Nutrients and Cervical Cancer Prevention
Nutrients and Cervical Cancer Prevention
August 2000; Volume 2; 57-60
By Charlea T. Massion, MD
The pap test is sometimes labeled "the best cancer test we have," since early detection and treatment of lesser dysplasias are very effective in the prevention of invasive cervical cancer. However, anyone who practices women’s health is well acquainted with the efforts and exasperations involved in monitoring abnormal Pap tests, handling minor degrees of dysplasia, and following up on abnormal colposcopies (just the time required to explain to patients that "an abnormal Pap is not cancer but does need follow-up" probably takes millions of hours of nurse and physician time annually). Relatively simple interventions, such as dietary supplements, that could improve the spontaneous regression rates of cervical dysplasias would have widespread individual and public health benefits. Unfortunately, several promising leads identified in epidemiological studies have not yet yielded any noteworthy role for nutritional supplements (except for retinoic acid applied directly to the cervix in treatment of cervical dysplasia). However, the groundwork research discussed in this article may eventually lead to nutritional regimens that will be effective alternatives to vaporizing, freezing, or burning the cervix.
In the United States, where Pap tests are widely available, about 2.5 million women are diagnosed annually with low-grade cervical abnormalities; and each year 15,800 women develop and 4,900 die of invasive cervical cancer. Globally, cervical cancer is the second most common cancer among women; in less-developed countries it is the most frequent neoplasm diagnosed in women. Worldwide in 1996, about 525,000 new cases of cervical cancer were diagnosed.
Although invasive cervical cancer develops from cervical dysplasia, milder dysplasias have a high rate of spontaneous regression. For example, cervical intraepithelial neoplasia (CIN) I, a mild degree of dysplasia, has about a 60% spontaneous regression rate. However, with CIN II and CIN III (moderate to severe dysplasias), only 38% spontaneously normalize and 16-36% will progress to invasive cervical cancer.1
Research indicates that sexually-acquired human papillomavirus (HPV), especially types 16, 18, 31 and 33, is the primary risk factor for cervical cancer. HPV DNA is present in > 90% of cervical cancers, and women who have persistent oncogenic-type HPV infections are at significantly greater risk of developing CIN lesions than those only transiently infected. In vivo studies show that after HPV is integrated into host DNA, specific oncogenes must be activated for dysplasias to occur. However, since only 28% of women who have HPV infections develop CIN at all, other factors must be essential in oncogenesis.2
The association between cervical cancer risk and various dietary components has been studied, but much of this research is problematic. Many studies were done before HPV testing was available or refined, and few studies controlled for confounders such as smoking and oral contraceptive (OCP) use. In women who have adequate nutritional intake, smoking decreases plasma levels of beta-carotene, folate, and vitamin C; and OCP use decreases beta-carotene, ascorbate, and red blood cell folate. Studies that do not control for these factors are seriously compromised. Despite these limitations, many studies of dietary intake and cervical cancer risk have been published. Most have shown definite inverse associations between risk for CIN and cervical cancer and dietary intake of dark green and yellow vegetables, beta-carotene, and vitamins C and E. There have not been consistent associations between serum retinol and CIN risk; however, serum retinol levels do decrease with increasing stages of invasive cervical cancer.3
More recent prospective studies have incorporated questions on diet and multiple measurements of HPV status and cervical cytology. One study showed that HPV persistence and CIN (both markers of cervical cancer risk) are related to levels of certain nutrients.4
Although observational studies indicate a link between dietary factors and relative risk of CIN and cervical cancer, interventional studies have been inconsistent. Several factors make this research especially difficult: Differences in diet or use of vitamin and mineral supplements between groups can confound results, and unlike drugs, most vitamins and micronutrients have not undergone phase I and II trials to clarify optimal doses before phase III trials are initiated.4 Despite these limitations, phase III studies have been done on folic acid, beta-carotene, vitamin C, and topical retinoic acid. This research is summarized here.
Folic Acid
Laboratory studies have indicated a role for folate, found in high amounts in green leafy vegetables, in cancer prevention. Folate is essential in the synthesis of purine nucleotides and thymidilate bases. Low tissue folate levels decrease DNA repair and increase the fragile sites on DNA, the risk of DNA attack by carcinogens and viruses, and chromosomal damage and oncogene expression. The degree of DNA hypomethylation in cervical tissue has been associated with CIN severity.
Yet, despite all this hopeful cell-level science, the results of the first two folic acid cervical cancer prevention studies do not show any significant effect of folic acid on rates of CIN regression or progression. The study designs were different, and both folate doses used are much higher than the 180 mcg RDA for reproductive age women.
In the Butterworth trial, 235 women diagnosed with mild to severe CIN by colposcopy were randomized to folate (10 mg) or control (10 mg vitamin C) daily for six months.5 The treatment and control groups were comparable in all cervical cancer risk factors except number of sexual partners. Most (71%) participants had CIN I. At two-month intervals, Pap tests, colposcopy, and blood tests were done. On the first and final visits, tests for HPV 16 were done, and at the final visit, a punch biopsy was done to determine the histologic grade of the final lesion. Approximately 85% of the participants completed the study, and serum folate levels in the treatment group increased significantly. However, at six months there were no significant differences between the groups; half of each group had normal Pap tests and two-thirds had normal cervical biopsies.
In the Childers trial, 331 participants with CIN I, CIN II, or histologically-confirmed koliocytic atypia (KA), were randomized to folate (5 mg qd) or placebo for six months.6 After a one-month run-in period, cervical cytology and colposcopy were repeated, and at this evaluation, 45% of the participants had no detectable lesion. However, all continued in the study. At three and six months, Pap tests, colposcopy, and serum folate were tested, but no HPV analysis was done. Seventy-nine percent of all participants completed the study, and the treatment group had significantly increased serum folate levels. At six months, 6% of the placebo group and 7% of the folate group had lesions that had improved (i.e., either resolved or had regressed to a milder dysplasia).
Neither study supports the use of folate for regression of cervical dysplasia. However, since both trials enrolled primarily patients with CIN I, which often resolves spontaneously, and the treatment periods were relatively short, they do not exclude a role for folate in more severe dysplasia.
Beta-Carotene
Much research has shown inverse relationships between beta-carotene, other carotenoids, or total dietary carotenoids, and invasive cervical cancer risk. Recent studies have indicated inverse associations between serum carotenoids, and CIN and invasive cervical cancer risk, as well as rates of HPV persistence. Beta-carotene may have anticarcinogenic properties independent of its provitamin A role, e.g., quenching singlet oxygen, inhibition of lipid peroxidation, modulation of immune response, and inhibition of viral gene expression.7
Again, despite these dietary promises, the first two phase III beta-carotene studies have not shown significant effects on cervical dysplasia regression. A multicenter study in the Netherlands randomized 333 women with CIN I, II, or III to placebo or beta-carotene (10 mg/d) for three months, after which Pap tests, colposcopies, and, for some, biopsies were obtained.8 HPV analysis was not done. Groups were comparable for cervical cancer risks, but the placebo group had a slightly higher dietary intake of beta-carotene. Eighty-three percent of the participants completed the study. By three months, 32% of both groups’ lesions had regressed to normal. Differences in CIN regression or progression showed no association with treatment or by total beta-carotene intake.
The second trial, by Romney et al, recruited 98 women with moderate dysplasia (CIN II), randomized them to beta-carotene 30 mg or placebo daily for nine months, and did rechecks at 1.5, 3, 6, and 9 months by cytology, colposcopy, plasma carotenoids, and tests for cervical HPV infection.9 A colposcopic biopsy also was done at the final visit. Unfortunately, at the baseline visit, 70% of the placebo group had a lesion < CIN II compared with only 35.9% of the intervention group; 74.5% of the participants completed the trial. The intervention group achieved beta-carotene levels four times higher than the controls, although 25% of the controls took a multivitamin or beta-carotene. Among the controls, more than 60% with initial lesions < CIN II regressed, and more control than intervention subjects (46.7% vs. 23.1%) had complete regression to normal. Also, CIN regression was not related to serum beta-carotene levels.
These two studies do not support use of beta-carotene for regression of cervical dysplasia. In fact, the Romney study suggests that beta-carotene supplements may decrease spontaneous healing. Beta-carotene supplementation has been disappointing in other cancer prevention studies, and epidemiological studies showing reduced risk of certain cancers in those with high beta-carotene levels may simply reflect that beta-carotene may be a marker for related compounds that are more protective.
Beta-Carotene and Vitamin C
A study by Mackerras et al used daily oral administration of 30 mg beta-carotene and/or 500 mg vitamin C to 141 women with minor squamous atypia or CIN I identified by colposcopy and histology.10 Over more than two years of follow-up, 43 lesions regressed to normal and 13 progressed to CIN II. The regression rate was not significantly different among groups. This study shows that neither beta-carotene nor vitamin C, even at high doses, promotes regression or progression of minor atypia and CIN I.
Retinoic Acid
Given its teratogenicity and the regulatory status of other vitamin A derivatives (Retin-A®, Accutane®, Renova®), would retinoic acid be an "alternative" therapy? Just because it is derived from vitamin A does not mean it will be regulated under the Dietary Supplement Health and Education Act (DSHEA).
9-cis retinoic acid and all trans retinoic acids are metabolites of vitamin A (retinol). Laboratory studies show that retinoid receptors control transcription of target genes that influence cell differentiation and proliferation. Several clinical studies show that retinoic acid can prevent progression of oral leukoplakia and secondary primary tumors of the head and neck. This information is the basis of testing retinoids in the regression of cervical dysplasias. However, since some retinoids have teratogenic effects, its systemic use is contraindicated in women who might become pregnant. Therefore, methods for topical application directly to the cervix have been developed and tested. After the maximum tolerated dose was researched, both a phase II efficacy and a phase III trial have been done. A pharmacokinetic study has shown that hours after a topical application, retinoic acid is measurable in cervical tissue, but there is no detectable serum level of retinoic acid measured 1-24 hours after treatment.
The phase III trial randomized 301 women with histologically confirmed CIN II or III to either placebo or 0.375% retinoic acid cream (1 ml applied for four consecutive days with retreatment for two days at months 3 and 6).11 Cytology and colposcopy were done at 9, 12, 15, 21, and 26 months after treatment. HPV analysis was not done. The primary endpoint, complete histologic regression of cervical lesions, was determined at 15 months. Seventy-eight percent of participants completed the study. Twenty-seven percent in the placebo and 43% in the treatment group experienced histologic regression of CIN II, but no effect of retinoic acid on CIN III regression was present. This study indicates that cervical cancer can be prevented by use of specific compounds applied for relatively short periods.
Conclusion
Of the research reviewed, only the topical retinoic acid study shows any promise for improvement of cervical dysplasia. More information is needed on where in the carcinogenesis process various nutrients are effective and if their effects are independent of other risks for cervical cancer. It is essential that research on nutrients and cervical cancer risk be prospective, have sufficient sample size, and include HPV assessments, both nutrient and other markers of cervical cancer risk, and use histologic measures of baseline and outcome lesion markers. Perhaps in the future physicians will have access to nontoxic, easily applied compounds that will cure cervical dysplasias and prevent the development of invasive cervical cancer.
References
1. Mitchell MF, et al. Cervical human papillomavirus infection and intraepithelial neoplasia: A review. J Natl Cancer Inst Monogr 1996;21:17-25.
2. Koutsky LA, et al. A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med 1992;327:1272-1278.
3. Potischman N, Brinton LA. Nutrition and cervical neoplasia. Cancer Causes Control 1996;7:113-126.
4. Giuliano AR, Gapstur S. Can cervical dysplasia and cancer be prevented with nutrients? Nutr Rev 1998;56:9-16.
5. Butterworth CE, et al. Oral folic acid supplementation for cervical dysplasia: A clinical intervention trial. Am J Obstet Gynecol 1992;166:803-809.
6. Childers JM, et al. Chemoprevention of cervical cancer with folic acid: A phase III Southwest Oncology Group Intergroup study. Cancer Epidemiol Biomarkers Prev 1995;4:155-159.
7. Giuliano AR, et al. Antioxidant nutrients: Associations with persistent human papillomavirus infection. Cancer Epidemiol Biomarkers Prev 1997;6:917-923.
8. de Vet HC, et al. The effect of beta-carotene and the regression and progression of cervical dysplasia: A clinical experiment. J Clin Epidemiol 1991;44:273-283.
9. Romney SL, et al. Effects of beta-carotene and other factors on the outcome of cervical dysplasia and human papillomavirus infection. Gynecol Oncol 1997;65:483-492.
10. Mackerras D, et al. Randomized double-blind trial of beta-carotene and vitamin C in women with minor cervical abnormalities. Br J Cancer 1999;79:1448-1453.
11. Meyskens FL Jr, et al. Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: A randomized trial. J Natl Cancer Inst 1994;86:539-543.
August 2000; Volume 2; 57-60
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