Chemoprophylaxis

In addition to increased surveillance, several agents are under investigation for prevention of ovarian cancer. Although, oral contraceptive use was noted in 1979 to reduce the risk of ovarian cancer in the general population by as much as 40% (23), risk reduction in BRCA1 and BRCA2 mutation carriers was not examined until 1998. Narod et al. (24) compared 207 women with BRCA1 and BRCA2 mutation related ovarian cancer with 161 of their cancer-free sisters. Any past use of oral contraceptives was associated with a 50% reduction in ovarian cancer risk, although no difference in breast cancer risk was noted. Other researchers have found conflicting results. Modan et al. (154) conducted a large population-based case-control study comparing 840 Jewish women in Israel with ovarian cancer and 751 controls. In this study, oral contraceptive use only appeared to reduce risk in women without BRCA mutations; among mutation carriers, the reduction in risk was only 0.2% per year of use. Any protective effects of oral contraceptives may not be solely because of ovulation suppression, as progestin only formulations (which do not suppress ovulation) have been observed to be as effective as combination preparations (155). Also, oral contraceptives with higher doses of progestin seem to confer a higher level of protection than those with lower doses (156). Evidence in primate models suggests that progesterone may mediate apoptosis of ovarian epithelial cells as well as changes in TGF-P production (157,158). The results of large prospective chemoprevention trials are necessary to resolve the question of the effectiveness of oral contraceptives for ovarian cancer risk reduction. However, it appears that mutation carriers may use premenopausal oral contraceptives without increase in their breast cancer risk.

Several other agents are under investigation for chemoprevention. Epidemiological evidence has previously suggested a role for retinoids in the prevention of ovarian cancer (52,159). Fenretinide (N-4-hydroxyphenyl retinamide) has been used in treatment of breast cancer, and may reduce risk for ovarian cancer. In vitro, the agent has been noted to decrease proliferation and increase apoptosis in ovarian epithelium and cancer cell lines (160-163). In a study of patients with breast cancer randomized to receive fenretinide or placebo for five years as a means of possible chemoprophylaxis for contralateral breast cancer, patients in the fenretinide group were noted to have no cases of ovarian cancer, vs 6 cases in the control arm during the period of active treatment (p = 0.03), although this effect was not observed after the drug was ceased (164). Gynecological Oncology Group trial No. 190 is currently underway to evaluate the benefit of fenretinide in high-risk women after prophylactic oophorectomy.

Vitamin D is also under study as a potential preventative agent. Ovarian cancer incidence has been noted to vary with latitude, and with lower rates in areas of higher ultraviolet exposure, the primary source of vitamin D (165,166). Lefkowitz et al. (167) investigated the association between average annual sunlight energy and age-specific ovarian cancer mortality rates and noted that the ovarian cancer mortality rate was inversely proportional to mean annual intensity of sunlight. These results were statistically significant on both univariate analysis and logistic regression. Prostate cancer mortality has also been noted to vary inversely with ultraviolet radiation (168), and the effects of vitamin D have been studied in more detail in this disease. Corder et al. (169) noted the level of 1,25-dihydroxyvitamin D, a metabolite of vitamin D, to be an important predictor of risk for palpable and anaplastic prostate tumors in men aged 57 or older. Unfortunately, the clinical use of pharmacological doses of vitamin D is limited by its hypercalcemic effects. Less calcemic vitamin D analogs have been studied by Schwartz et al. (170) in vitro and were found to exert significant antiproliferative activity on multiple prostate carcinoma cell lines. Studies of vitamin D as a chemopreventative agent are underway in animal models and as part of the Women's Health Initiative in relation to fracture and colon cancer risk, although data gathered will likely provide insight into ovarian cancer incidence as well (171).

Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk of ovarian cancer as well as other tumors (172-176). Rosenberg et al. performed a case-control study of 780 women with EOC compared with 2570 controls and noted a statistically significant decrease in ovarian cancer risk with use of NSAIDs, four days or more a week for at least 5 years (174). Although, the basis for a protective effect is not well delineated, in vitro COX-2 inhibitors have been found to decrease cell proliferation, whereas increasing apoptosis in ovarian cancer cell lines (177), and limiting COX-2 catalyzed production of prostaglandins with subsequent effects of proliferation, apoptosis, and angiogenesis (178,179). Others have proposed that COX-2 inhibition might lead to decreased loss of ovarian surface epithelium basement membrane and reduction of malignant transformation (180). Additional studies are necessary for evaluation of these agents as chemopreventatives for ovarian cancer.

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