hospitals and surveying
the Connecticut Tumor Registry on a regular basis. Connecticut
participates in the National Cancer Institute SEER (Surveillance,
Epidemiology and End Results) Program.
IRB3
approval was obtained from all of the 49 hospitals from which
patients were recruited.
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Protocol and Treatment Assignment.
The patient’s physician was contacted to determine eligibility and to
obtain physician consent prior to contacting potential participants.
Participants were approached for participation by letter and then by
phone; those who agreed were subsequently visited by a trained nurse-
or physician-interviewer/phlebotomist (usually in the participant’s
home), who obtained signed consent prior to proceeding. Participants
were enrolled in a 1-month placebo run-in period. Patients who
were able to complete the run-in protocol (consumed >75% of the
capsules and did not drop out) were randomized to receive either
supplemental ß-carotene (50 mg/day, Lurotin; BASF, Wyandotte, MI) or
a corresponding identical placebo. Study medications were blister
packed (one capsule per day) into monthly calendar packs to facilitate
compliance with the intervention. A stratified randomization was used,
with patients stratified on the basis of tumor site (oral cavity
versus pharynx versus larynx) and smoking history
(<25 pack-years versus 
25 pack-years). The randomization
list was prepared by the study biostatistician (J. B.) using
random permuted blocks with a block size of four within each stratum,
and an allocation ratio of 1:1. The Yale and University of Miami
Research Pharmacies administered the randomization list, and all of the
study personnel remained blinded to the treatment allocation throughout
the trial.
Visits were made to subjects’ homes by nurse- or physician-interviewer/phlebotomists at the following time points: -1 month (baseline, start of run-in), time 0 (randomization, post-run-in), 3 months, 12 months, and annually thereafter. New calendar packs (up to 6-month supply) were given at these time points; used calendar packs were retrieved to estimate compliance (pill counts). In between these visits, calendar packs were mailed to the participant by the research pharmacies, and participants were sent prepaid return mailers to facilitate the return of used calendar packs.
Patients were contacted every 3 months by phone or visit. Patients who stopped taking the capsules were contacted every 6 months. Information on second cancers was obtained in several ways. Patients were asked to report any possible second cancers, and pathology reports were obtained from the diagnosing institution. Because both Connecticut and south Florida are covered by population-based tumor registries (Connecticut Tumor Registry, Florida Cancer Data System), searches were made of the registries to identify any newly diagnosed malignancies. Death certificates were obtained for deceased participants, and coded by a trained nosologist.
End Point Review.
All of the suspected clinical end points were evaluated by an End Point
Review Committee comprised of three study physicians. Briefly, an end
point review packet that included pathology reports for the first and
second cancers for each subject with a suspected end point was assigned
to a study physician. That study physician then contacted the
patient’s primary physician to seek additional clinical information,
which was documented in the patient’s end point review packet. That
same study physician then categorized clinical end points into local
recurrences, new primary tumors in the field of prevention (head and
neck, esophagus, lung), other incident cancers, regional recurrences,
or metastases. A second study physician was then given the end point
review packet and classified the end point without knowledge of the
first reviewer’s classification. If the two agreed, the end point was
accepted. End point review meetings involving all three of the study
physicians were convened to discuss end points when there was
disagreement. Tumors were considered to be second primaries if they
occurred >2 cm away from the site of the initial tumor in a patient
treated by irradiation, >2 cm away from the suture line in a patient
treated by surgery, or >5 years after diagnosis of the first primary
tumor. This definition is used clinically but is thought to misclassify
some new primary tumors as local recurrences. Patients classified as
having curatively treated local recurrences were allowed to continue on
the supplement and were followed for second primary tumors; patients
with any other end point were taken off the supplement but were
followed for the duration of the trial.
Other Data Collection.
All of the subjects were asked to report potential side effects at the
end of the run-in and at the end of each 3-month interval, using
standard toxicity grading scales. Dose-reduction procedures were in
place for patients with perceived side effects.
Approximately 20 ml of venous blood was obtained in heparinized vacuum
tubes at each of the visits. After centrifugation, plasma was
aliquotted and stored at -70°C pending analysis. Samples from Miami
were shipped in batches to the Yale Micronutrient Analysis laboratory
for analysis. Plasma ß-carotene, carotenoids, retinol, and
-tocopherol were analyzed by reverse-phase high-performance liquid
chromatography as described previously (14)
. Laboratory
technicians were blinded to treatment assignment. Formal quality
control procedures were in place, including use of internal standards,
external standards, plasma pools, and participation in the
micronutrient measurement proficiency testing program of the National
Institute of Standards and Technology. Non-laboratory study personnel
did not have access to the plasma ß-carotene concentration data from
the laboratory, to maintain the blinding.
Patients with newly diagnosed head and neck cancers may temporarily quit smoking at the time of diagnosis. Thus, for these analyses, baseline smoking status is defined as the smoking status immediately prior to the diagnosis of the first cancer. Smoking status was updated annually thereafter for use as a time-dependent covariate in the analysis.
Monitoring.
Recruitment for the trial was initiated in late 1990, with the first
patients randomized at the Connecticut site in early 1991 and at the
Florida site in 1993. In 1994, the ATBC trial, which was a two-by-two
factorial trial of -tocopherol and ß-carotene in the primary
prevention of lung cancer in smokers, reported a significant excess of
lung cancer in ß-carotene-supplemented smokers (15)
. The
external data and safety monitoring committee for our trial was
convened, and recommended continuation of this trial. All of the
participants were notified in writing of the ATBC results immediately
prior to public release of the results. In January 1996, investigators
from CARET, a clinical trial of ß-carotene plus retinyl palmitate in
patients at high risk for lung cancer, announced that CARET was being
terminated early because of an excess of lung cancer in the
intervention group, with the results published in May of 1996
(16)
. As before, all of the participants in our trial were
notified in writing of the CARET results immediately prior to public
release; patients who continued to take capsules were reconsented. The
external data and safety monitoring committee for our trial was again
convened and was given unblinded end point data from this trial, along
with unblinded confidential end point data for head and neck cancers
provided generously by the three other major ß-carotene trials
[ATBC, CARET, and the Physicians’ Health Study (17)
].
Our monitoring committee recommended unanimously that the trial be
continued in all of the participants including smokers. However,
recruitment of new subjects to the protocol was terminated in January
1996 by the investigators because of concerns about the feasibility of
recruiting additional subjects. Thus, recruitment was closed prior to
reaching the target sample size. A conditional power analysis was
conducted to explore the likely gain from extending the duration of
intervention and follow-up in the trial. This analysis indicated that
it would not be cost-effective to extend intervention beyond the
planned ending date of June 30, 1998.
Statistical Analysis.
All of the analyses were performed with SAS (SAS Institute, Cary, NC),
using an intention-to-treat analysis. Differences between the two
groups in selected demographic characteristics were evaluated using
Student’s t test or 
2 analyses as
appropriate. Survival curves were generated according to the method of
Kaplan and Meier, and the log-rank test was used to compare
survival distributions between the two groups. All of the Ps
were two-tailed. Cox proportional hazards models were used to calculate
the RR of having an end point in the ß-carotene group relative to
those taking placebo, adjusted for other covariates. Several covariates
were examined, including several indices of tobacco exposure, plasma
ß-carotene levels at baseline, gender, and age. Two time-dependent
variables were also incorporated into the models: annual smoking status
during the period the subject was active in the trial, and annual mean
compliance based on the pill counts. Interaction terms were used in the
model to assess whether the treatment effect varied according to
smoking status and compliance level. The interaction between age and
treatment assignment was also investigated, although the mean age in
each treatment arm was essentially the same.
The primary end point of the trial was the combined end point of local recurrence and second primary cancers of the head and neck, esophagus, and lung. The combined end point was selected a priori because of diagnostic difficulties in discriminating second primary tumors from local recurrences. Secondary end points included the following: local recurrence; second primary cancers in the field of prevention (head and neck, esophagus, lung); and local recurrence plus second primary cancers in the head and neck. In addition, all-cause mortality was a prespecified secondary end point. Lung cancer was added as an additional end point of interest after the release of the results of CARET and ATBC. For patients with multiple primary tumors, the date of diagnosis of the first primary tumor after randomization was used in the survival analysis.
The Cox proportional hazards model was fitted two ways: no weighting and linear down-weighting for events occurring in the first 12 months after randomization. The results were essentially unchanged; therefore, we present the results based on the nonweighted analysis. Of the patients who were randomized, 6 were later identified as protocol violators: 4 were found to have had a previous head and neck cancer within the past 5 years and 2 were found to have had stage III cancer at the time of randomization. All of the analyses were run with and without protocol violators. The results were not altered; therefore, we present the results based on the full population of 264 randomized subjects.
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RESULTS |
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The flow of the 694 eligible patients is shown in Fig. 1
. A total of
264 patients were randomized. The characteristics of the 264 randomized
patients are shown in Table 1
. The two treatment groups were well balanced with no significant
differences in any known prognostic factors.
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-tocopherol in
this population has been reported previously (14)
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Supplementation with ß-carotene produced a persistent 9- to
10-fold increase in median plasma ß-carotene concentrations and a
persistent 2-fold increase in median plasma -carotene concentrations
[small quantities of -carotene were detected in the supplement
(14)
]. Plasma ß-carotene concentrations were stable
over the multiyear intervention in the placebo group. This intervention
did not alter concentrations of lycopene, lutein/zeaxanthin, retinol,
or -tocopherol. A total of nine patients (five randomized to ß-carotene and four to placebo) reported having grade 2 or higher toxicity for one or more of the following symptoms: depression, headache, bone pain, cheilitis, dry skin, and diarrhea. The frequency of reporting of each of these side effects was similar in the two groups. As was expected, skin yellowing was reported more frequently in patients randomized to ß-carotene as compared with placebo, with 25 (18%) of 135 in the ß-carotene group reporting skin yellowing on at least one occasion as compared with 8 (6%) of 129 participants in the placebo group.
End points by treatment arm, and adjusted RR estimates are shown in
Table 3
. None of the differences between the two groups were statistically
significantly different, although the ß-carotene supplemented group
had reduced risks for all of the end points with the exception of lung
cancers (RR, 1.44; 95% CI, 0.62–3.39). Because lung was the most
common site for second primary tumors, this resulted in an overall
increased risk of total second primary tumors (RR, 1.20; 95% CI,
0.59–2.45). The relatively low number of second primary tumors in the
head and neck region is partially a result of diagnostic
misclassification, in that some tumors classified as local recurrences
were most likely new primary tumors. However, it is difficult to
differentiate local recurrences from new primary tumors in the head and
neck region in the absence of a detailed molecular analysis.
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Total mortality was nonsignificantly decreased by 14% with ßcarotene supplementation, primarily because of fewer cardiovascular disease end points in the ß-carotene supplemented group. Patients randomized to ß-carotene also were significantly (P = 0.01) older at their time of death compared with patients randomized to placebo (mean, 69.7 years versus 64.4 years; corresponding medians are 70.4 years in the ß-carotene group and 66.3 years in the placebo group).
The survival curves for the primary end point and for total mortality,
the end points with the greatest number of events, are shown in Figs. 2
and 3
. Supplemental ß-carotene had no significant effect on time to failure
for the primary end point (Fig. 2, P
= 0.59,
log-rank test) or time to death (Fig. 3, P
= 0.41, log-rank test). Further stratification of the mortality
distribution by tobacco use at the time of diagnosis is shown in Fig. 4
, and the log-rank test revealed significant differences in the survival
distributions (P = 0.03). The cumulative
probability of survival for both smokers and nonsmokers was
nonsignificantly better for those in the ß-carotene group. In a model
that included variables for age, treatment arm, and smoking status as
predictors of mortality, the interaction of age with treatment arm was
statistically significant (P = 0.02). None of
the other Ps from the log-rank tests for the other end
points were statistically significant.
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DISCUSSION |
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A trial aimed at the primary prevention of oral cancer would have required tens of thousands of randomized patients; however, recruitment of patients with a prior malignancy provided a cost-effective alternative for evaluating efficacy. This is a consequence of the substantial risk that these patients face in terms of the development of second cancers. Also, efficacy in this patient setting would have direct clinical relevance, leading to our decision to evaluate this agent in secondary prevention.
Chemoprevention trials generally require several years to complete recruitment, followed by several years of intervention and follow-up. During this process, results of other trials may become available that impact the conduct of ongoing trials. In our case, results of two primary prevention trials of lung cancer were released (15 , 16) , indicating that supplemental ß-carotene, alone or in combination with retinyl palmitate, could increase rather than reduce the risk of lung cancer. At the same time, a third report suggested no benefit and a slight worsening of abnormal sputum cytology in asbestos-workers supplemented with ß-carotene plus retinol (21) .
The safety of the participants enrolled in this trial was of utmost concern; therefore, all of the patients were informed of the findings, as were all of the hospital IRBs. The data and safety monitoring committee for this trial reviewed all of the pertinent results, as described previously. Continuation of the trial was recommended, largely because of the observation that the participants randomized to ß-carotene were doing better, not worse. At the time of the interim analysis in June 1996, the rate ratio comparing the rate of incident events in the ß-carotene group versus the placebo group was 0.81 for the primary end point, 0.65 for local recurrence, and 0.61 for mortality. The rate ratio for lung cancer at that time was 1.29. Recruitment was terminated because of feasibility concerns because all of the interim data were confidential and could not be shared with either patients or hospital IRBs. Many patients stopped supplementation after the release of the CARET results, so that additional follow-up would add very little in terms of study power, considering the number of participants who had already experienced an end point in addition to those who had stopped supplementation.
The results, although not significant, were in the direction hypothesized with regard to head and neck cancers (RR, 0.69), and all of the point estimates for head and neck cancers throughout the interim and final analyses were consistently beneath 1.0. However, the CIs (0.39–1.25) surrounding this estimate do not exclude the possibility of a null or even adverse effect on head and neck cancers. Despite the small sample size as compared with primary prevention trials, our results are consistent with other findings suggesting that supplemental ß-carotene increased the risk of lung cancer, although the CIs around this estimate are also wide (0.62–3.39). In support of possible differential site-specific effects are data from intermediate end point biological marker trials, in which ß-carotene regresses oral precancerous lesions (8) but has no effect on, or slightly worsens, sputum cytology (21) , a putative intermediate end point for lung cancer. Retinoids, structurally related to carotenoids and ß-carotene, similarly have been shown to have efficacy in trials of oral precancerous lesions but not in trials using intermediate end points for lung cancer [e.g., bronchial metaplasia (8) ]. Animal data also support site-specific effects: ß-carotene was effective in preventing buccal pouch carcinogenesis in hamsters in about 20 studies (19) ; it was ineffective in only one study when also given after tumor development. In contrast, ß-carotene was ineffective in three studies in respiratory tract carcinogenesis in hamsters and two studies of lung carcinogenesis in mice, and there were indications of weak promotional effects in some of these studies (19) . The mechanistic basis for why ß-carotene is effective in oral precancerous lesions/hamster buccal pouch carcinogenesis but not in intermediate end points for lung cancer/animal models of respiratory tract/lung carcinogenesis is not known.
The possibility that a chemopreventive agent might have differential site-specific effects is not new; tamoxifen, e.g., is known to reduce the risk of breast cancer while increasing the risk of endometrial cancer (22) . In such a situation, it is imperative to consider the effects of the agent on total mortality. In this patient population, persons randomized to ß-carotene had a mortality advantage at the two interim analyses and in the final analysis. Also, both mean and median age at death significantly favored persons randomized to ß-carotene as compared with persons on placebo.
The strength of this study lies in the fact that, to our knowledge, this trial is the only randomized, double-blind, placebo-controlled trial of ß-carotene in head and neck cancer prevention. Italian investigators randomized 211 patients with early-stage head and neck cancer to ß-carotene [75 mg/day for 3-month cycles with 1-month intercycle intervals) versus follow-up (23) ]. The final results of that trial have not yet been reported; we anxiously await a final report from that trial to see if these findings are replicated. A meta-analysis of the data from the two trials may help to rectify the lack of statistical power found in each of the individual trials. Also, an examination of incident oral, pharyngeal, and laryngeal cancers in persons in ATBC and in the Physicians’ Health Study, the two other major trials that used ß-carotene as a single agent, might also provide insight into the plausibility of a possible reduction in head and neck cancers but not lung cancers with supplemental ß-carotene.
Another strength of this trial is that we successfully randomized 38% of eligible patients in these two regions into a multiyear trial, increasing the generalizability of the results. In comparison, only about 3% of adults with cancer are enrolled in therapeutic trials (24) .
Although this is the only randomized, placebo-controlled trial of ß-carotene in this patient population, this trial also had some important limitations, particularly the compromised sample size and study power after reports of adverse effects on lung cancer and no overall benefit to ß-carotene in other major trials. Seventy-six participants stopped taking study medication in early 1996; however, many of these persons had already been on supplement for several years. Furthermore, ß-carotene is lipid-soluble, and blood levels of ß-carotene remain significantly elevated above baseline even at 12 months after ceasing supplementation.4,5
Considering our overall results along with the results of other clinical trials involving ß-carotene, reviewed elsewhere (8) , we cannot recommend supplemental ß-carotene for the prevention of second head and neck cancers. Although there were some suggestions of benefit, these were not statistically significant and should be considered against the increasingly consistent and statistically significant findings from other trials of an increased risk of lung cancer with supplemental ß-carotene; in CARET, increased risk was particularly noted for large-cell carcinomas but was also observed for squamous cell carcinomas and adenocarcinomas (25) . The suggested benefit that we observed in head and neck cancer is consistent with intermediate end point trials of ß-carotene, and with animal carcinogenesis studies. This finding, if confirmed in ongoing/completed trials or in a meta-analysis using data from our trial combined with the Italian trial (23) , could be the basis for mechanistic studies addressing differential responses in one epithelial site (head and neck) versus another (lung).
In the meantime, the search for other more efficacious agents for the prevention of these cancers continues. A large, intergroup trial is investigating the efficacy of low-dose 13-cis-retinoic acid in this clinical setting (26) . Results of that trial are anticipated in the next few years. Pending results of that study, efforts to encourage tobacco cessation in patients who have been cured of an early-stage head and neck cancer should be intensified, given our findings that continuing tobacco exposure adversely affects the risk of all-cause mortality.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Grants R01 CA 42101 and CA
64567 from the U. S. National Cancer Institute. 
2 To whom requests for reprints should be
addressed, at Yale University School of Medicine and Yale Cancer
Center, Department of Epidemiology and Public Health, 60 College
Street, P. O. Box 208034, New Haven, CT 06520-8034. Phone: (203)
785-6274; Fax: (203) 785-6980; E-mail: Susan.Mayne{at}Yale.Edu
3 The abbreviations used are: IRB, institutional
review board; ICD, International Classification of Disease; ATBC,
-Tocopherol and ß-Carotene (trial); CARET, Carotene and Retinol
Efficacy Trial; RR, relative risk; CI, confidence interval.
4 Unpublished data from CARET.
5 Dr. Carrie Redlich, personal communication.
Received 8/ 7/00. Accepted 12/27/00.
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REFERENCES |
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