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A Randomized, Double Blind, Phase III Trial Using Oral ß-Carotene Supplementation for Women with High-Grade Cervical Intraepithelial Neoplasia¹

Division of Gynecologic Oncology [K. A. K., M. M.,W. B., M. L. B.] and Chao Family Comprehensive Cancer Center [K. A.K., M. J. S., C. B., M. M., W. B., J. A. C., G. S. R., D. S. M., W. L., H. A-C., F. L. M., M. L. B.], University of California, Irvine, Medical Center, Orange, California 92868; Epidemiology Division, Department of Medicine, University of California, Irvine, Irvine, California 92697 [W. B., H. A.-C.]; Division of Gynecologic Oncology, Women and Infant’s Hospital, Brown University, Providence, RI 02905 [K. A. K.]; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27514 [M. J. S.]; Division of Gynecologic Oncology, University of Illinois at Chicago, Peoria, Illinois [C. B.]; Division of Gynecologic Oncology, Bethesda Naval Hospital, San Diego, California 92134 [M. M.]; Division of Gynecologic Oncology, University of Kansas Medical Center, Kansas City, Kansas 66101 [J. A. C.]; Division of Gynecologic Oncology, Walter Reed Army Medical Center, Washington, DC 20012 [G. S. R.]; Division of Gynecologic Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73101 [S. S. M.]; Leon Levy Cancer Center, University of Arizona, Tucson, Arizona 85701 [Y-M. P.]; and City of Hope Medical Center, Duarte, California 91009 [S. P. W.]

To evaluate the effect of daily ß-carotene (30 mg) versus placebo over a 2-year period on cervical intraepithelial neoplasia (CIN) 2 and 3 lesions. Human papillomavirus (HPV) typing was done to determine whether lesion regression was related to HPV. Micronutrient levels were measured to determine whether levels were predictive of regression. Variables that influence the risk of HPV infection and CIN, such as cigarette smoking and sexual behavior, were evaluated. Women were randomized to ß-carotene or placebo, with cytology and colposcopy every 3 months. Cervical biopsies were performed before treatment and after 6 and 24 months to evaluate response. Persistence of or progression to CIN 3 resulted in removal from the study, whereas treatment continued for 2 years on all others. The presence and type of HPV was determined by PCR. Response was defined as an improvement in CIN by 2 grades. Mantel-Haenszel ² test was used to analyze response to treatment. Fisher’s exact test was used to determine the effect of HPV and CIN grade on response Wilcoxon’s rank-sum tests were used to compare micronutrient levels between groups. Twenty-one of 124 enrolled women were not randomized because they either moved, became pregnant, voluntarily withdrew, or the pathological review of their initial cervical biopsies did not confirm CIN 2 or 3. Of the remaining 103 women, 33 experienced lesion regression, 45 had persistent or progressive disease, and 25 women did not complete the study and were considered nonresponders in the final analysis. The overall regression rate (32%) was similar between treatment arms and when stratified for CIN grade. Data on 99 women with HPV typing showed that 77% were HPV-positive and 23% HPV-negative at enrollment. HPV-positive lesions were subdivided into indeterminate-, low-, and high-risk categories; the response rate was highest for women with no HPV detected (61%), lower for indeterminate/low-risk (30%), and lowest for high-risk (18%; P = .001). CIN regression was negatively correlated with retinol levels. In conclusion, ß-carotene does not enhance the regression of high-grade CIN, especially in HPV-positive subjects.

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