© The Author 2006. Published by Oxford University Press.
CORRESPONDENCE |
Re: Randomized Double-Blind Factorial Trial of Three Treatments to Reduce the Prevalence of Precancerous Gastric Lesions
Affiliations of authors: Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN (RM, MBP, MCC, PC); School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA (ETHF); Department of Pathology, Universidad del Valle, Cali, Colombia (LEB, JCB)
Correspondence to: Pelayo Correa, MD, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University, 2215 Garland Ave., 1030 MRB IV, Nashville, TN 37232-0252 (e-mail: pelayo.correa{at}vanderbilt.edu).
We congratulate You et al. (1) for the successful completion of their chemoprevention trial. Their results have clear implications for gastric cancer prevention. As emphasized by the authors, all available reports conclude that curing Helicobacter pylori infection is a promising strategy to control gastric cancer. Previously, we supplied the authors with raw data from our Colombian chemoprevention trial at 6 years of follow-up (2,3). Because our published conclusions, based on the same data, differed considerably from theirs (1), we would like to comment on the discrepant interpretations of our results.
Although an analysis based on main effects is customary for a factorial design, it assumes that there are no negative interactions among the interventions given (i.e., it assumes that all the interventions would have an effect in the same direction). Our analysis at 6 years showed that there was a statistically significant negative interaction between H. pylori treatment and beta-carotene supplementation. Basing the analysis on the main effects (1) in this case is not appropriate because some subjects who received H. pylori treatment showed improvement, but those who received H. pylori treatment and beta-carotene supplementation did worse than those on placebo. Only the full factorial analysis accomplished through polytomous and binary multivariate logistic regression models using data collected over time from the same individual demonstrates that after taking into account the negative effect of beta-carotene supplementation, patients who underwent anti–H. pylori therapy have statistically significant more regression of precancerous lesions than those on placebo.
In our 12-year follow-up report (4), because we had multiple biopsy samples and a wealth of longitudinal data, we took into account the duration of exposure to interventions and the time free of H. pylori infection and used the change in the score of gastric lesions in the same patient over time as the main outcome. Because we recognized the slowly progressing continuum of the gastric carcinogenesis process, we created a very detailed histopathology score to reflect the extent and severity of the classical global diagnostic categories of atrophy, intestinal metaplasia, and dysplasia. This approach allows an estimation of the effect of the duration of a preventive measure, such as the time of H. pylori–free status, independent of the time at which the anti–H. pylori therapy was received (baseline or 6 years). We submit that this type of analysis is the most sensitive and appropriate for chemoprevention trials such as ours, based on precancerous endpoints.
Finally, we believe that the results of our trial emphasize two important points. First, we found that curing the H. pylori infection and supplying antioxidants for 6 years are both protective interventions, but their effects are not additive. This finding strongly suggests that both interventions have a final common pathway: decreasing oxidative damage to the gastric epithelial cell. This finding also seems to indicate that the H. pylori exerts its carcinogenic influences via oxidative stress and suggests that other cancers, especially those in which inflammation plays an important role, may follow similar mechanisms. Second, the process of chemoprevention follows an exponential sigmoid curve, the reverse of the one observed in the lung carcinogenic process associated to cigarette smoking (5). Therefore, any intervention to prevent cancer may not yield statistically significant results during the first few years, in which the sigmoid curve is almost flat.
NOTES
Editor's note: You et al. declined an invitation to respond to this correspondence.
REFERENCES
(1) You WC, Brown LM, Zhang L, Li JY, Jin ML, Chang YS, et al. Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. J Natl Cancer Inst 2006;98:974–83.
(2) Correa P, Fontham ET, Bravo JC, Bravo LE, Ruiz B, Zarama G, et al. Re: chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy. J Natl Cancer Inst 2001;93:559–60.
(3) Correa P, Fontham ET, Bravo JC, Bravo LE, Ruiz B, Zarama G, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-Helicobacter pylori therapy. J Natl Cancer Inst 2000;92:1881–8.
(4) Mera R, Fontham ET, Bravo LE, Bravo JC, Piazuelo MB, Camargo MC, et al. Long term follow up of patients treated for Helicobacter pylori infection. Gut 2005;54:1536–40.
(5) Doll R, Peto R. Cigarette smoking and bronchial carcinoma: dose and time relationships among regular smokers and lifelong non-smokers. J Epidemiol Community Health 1978;32:303–13.
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