The New England Journal of Medicine
e-mail icon  FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |    Advanced Search
Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe
 
A correction has been published: N Engl J Med 1994;331(25):1720.

Original Article
Volume 331:141-147 July 21, 1994 Number 3
NextNext

A Clinical Trial of Antioxidant Vitamins to Prevent Colorectal Adenoma
E. Robert Greenberg, John A. Baron, Tor D. Tosteson, Daniel H. Freeman, Gerald J. Beck, John H. Bond, Thomas A. Colacchio, John A. Coller, Harold D. Frankl, Robert W. Haile, Jack S. Mandel, David W. Nierenberg, Richard Rothstein, Dale C. Snover, Marguerite M. Stevens, Robert W. Summers, Rosalind U. van Stolk, for The Polyp Prevention Study Group

 

This Article
-Abstract

Commentary
-Letters
-Letters

Tools and Services
-Add to Personal Archive
-Add to Citation Manager
-Notify a Friend
-E-mail When Cited

More Information
-Related Article
by Burke, H. B.
-PubMed Citation
ABSTRACT

Background People who consume a diet high in vegetables and fruits have a lower risk of cancer of the large bowel. Antioxidant vitamins, which are present in vegetables and fruits, have been associated with a diminished risk of cancers at various anatomical sites. We conducted a randomized, controlled clinical trial to test the efficacy of beta carotene and vitamins C and E in preventing colorectal adenoma, a precursor of invasive cancer.

Methods We randomly assigned 864 patients, using a two-by-two factorial design, to four treatment groups, which received placebo, beta carotene (25 mg daily), vitamin C (1 g daily) and vitamin E (400 mg daily), or beta carotene plus vitamins C and E. In order to identify new adenomas, we performed complete colonoscopic examinations in the patients one year and four years after they entered the study. The primary end points for analyses were new adenomas identified after the first of these two follow-up examinations.

Results Patients adhered well to the prescribed regimen, and 751 completed the four-year clinical trial. There was no evidence that either beta carotene or vitamins C and E reduced the incidence of adenomas; the relative risk for beta carotene was 1.01 (95 percent confidence interval, 0.85 to 1.20); for vitamins C and E, it was 1.08 (95 percent confidence interval, 0.91 to 1.29). Neither treatment appeared to be effective in any subgroup of patients or in the prevention of any subtype of polyp defined by size or location.

Conclusions The lack of efficacy of these vitamins argues against the use of supplemental beta carotene and vitamins C and E to prevent colorectal cancer. Although our data do not prove definitively that these antioxidants have no anticancer effect, other dietary factors may make more important contributions to the reduction in the risk of cancer associated with a diet high in vegetables and fruits.

Although the causes of colorectal cancer are incompletely understood, dietary factors appear to be important1,2,3. Rates of colorectal cancer are lowest in populations whose diets typically are rich in vegetables and fruits1. In studies of individual subjects, high levels of consumption of vegetables and fruits are consistently associated with lower risk of colorectal cancer4,5. One explanation for these findings is that people who eat more vegetables avoid possible carcinogens in meats and fats6. Another is that vegetables and fruits contain anticarcinogens that block the development of colorectal tumors.

Many compounds in vegetables and fruits prevent cancer in experiments with animals7. The antioxidant vitamins, particularly vitamin C (ascorbic acid), vitamin E (tocopherols), and beta carotene, appear especially promising as candidates for preventing cancer in humans8,9. Their toxicity is minimal, and they have been linked to a lower risk of colorectal cancer in most studies that have examined dietary intake (for all three substances) or serum levels (for beta carotene and vitamin E)4,8,10,11,12,13,14.

Four reported clinical trials have tested the ability of antioxidant vitamins to prevent colorectal adenomas, which are neoplastic precursors of invasive cancer15,16; the results have been inconsistent17,18,19,20. However, each of these investigations involved relatively few patients and had incomplete assessment of adenomas, the primary study end points. In 1984, we began a large clinical trial of the effects of beta carotene and the combination of vitamin C and vitamin E on the recurrence of colorectal adenomas. In this report we describe our findings regarding the efficacy of these substances.

Methods

The Polyp Prevention Study involved six clinical centers whose staff reviewed colonoscopy reports and pathology logs to identify patients who had at least one histologically confirmed adenoma removed from the large bowel between December 1984 and June 1988. To be eligible, patients must have had an adenoma diagnosed within the previous three months; must have undergone colonoscopy with the entire large bowel seen and judged to be free of further polyps; must have been in good health; and must have been less than 80 years old. We excluded patients with familial polyposis, a history of invasive colorectal cancer, malabsorption syndromes, or any conditions (such as a history of renal calculi or thrombophlebitis) that might be worsened by dietary supplementation with vitamin C or E.

We reviewed data on 2029 potentially eligible patients. We were unable to contact 152, and 891 were unwilling to participate or were found to be ineligible when interviewed. Five patients did not enroll for unknown reasons. The remaining 981 patients provided informed consent, which included agreeing not to take supplemental vitamin C or E or beta carotene outside the study. Each began a three-month placebo run-in period to assess adherence to the study regimen. After three months, 864 patients had taken at least 80 percent of their prescribed capsules and pills and wished to continue to participate.

We randomly assigned these patients to treatment groups, with blocking according to study center only, using a two-by-two factorial design21. The two active treatments were 25 mg of beta carotene daily and the combination of 1 g of vitamin C and 400 mg of vitamin E (d-alpha tocopherol) per day. Thus, the four treatment groups received placebo only, beta carotene plus placebo, vitamins C and E plus placebo, or beta carotene plus vitamins C and E. The dosages were selected because they met or exceeded the levels of intake at which benefit was indicated in epidemiologic studies and because we were concerned about the possibility of symptomatic side effects at higher doses. We provided the study agents in the form of soft gelatin capsules (containing placebo, beta carotene alone, vitamin E alone, or beta carotene plus vitamin E) and tablets (containing placebo or vitamin C) packaged in calendar packs, with each day's blister containing one capsule and one pill. Treatment assignments were not revealed to the patients, their doctors, or the study investigators before the end of the trial.

The study protocol called for two follow-up colonoscopic examinations, the first approximately 1 year after the colonoscopy that qualified the patient for study (year 1), and the second 36 months after the first (year 4). Endoscopy at other times was discouraged but could be performed if there was a change in the patient's clinical condition (for example, rectal bleeding) or if the patient's doctor required the procedure for particularly close surveillance. A colonoscopy was considered to be satisfactory for study purposes if the cecum was reached, the entire mucosa was seen, and all polyps were removed. At each colonoscopy, the endoscopist recorded the size and location of all raised mucosal lesions. These were excised, and microscopical slides were sent for review to the study pathologist for classification as neoplastic (adenoma) or non-neoplastic (hyperplastic polyp, lymphoid follicle, or another type of lesion).

At enrollment and at the time of the two colonoscopic examinations scheduled during follow-up, we obtained a specimen of venous blood for measurement of beta carotene and alpha-tocopherol by high-performance liquid chromatographic assay22,23. We did not measure vitamin C because blood levels are not a reliable indicator of intake in persons using oral supplements24. All assays in the laboratory were performed by personnel who had no knowledge of the patients' treatment assignments, and the results of individual assays were not given to clinical-center staff.

At enrollment and at the end of the study, we assessed patients' diets by means of a standardized food-frequency questionnaire25. Every six months we asked patients about their adherence to the prescribed regimen and about symptoms, illnesses, and hospitalizations. We also asked about their use of vitamin supplements containing beta carotene, vitamin C, or vitamin E, in addition to the study agents.

The primary study end point was the occurrence of new adenomas between the colonoscopic examinations conducted at year 1 and year 4. For two reasons, we decided at the start of the study that adenomas diagnosed during or before the colonoscopy at year 1 should not be counted as end points for the primary analysis. First, some adenomas found at year 1 may have been present, but not seen and removed, at the colonoscopy performed before study entry26. Second, because of the time necessary to identify and recruit patients and the three-month run-in period before randomization, patients did not begin to take the active study agents until three to six months after the removal of the adenoma that qualified them for the trial. Thus, the findings at the year 1 colonoscopy may in part have reflected the presence of preexisting adenomas and the growth of new adenomas during the period before randomization, thus diluting any real effect of the intervention.

Our principal hypotheses concerned the separate effects of the two treatments (beta carotene and the combination of vitamins C and E) on the proportion of patients in whom at least one new adenoma developed between the colonoscopic examinations at year 1 and year 4. For all analyses, adenomas found during endoscopic examinations conducted outside the protocol after the year 1 colonoscopy were counted together with those found at year 4. We used log-linear regression for binary data27 to produce unadjusted and adjusted estimates and confidence intervals for the relative risk (risk ratio) of adenoma associated with these two treatments. The length of time between the year 1 and year 4 examinations was included as a covariate in the adjusted analyses. We also tested for possible interactions between the two treatments.

In a secondary analysis, we assessed whether treatment was related to the number of adenomas occurring per patient, using a log-linear quasi-likelihood model for overdispersed Poisson count data, since the estimated variance was more than twice that expected with Poisson data27. We compared treatments according to the size of the largest adenoma in each patient, using the Kruskal-Wallis test28. We also used longitudinal models for binary data to examine the effects of treatment at year 1 and year 4 simultaneously29.

Results

Of the 864 patients who were randomly assigned to the four treatment groups, 751 (87 percent) underwent both follow-up colonoscopic examinations. Of the 113 patients who did not complete the study, and thus were not counted in the main outcome analyses, 44 died, 32 no longer wished to participate, 19 could not be examined because they were too ill or had moved, and 18 had unknown reasons for dropping out. The treatment assignments of these 113 patients were as follows: placebo, 27; beta carotene, 33; vitamins C and E, 20; and beta carotene plus vitamins C and E, 33. The remaining 751 patients provided data for the primary analyses of efficacy, and all subsequent data in this report (except for the results of the longitudinal analysis) pertain only to them. Their mean (±SD) age was 61 ±8.3 years; 79 percent were men, and 44 percent had only one adenoma removed from the large bowel before entering the study. The four groups were similar in their demographic characteristics and history of colorectal adenoma (Table 1).

View this table:
[in this window]
[in a new window]
  		Table 1. Demographic and Clinical Characteristics at Entry of the 751 Patients Who Completed the Study.

 
Patients in the four treatment groups differed little in the diets they reported when they entered the study (Table 2). The usual dietary consumption of beta carotene, vitamin C, and vitamin E was only a fraction of the amount later provided in the interventional supplements. At the completion of the study, the reported dietary intake of these vitamins had increased, but only slightly, in each of the patient groups (Table 2). Fat consumption and caloric consumption did not change appreciably (data not shown).

View this table:
[in this window]
[in a new window]
  		Table 2. Dietary Intake at Entry and at Year 4 among the 751 Patients Who Completed the Study.

 
The proportion of patients who reported taking the study agents declined gradually over time (Table 3). Nevertheless, even during their fourth year of the study, 82 percent of all patients reported taking the study agents at least six days per week, and a further 5 percent took them three to five days per week. Only five patients stopped taking the medications because of their presumed toxicity: none in the placebo group, one in the beta carotene group, and two in each of the other treatment groups. The use of supplements containing vitamin C, vitamin E, or beta carotene was reported by 108 patients (14 percent), and this proportion did not differ significantly among the treatment groups (P = 0.65).

View this table:
[in this window]
[in a new window]
  		Table 3. Adherence to Therapy, According to Treatment Group, in Each Year of the Study.

 
Serum beta carotene levels more than doubled after one year among patients in the beta carotene group and the beta carotene-vitamin C and E group; these elevations persisted to the end of year 4 (Table 4). In contrast, serum beta carotene levels remained essentially unchanged in the placebo group and the vitamin C and E group. Serum alpha-tocopherol levels increased approximately 40 percent among the patients in the groups given vitamins C and E or beta carotene plus vitamins C and E; these levels were relatively constant in the groups given placebo or beta carotene alone (Table 4).

View this table:
[in this window]
[in a new window]
  		Table 4. Serum Levels of Beta Carotene and Alpha-Tocopherol at Base Line, Year 1, and Year 4, According to Treatment Group.

 
The mean length of follow-up between the colonoscopic examinations at year 1 and year 4 was 36.8 months in the placebo group, 36.8 months in the beta carotene group, 36.6 months in the vitamin C and E group, and 36.3 months in the beta carotene-vitamin C and E group. The colonoscopic examination at year 4 was deemed completely satisfactory in all but 37 (5 percent) of the 751 patients. The reasons for an incomplete examination were as follows: cecum not reached, 7 patients; not all polyps removed, 19; and multiple difficulties related to incomplete cleansing of the colon, 11. Colonoscopy or sigmoidoscopy was performed between the year 1 and year 4 colonoscopic examinations in 140 of the patients (19 percent); the proportion having such an examination did not differ significantly among the four treatment groups (P = 0.18).

At the year 1 colonoscopy, at least one colorectal adenoma was removed from 245 of the 751 patients (33 percent). Between the year 1 and year 4 examinations (including the year 4 result), at least one adenoma developed in 279 patients (37 percent) (Table 5). The proportions of patients who had an adenoma did not differ significantly between the two groups prescribed beta carotene and those not prescribed beta carotene (37 percent vs. 38 percent; P = 0.84). There also were no statistically significant differences in the proportion of patients with adenoma between the groups prescribed vitamins C and E and those not prescribed these vitamins (38 percent vs. 36 percent; P = 0.56).

View this table:
[in this window]
[in a new window]
  		Table 5. Number of Colorectal Adenomas and Size of the Largest Adenoma Detected after Colonoscopy at Year 1, According to Treatment Group.

 
There were no material differences among the treatment groups with regard to the number of adenomas (Table 5) or the median size of the largest adenoma (P = 0.90 by the Kruskal-Wallis test). Between the examinations at year 1 and year 4, two patients were given a diagnosis of adenoma showing carcinoma in situ: one in the group given vitamins C and E, and one in the group given beta carotene plus vitamins C and E.

In the statistical models of treatment effect, there was no statistically significant or biologically meaningful interaction between treatment with beta carotene and treatment with vitamins C and E. Therefore, we report only the main effects of these treatments from our models. In the relative-risk model there was no evidence of a protective effect of either beta carotene or vitamins C and E (Table 6). Adjustment for age, sex, number of prior adenomas, length of follow-up, and study center did not materially alter these results.

View this table:
[in this window]
[in a new window]
  		Table 6. Relative Risk (RR) of the Development of at Least One Adenoma after Colonoscopy at Year 1, According to Treatment.

 
We examined treatment effects in subgroups of patients, using a multivariate model to adjust for the possible confounding effects of age, sex, number of prior adenomas, study center, and actual length of time between the year 1 and year 4 colonoscopic examinations. We found no reduction in risk of adenoma associated with either beta carotene or vitamins C and E in any subgroup defined by sex, age, or number of prior adenomas (Table 7). Moreover, among the 25 percent of patients with serum beta carotene levels below 102 µg per liter at study entry, there was no reduction in the risk of adenoma associated with subsequent beta carotene treatment (relative risk, 1.18; 95 percent confidence interval, 0.88 to 1.57). Likewise, in the 25 percent of patients with an initial serum alpha-tocopherol level of 10.0 mg per liter or less, supplementation with vitamins C and E was not associated with a clear reduction in the risk of adenoma (relative risk, 0.84; 95 percent confidence interval, 0.57 to 1.25). There was also no evidence of benefit of treatment among the 25 percent of patients with the lowest dietary intake of beta carotene, vitamin C, or vitamin E, as reported at enrollment (data not shown).

View this table:
[in this window]
[in a new window]
  		Table 7. Relative Risk (RR) Associated with Supplementation in Subgroups of Patients Defined by Their Characteristics at Enrollment.

 
At least one adenoma with a diameter of 0.5 cm or greater was found in 103 patients. The relative risk for these larger tumors was 0.92 (95 percent confidence interval, 0.64 to 1.31) for beta carotene treatment and 0.99 (95 percent confidence interval, 0.69 to 1.42) for vitamin C and E treatment. One or more adenomas developed in the left colorectum (at or distal to the splenic flexure) in 161 patients; the relative risks for these tumors were 1.16 (95 percent confidence interval, 0.88 to 1.52) for patients treated with beta carotene and 0.88 (95 percent confidence interval, 0.67 to 1.15) for those treated with vitamins C and E. At least one adenoma occurred in the right colon (proximal to the splenic flexure) in 172 patients; the relative risk was 0.97 (95 percent confidence interval, 0.74 to 1.26) for beta carotene treatment and 1.35 (95 percent confidence interval, 1.04 to 1.77) for treatment with vitamins C and E.

In the model analyzing the number of adenomas per patient, the ratio of the observed to the expected number was 0.98 (95 percent confidence interval, 0.73 to 1.30) for beta carotene treatment and 1.06 (95 percent confidence interval, 0.89 to 1.41) for treatment with vitamins C and E. These results were essentially unaltered in models in which we adjusted for covariates. In the longitudinal analysis in which adenomas detected both up to and after the year 1 examination were simultaneously considered as end points (assuming equal treatment effects for year 1 and year 4), the relative risk associated with beta carotene treatment was 1.04 (95 percent confidence interval, 0.90 to 1.21) and that associated with treatment with vitamins C and E was 0.94 (95 percent confidence interval, 0.81 to 1.08).

Discussion

Treatment for four years with either beta carotene or vitamins C and E did not affect the rate of occurrence of new adenomas in patients who had had an adenoma removed before entering the study. There was no evidence of effectiveness overall, among subgroups of the study population, or for subtypes of adenoma. Patients adhered well to therapy. Though some were lost to follow-up because they died or because data on colonoscopy procedures were lacking, the vast majority had complete examinations that were performed according to the protocol. Therefore, it is unlikely that our results were materially affected by bias in assessing the end point. The small increase in the risk of right colonic adenomas among patients receiving vitamins C and E was unexpected and is plausibly due to chance, given the null findings for total adenomas and the numerous subgroups examined. The high proportion of male participants is comparable to that in other trials of patients with adenoma30 and is partly attributable to the participation of Veterans Affairs hospitals at three of the clinical sites.

The four previously published studies of antioxidants and colorectal neoplasia also dealt with adenomas rather than invasive cancer. In patients with familial polyposis, supplemental vitamin C appeared to decrease the number of polyps in the rectal stump in one study,17 but a subsequent trial found no effect when vitamins C and E were given together to a similar group of patients18. Both studies included relatively few subjects (19 and 58, respectively), and accurate assessment of the number of adenomas was probably difficult because these patients had numerous unresected polyps.

A Canadian study of patients with sporadic adenomas found no effect of supplemental vitamins C and E on the rate of recurrence of adenomas over a two-year period among 143 patients randomly assigned to vitamins or placebo19. However, a trial in Italy showed a statistically significant reduction in the incidence of adenomas in 70 patients randomly assigned to receive supplemental vitamins A, C, and E, as compared with 78 patients who received no treatment20. In both of these studies the relatively small number of patients made the estimates of treatment efficacy imprecise. Also, in both studies a substantial fraction of randomly assigned patients did not undergo follow-up endoscopy, and the length of follow-up appeared to be highly variable for the others. We cannot readily explain the difference between our results and those of the small study from Italy20. The latter used preformed vitamin A (retinol), whereas we used beta carotene, a precursor of retinol. Since blood levels of retinol do not increase appreciably after supplementation, except in patients with vitamin A deficiency,31 it is not clear why retinol would be effective.

Relatively few epidemiologic studies have specifically examined diet and the risk of adenoma. The results of some suggest a protective effect of the consumption of vegetables and fruits,32,33,34,35,36 but others found no such effect37,38,39. Interpretation of these studies is difficult because most involved relatively few cases and because the possibility of bias in case detection cannot be ruled out.

The lack of benefit of antioxidants in our study appears to conflict with the reduced risk suggested by epidemiologic investigations of invasive cancers of the colon and rectum. It is possible that these studies have detected an effect that occurs only after adenomas develop -- an issue we could not address. Indeed, most of the adenomas detected in our patients were small, less than 0.5 cm in diameter, and only a small fraction of these would ever progress to cancer if untreated40,41. Nevertheless, any adenoma that becomes an invasive cancer must once have been small, so effectively suppressing small adenomas might well prevent cancer also.

There are at least two other plausible explanations for the discrepancy between our results and those of epidemiologic studies of vitamin consumption and the risk of colorectal cancer. One is that dietary levels of antioxidant vitamins simply reflect the consumption of fruits and vegetables, which in turn contain other substances that reduce the risk of colorectal cancer. Supporting this notion are findings that fiber34 or folate,35 rather than beta carotene or vitamins C and E, better explains the lower risk of adenoma associated with the consumption of vegetables and fruits. A second possibility is that antioxidants must be consumed at high levels for many years to inhibit neoplasia. To correspond with prevailing practice for the surveillance of patients with adenoma, our intervention lasted four years, so only a relatively rapid effect on the incidence of tumors could possibly have been seen. Arguing against a long latency, however, is the report that supplementation with vitamins A, C, and E rapidly reduces abnormalities of cell proliferation in the rectal mucosa of patients previously treated for adenoma42. Hyperproliferation is implicated as the immediate precursor of adenoma formation in some models of colorectal carcinogenesis,43,44 so a prompt reduction in the recurrence of adenoma could have been expected.

Antioxidant supplements have failed to reduce the incidence of tumors in two other large clinical trials45,46. Although lower mortality due to cancer and other causes was found after supplementation with beta carotene, alpha-tocopherol, and selenium in a trial in China,47 the benefit occurred very early and may indicate improved general health rather than averted cancer among the marginally nourished population studied. Some longer-term trials have not been completed, but current data do not support the use of antioxidant vitamin supplements for purposes of cancer prevention. Other dietary factors should be considered as explanations for the reduced risk of cancer associated with eating vegetables and fruits.

Supported in part by grants (CA37287 and CA23108) from the National Institutes of Health.

We are indebted to the many patients and their physicians whose cooperation made this study possible and to the study coordinators at the clinical sites and the data-processing, pharmacy, and laboratory staff at the coordinating center for their tireless efforts throughout the course of this investigation.


Source Information

From Dartmouth-Hitchcock Medical Center and the Norris Cotton Cancer Center, Lebanon, N.H. (E.R.G., J.A.B., T.D.T., D.H.F., T.A.C., D.W.N., R.R., M.M.S.); the Cleveland Clinic Foundation, Cleveland (G.J.B., R.U.S.); the University of Minnesota, Minneapolis (J.H.B., J.S.M., D.C.S.); the Lahey Clinic, Burlington, Mass. (J.A.C.); Kaiser Permanente Medical Center-Sunset, Los Angeles (H.D.F.); UCLA, Los Angeles (R.W.H.); and the University of Iowa, Iowa City (R.W.S.). The members of the Polyp Prevention Study Group are listed in the Appendix.

Address reprint requests to Dr. Greenberg at Dartmouth Medical School, Hanover, NH 03755-3861.

References

  1. Boyle P, Zaridze DG, Smans M. Descriptive epidemiology of colorectal cancer. Int J Cancer 1985;36:9-18. [Medline]
  2. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. Oxford, England: Oxford University Press, 1981.
  3. Willett W. The search for the causes of breast and colon cancer. Nature 1989;338:389-394. [CrossRef][Medline]
  4. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 1991;2:325-357. [CrossRef][Medline]
  5. Block G, Patterson B, Subar A. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer 1992;18:1-29. [Medline]
  6. Willett WC, Stampfer MJ, Colditz GA, Rosner BA, Speizer FE. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 1990;323:1664-1672. [Abstract]
  7. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control 1991;2:427-442. [CrossRef][Medline]
  8. Byers T, Perry G. Dietary carotenes, vitamin C, and vitamin E as protective antioxidants in human cancers. Annu Rev Nutr 1992;12:139-159. [CrossRef][Medline]
  9. Block G. Micronutrients and cancer: time for action? J Natl Cancer Inst 1993;85:846-848. [Free Full Text]
  10. Block G. Vitamin C and cancer prevention: the epidemiologic evidence. Am J Clin Nutr 1991;53:Suppl:270S-282S. [Free Full Text]
  11. Bostick RM, Potter JD, McKenzie DR, et al. Reduced risk of colon cancer with high intake of vitamin E: the Iowa Women's Health Study. Cancer Res 1993;53:4230-4237. [Free Full Text]
  12. Knekt P. Role of vitamin E in the prophylaxis of cancer. Ann Med 1991;23:3-12. [Medline]
  13. Longnecker MP, Martin-Moreno J-M, Knekt P, et al. Serum alpha-tocopherol concentration in relation to subsequent colorectal cancer: pooled data from five cohorts. J Natl Cancer Inst 1992;84:430-435. [Free Full Text]
  14. van Poppel G. Carotenoids and cancer: an update with emphasis on human intervention studies. Eur J Cancer 1993;29:1335-1344. [CrossRef]
  15. Morson BC, Bussey HJR, Day DW, Hill MJ. Adenomas of large bowel. Cancer Surv 1983;2:451-477. 
  16. Powell SM, Zilz N, Beazer-Barclay Y, et al. APC mutations occur early during colorectal tumorigenesis. Nature 1992;359:235-237. [CrossRef][Medline]
  17. Bussey HJ, DeCosse JJ, Deschner EE, et al. A randomized trial of ascorbic acid in polyposis coli. Cancer 1982;50:1434-1439. [CrossRef][Medline]
  18. DeCosse JJ, Miller HH, Lesser ML. Effect of wheat fiber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis. J Natl Cancer Inst 1989;81:1290-1297. [Free Full Text]
  19. McKeown-Eyssen G, Holloway C, Jazmaji V, Bright-See E, Dion P, Bruce WR. A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps. Cancer Res 1988;48:4701-4705. [Free Full Text]
  20. Roncucci L, Di Donato P, Carati L, et al. Antioxidant vitamins or lactulose for the prevention of the recurrence of colorectal adenomas. Dis Colon Rectum 1993;36:227-234. [CrossRef][Medline]
  21. Byar DP, Piantadosi S. Factorial designs for randomized clinical trials. Cancer Treat Rep 1985;69:1055-1063. [Medline]
  22. Nierenberg DW. Serum and plasma beta-carotene levels measured with an improved method of high-performance liquid chromatography. J Chromatogr 1985;339:273-284. [Medline]
  23. Nierenberg DW, Lester DC. Determination of vitamins A and E in serum and plasma using a simplified clarification method and high-performance liquid chromatography. J Chromatogr 1985;345:275-284. [Medline]
  24. Sinha R, Block G, Taylor PR. Determinants of plasma ascorbic acid in a healthy male population. Cancer Epidemiol Biomarkers Prev 1992;1:297-302. [Free Full Text]
  25. Block G, Hartman AM, Dresser CM, Carroll MD, Gannon J, Gardner L. A data-based approach to diet questionnaire design and testing. Am J Epidemiol 1986;124:453-469. [Free Full Text]
  26. Hixson LJ, Fennerty MB, Sampliner RE, McGee D, Garewal H. Prospective study of the frequency and size distribution of polyps missed by colonoscopy. J Natl Cancer Inst 1990;82:1769-1772. [Free Full Text]
  27. McCullagh P, Nelder JA. Generalized linear models. 2nd ed. London: Chapman & Hall, 1989.
  28. Conover WJ. Practical nonparametric statistics. 2nd ed. New York: John Wiley, 1980.
  29. Liang K-Y, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13-22. [Free Full Text]
  30. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993;329:1877-1881. 
  31. Willett WC, Stampfer MJ, Underwood BA, Taylor JO, Hennekens CH. Vitamins A, E, and carotene: effects of supplementation on their plasma levels. Am J Clin Nutr 1983;38:559-566. [Free Full Text]
  32. Hoff G, Moen IE, Trygg K, et al. Epidemiology of polyps in the rectum and sigmoid colon: evaluation of nutritional factors. Scand J Gastroenterol 1986;21:199-204. [Medline]
  33. Kato I, Tominaga S, Matsuura A, Yoshii Y, Shirai M, Kobayashi S. A comparative case-control study of colorectal cancer and adenoma. Jpn J Cancer Res 1990;81:1101-1108. [CrossRef][Medline]
  34. Giovannucci E, Stampfer MJ, Colditz G, Rimm EB, Willett WC. Relationship of diet to risk of colorectal adenoma in men. J Natl Cancer Inst 1992;84:91-98. [Free Full Text]
  35. Giovannucci E, Stampfer MJ, Colditz GA, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;85:875-884. [Free Full Text]
  36. Sandler RS, Lyles CM, Peipins LA, McAuliffe CA, Woosley JT, Kupper LL. Diet and risk of colorectal adenomas: macronutrients, cholesterol, and fiber. J Natl Cancer Inst 1993;85:884-891. [Free Full Text]
  37. Kono S, Imanishi K, Shinchi K, Yanai F. Relationship of diet to small and large adenomas of the sigmoid colon. Jpn J Cancer Res 1993;84:13-19. [Medline]
  38. Macquart-Moulin G, Riboli E, Cornee J, Kaaks R, Berthezene P. Colorectal polyps and diet: a case-control study in Marseilles. Int J Cancer 1987;40:179-188. [Medline]
  39. Little J, Logan RFA, Hawtin PG, Hardcastle JD, Turner ID. Colorectal adenomas and diet: a case-control study of subjects participating in the Nottingham faecal occult blood screening programme. Br J Cancer 1993;67:177-184. [Medline]
  40. Hoff G, Foerster A, Vatn MH, Sauar J, Larsen S. Epidemiology of polyps in the rectum and colon: recovery and evaluation of unresected polyps 2 years after detection. Scand J Gastroenterol 1986;21:853-862. [Medline]
  41. Winawer SJ, Shike M. Dietary factors in colorectal cancer and their possible effects on earlier stages of hyperproliferation and adenoma formation. J Natl Cancer Inst 1992;84:74-75. [Free Full Text]
  42. Paganelli GM, Biasco G, Brandi G, et al. Effect of vitamin A, C, and E supplementation on rectal cell proliferation in patients with colorectal adenomas. J Natl Cancer Inst 1992;84:47-51. [Free Full Text]
  43. Lipkin M. Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects. Cancer Res 1988;48:235-245. [Free Full Text]
  44. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-767. [CrossRef][Medline]
  45. Greenberg ER, Baron JA, Stukel TA, et al. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. N Engl J Med 1990;323:789-795. [Erratum, N Engl J Med 1991;325:1324.] [Abstract]
  46. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-1035. [Free Full Text]
  47. Blot WJ, Li J-Y, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993;85:1483-1492. [Free Full Text]
Appendix

In addition to the authors, the Polyp Prevention Study Group investigators were as follows: L. Pearson and L.A. Mott, Dartmouth-Hitchcock Medical Center; D. Howell, Maine Medical Center, Portland; J. Church, Cleveland Clinic Foundation; and S. Shirazi and N.S. Dusdieker, University of Iowa, Iowa City. The clinical coordinators were C. Robinson and K. Seaver at Dartmouth-Hitchcock Medical Center, Maine Medical Center, and the Lahey Clinic; B. Cheyne at the University of Iowa; P. Harmon at UCLA and Kaiser-Sunset; J. Rex and H. Hasson at the Cleveland Clinic; and S. Wolgamot at the University of Minnesota. The members of the Safety and Data Monitoring Committee were S.H. Greenhouse, J.E. Grizzle, R.H. Hunt, G.D. Luk, and R.S. Sandler.


 

This Article
-Abstract

Commentary
-Letters
-Letters

Tools and Services
-Add to Personal Archive
-Add to Citation Manager
-Notify a Friend
-E-mail When Cited

More Information
-Related Article
by Burke, H. B.
-PubMed Citation

Related Letters:

Antioxidant Vitamins and Colorectal Adenoma
Burke H. B., Ponz de Leon M., Roncucci L., Wroth T. H., Greenberg E. R., Baron J. A., Tosteson T. D.
Extract | Full Text  
N Engl J Med 1994; 331:1720-1721, Dec 22, 1994. Correspondence

Aspirin and the Risk of Colorectal Cancer in Women
Johnson K. A., Prindiville S. A., Morgan G., Roychowdhury D. F., van Bodegraven A.A., Lourens J., Sindram J.W., Kaufmann H. J., Schuler M., Giovannucci E., Speizer F. E., Egan K., Marcus A. J.
Extract | Full Text  
N Engl J Med 1996; 334:119-122, Jan 11, 1996. Correspondence

This article has been cited by other articles:


HOME  |  SUBSCRIBE  |  SEARCH  |  CURRENT ISSUE  |  PAST ISSUES  |  COLLECTIONS  |  PRIVACY  |  HELP  |  beta.nejm.org

Comments and questions? Please contact us.

The New England Journal of Medicine is owned, published, and copyrighted © 2008 Massachusetts Medical Society. All rights reserved.