Ovarian Cancer Chemoprevention in the General Population

Many investigations have evaluated the effect of oral contraceptive pills on ovarian cancer risk. The evidence supporting a protective influence of birth control pills on ovarian cancer risk has been obtained primarily from case-control studies. These investigations identify patients (cases) who have been diagnosed with ovarian cancer and women (controls) who do not have the disease. The two groups are then compared with respect to their exposure to oral contraceptive pills (a suspected protective agent). This allows for the generation of an odds ratio. However, attributable risk cannot be determined with this design. Adjustments can be made for confounding factors. Without an identification of these factors, however, these corrections cannot be performed.

Hankinson and colleagues5 performed a meta-analysis including 20 epidemiologic studies that assessed the association between oral contraceptive use and ovarian cancer. They reported a summary relative risk of ovarian cancer of 0.64 (95% confidence interval [CI], 0.57-0.73) in women who ever used oral contraceptives. This translated into a 36% reduction in risk. Longer duration of oral contraceptive use resulted in a greater reduction in ovarian cancer risk. One year of use was associated with a 10% to 12% reduction in risk, and 5 years of use resulted in a decrease of about 50%. Whittemore and associates6 performed a meta-analysis of 12 U.S.

case-control studies and demonstrated a clear trend of decreasing risk of ovarian cancer with increased duration of oral contraceptive use. Most of the studies included in these meta-analyses assessed the high-dose oral contraceptive formulations used in the 1960s and 1970s.

Several investigations have evaluated lower doses of oral contraceptive formulations and its association with ovarian cancer risk. One of the investigations in the meta-analysis of Hankinson and associates5 included subjects who used lower doses of oral contraceptives. From 1980 to 1982, the Cancer and Steroid Hormone Study7 enrolled 546 women with ovarian cancer and 4228 controls. Use of oral contraceptives was associated with risk of ovarian cancer of 0.6 (95% CI, 0.5-0.7). A benefit was seen in women with as little as 3 to 6 months of contraceptive use and was independent of oral contraceptive formulation. Ness and colleagues8 reported findings from the Steroid Hormones and Reproductions (SHARE) Study Group. From 1994 to 1999, the investigation enrolled 767 women with ovarian cancer and 1367 community controls. Oral contraceptive use was associated with a 40% reduction in ovarian cancer risk. Both high-estrogen/high-progestin pills and low-estrogen/low progestin pills conferred an identical reduction in risk of ovarian cancer (odds ratio 0.5 for both types). In contrast, Schildkraut and associates9 identified 360 women with epithelial ovarian cancer and 2865 control subjects from the Cancer and Steroid Hormone Study. They found a higher risk of ovarian cancer in women who used low-potency progestin oral contraceptive formulations compared with subjects who used high-potency progestin oral contraceptives (adjusted odds ratio 2.2; 95% CI, 1.3-3.9). These findings indicate that the protective effect of oral contraceptives on ovarian cancer risk is independent of estrogen dose. However, lower-dose progestin may not be associated with as great a protective effect.

Most investigations have focused on white women. John and colleagues10 combined data from seven case-control studies. From the data of the investigations, 110 black women with ovarian cancer were identified and served as case subjects. This group was compared with 365 black control subjects. The use of oral contraceptives for 6 years or longer was associated with an odds ratio of 0.62, but the 95% CI equaled 0.24 to 1.6. Although oral contraceptive use in black women may protect against ovarian cancer, this investigation may not have been adequately powered to identify a significant association.

Oral contraceptive use occurs almost exclusively before menopause. The median age of diagnosis of ovarian cancer is 63. If oral contraceptives do not provide long-lasting protection, the benefit of this intervention may not be relevant to the majority of women at risk. Several studies have reported on the durability of the protective effect of oral contraceptives on ovarian cancer risk. Protection against ovarian malignancy continues to be identified for approximately 15 years after discontinuation of oral contraceptive use.5,7,11-13 Bosetti and colleagues14 combined data from six case-control investigations. Compared with never users, oral contraceptive users experienced a significant reduction in ovarian cancer risk; odds ratio was equal to 0.66 (95% CI, 0.56-0.79). Risk reduction was similar for women who had discontinued oral contraceptives for less than 10 years compared with those who had stopped for 20 years or more. Oral contraceptive pill use continues to protect against ovarian cancer for at least 15 years and probably longer.

In summation, in the general female population, oral contraceptive use appears to be effective in reducing the risk of ovarian cancer. Case-control studies demonstrate a relative risk of approximately 0.6 associated with oral contraceptives. A longer duration of use results in an improved protective effect. Low-dose estrogen pills appear to provide a protective benefit. However, lower progestin dosages may not be as effective. The protective effects of oral contraceptive pills appear to persist beyond 15 years (Table 4-2).

Table 4-2. Ovarian Cancer Risk Reduction: Oral Contraceptives in the General Population Investigation Odds Ratio 95% CI

The Cancer and Steroid Hormone Study7

Parazzlni et al28

Stanford13

Hankinson et al5

Whittemore et al6

Whittemore et al6

John et al10

Rosenberg et al12

Ness et al8

Bosetti et al14

*Hospital study, controls obtained from hospitals.

fPopulation studies, involved random digit dial of neighborhood controls.

African-American population.

0.6

0.5-0.7

0.7

0.5-1.0

0.7

0.6-0.7

0.64

0.57-0.73

0.70*

0.52-0.94

0.66+

0.55-0.78

0.62*

0.24-1.6

0.6

0.4-0.8

0.60

0.5-0.7

0.66

0.56-0.79

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