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Prevention of ovarian cancer

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Summary Of Evidence
Significance
Evidence Of Benefit

CancerMail from the National Cancer Institute

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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SUMMARY OF EVIDENCE

Note: Separate PDQ summaries on Screening for Ovarian Cancer and Ovarian Epithelial Cancer Treatment are also available.

Sustained contraceptive use, having had at least one live-born child, and having breast fed are associated with a reduction in the risk of ovarian cancer. Tubal ligation, hysterectomy, and a low-fat diet may also be associated with a decreased incidence of ovarian malignancy. Hormone replacement therapy (HRT) in postmenopausal women may be associated with an increased risk of developing ovarian cancer.

Level of Evidence:

3aii: Evidence obtained from well-designed and conducted cohort and case- control studies, preferably from more than one center or research group, that have a cancer incidence endpoint.

Prophylactic oophorectomy is generally reserved for women with documented inherited breast and ovarian cancer syndromes.

Level of Evidence:

5: Opinions of respected authorities based on clinical experience or reports of expert committees.

SIGNIFICANCE

Incidence and Mortality

The lifetime risk of ovarian cancer is 1.7% with an annual incidence approaching 61.3 per 100,000 women who reach the ages of 75 to 79.[1,2] In 2002, it is estimated that 23,300 new cases of ovarian cancer will be diagnosed and 13,900 deaths due to ovarian cancer will occur.[3] Women who carry mutations in BRCA1 and BRCA2 genes have an increased lifetime risk of developing ovarian cancer ranging from 16% to 60%.[4,5]

Ovarian cancer is the deadliest gynecologic malignancy in the United States, killing more women each year than cervical and endometrial cancers combined. Despite aggressive operations and intensive chemotherapy, the 5-year survival rate is less than 50%. Screening for the early detection of ovarian malignancies has not been proven effective. Thus, primary prevention may prove to be the mainstay of averting morbidity and mortality from this malignancy.

Pathogenesis

The pathogenesis of ovarian carcinoma remains unclear. Numerous theories have been proposed to explain the epidemiology of ovarian cancer. In 1972, one theory proposed that constant, uninterrupted ovulation may lead to an increased risk of ovarian cancer.[6] It was concluded that the repeated involvement of the ovarian surface (germinal) epithelium during the process of ovulation without adequate physiologic rest was associated with the development of ovarian neoplasia. This process involves repetitive trauma to the ovarian surface associated with ovulation and may result in cellular proliferation, epithelial entrapment, and, ultimately, transformation of epithelial inclusion cysts within the ovarian stroma leading to the genesis of ovarian cancer. This concept may explain why events such as pregnancy, breast-feeding, and oral contraceptive use are associated with a decreased risk of ovarian cancer. Others have used this theory to explain a possible association between the use of infertility drugs and an increased risk of ovarian cancer. A second theory hypothesized that increased pituitary gonadotropin levels and not cellular changes on the surface of the ovary are associated with a corresponding increased risk of developing ovarian cancer.[7,8] This speculation is difficult to prove since many of the modalities which inhibit ovulation, and therefore decrease risk of ovarian cancer, do so through the inhibition of gonadotropin release. Finally, alterations in ovarian blood flow or the transtubal transportation of carcinogens may be involved in the development of ovarian neoplasia.[9]

References:

  1. American Cancer Society: Cancer Facts and Figures-1998. Atlanta, Ga: American Cancer Society, 1998.
  2. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review 1973-1995. Bethesda, Md: National Cancer Institute, 1998.
  3. American Cancer Society: Cancer Facts and Figures-2002. Atlanta, Ga: American Cancer Society, 2002.
  4. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New England Journal of Medicine 336(20): 1401-1408, 1997.
  5. Easton DF, Ford D, Bishop DT: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. American Journal of Human Genetics 56(1): 265-271, 1995.
  6. Fathalla MF: Factors in the causation and incidence of ovarian cancer. Obstetrical and Gynecological Survey 27(11): 751-768, 1972.
  7. Stadel BV: The etiology and prevention of ovarian cancer. American Journal of Obstetrics and Gynecology 123(7): 772-774, 1975.
  8. Gardner WU: Tumorigenesis in transplanted irradiated and nonirradiated ovaries. Journal of the National Cancer Institute 26(4): 829-853, 1961.
  9. Irwin KL, Weiss NS, Lee NC, et al.: Tubal sterilization, hysterectomy, and the subsequent occurrence of epithelial ovarian cancer. American Journal of Epidemiology 134(4): 362-369, 1991.

EVIDENCE OF BENEFIT

Risk Factors

Risk factors associated with decreased ovarian cancer include (in the order of descending significance): 1) using oral contraceptives, 2) having and breast-feeding children, 3) having a bilateral tubal ligation or hysterectomy, 4) having a prophylactic oophorectomy, and 5) avoiding agents associated with
an increased risk of ovarian cancer, such as fertility drugs, talc, and a high-fat diet.

Birth Control Pills

Protection against ovarian cancer may be a noncontraceptive benefit of the birth control pill. Multiple studies have demonstrated a 40% to 50% decrease in ovarian cancer risk in women who take oral contraceptives.[1,2] The protective effect appears to increase with the duration of oral contraceptive use and to persist for 10 to 15 years after oral contraceptives have been discontinued. For example, a review of the literature demonstrated a 10% to 12% decrease in risk associated with use for 1 year and an approximate 50% decrease after 5 years of use. This reduced risk was present among both nulliparous and parous women.[1] All of the studies were conducted with high-dose oral contraceptives. The association between oral contraceptives and decreased risk of ovarian cancer in general has also been observed among women who carry mutations in BRCA1 and BRCA2 genes.[3]

Hormone Replacement Therapy

Postmenopausal use of hormone replacement therapy (HRT) is associated with an increased risk of developing ovarian cancer.[4] This effect is weak, with an estimated overall relative risk of 1.15 (95% confidence interval (CI) 1.05-1.27) for ever users compared to never users. If HRT is used longer than 10 years, the relative risk is 1.27 (95% CI 1.00-1.61). An association between postmenopausal estrogen use and ovarian cancer mortality also has been shown. Vital status of 211,581 postmenopausal women, all of whom completed a baseline questionnaire in 1982 documenting no history of cancer, hysterectomy, or ovarian surgery was assessed through December 31, 1996. Women who were using estrogen at baseline had a significantly higher risk of ovarian cancer death than women who never used estrogen (relative risk = 1.51; 95% CI 1.16-1.96). Duration of use was important. Women using estrogen at baseline and those who had used estrogen for at least 10 years had a higher risk of ovarian cancer death than did women who had never used estrogen, respectively (RR = 2.20; 95% CI 1.53-3.17) and (RR = 1.59; 95% CI 1.13-2.25). Lengthening the period of use to 15 years or more made little difference. Because ovarian cancer is a rare disease (lifetime risk 1.7%), the risk of dying from ovarian cancer even among women who used estrogen 10 or more years is still very low compared to the risk of lung cancer death among smokers or breast cancer death among average risk women.[5]

Tubal Sterilization

In a prospective study, a 33% decrease in the risk of ovarian cancer among women who underwent tubal sterilization was observed after adjusting the data for oral contraceptive use, parity, and other ovarian cancer risk factors. This study also demonstrated a weaker, although statistically significant, decrease in risk associated with simple hysterectomy.[6] In 1988, about 35 million U.S. women of reproductive age were using contraception. The most popular method, the oral contraceptive, was used by 31% and tubal sterilization, the next most popular, by 28%.[7]

Prophylactic Oophorectomy --

Prophylactic oophorectomy is of unproved, and perhaps limited, benefit even in BRCA1 and BRCA2 high-risk mutation carriers.[8] One study reported 3 cases of disseminated intra-abdominal malignancy consistent with ovarian cancer occurring after prophylactic oophorectomy among 28 members of 16 families at high risk for ovarian cancer.[9] In a pilot study of women from 12 of these families, the risk of ovarian cancer among women without oophorectomy was 24-fold compared to a 13-fold excess risk among women who had prophylactic oophorectomy.[10] Primary peritoneal carcinoma after prophylactic oophorectomy has also been reported in 6 women from the Gilda Radner Familial Ovarian Cancer Registry [11] with cancer occurring 1 to 27 years following surgery. The potential morbidity and mortality of surgery, the risks associated with early menopause, the need for long-term HRT, and the incomplete prevention of ovarian cancer may outweigh the theoretical decrease in ovarian cancer risk. Despite the uncertainties, some women at increased ovarian cancer risk decide to have prophylactic surgery. Underlying ovarian cancer risk can be assessed through accurate pedigrees and/or genetic markers of risk. Because of uncertainties about cancer risks associated with specific gene mutations, genetic information may be difficult to interpret outside of families with a high incidence of ovarian cancer. Three inherited ovarian cancer susceptibility syndromes have been described: 1) familial site-specific ovarian cancer; 2) familial breast/ovarian cancer; and 3) the Lynch II Syndrome which is a combination of breast, ovarian, endometrial, gastrointestinal, and genitourinary cancers.[12,13] Considering family history in the absence of specific information on BRCA1/2 mutation status, unaffected women who have 2 or 3 relatives with ovarian cancer have a cumulative ovarian cancer risk of about 7%.[14,12] Women who have a mother or sister with ovarian cancer have a cumulative ovarian cancer risk of about 5%.

External Agents

The exposure to certain agents has been associated with an increased risk of ovarian cancer. In a collaborative analysis of ovarian cancer risk factors, a positive correlation between fertility drug use and invasive ovarian cancer was suggested.[15] A collaborative ovarian cancer group analyzed data from approximately 2,200 ovarian cancer patients and about 8,900 controls in 12 U.S. case-control studies. They reported that the use of fertility drugs increased a woman's risk of invasive epithelial ovarian cancer nearly 3-fold (odds ratio (OR) = 2.8, 95% CI 1.3-6.1), and risk was substantially greater among nulligravid women (OR = 27.0); the study did not differentiate among specific fertility drugs. Two case-control studies published subsequent to the collaborative analysis did not find an association between fertility drug use and risk of ovarian cancer.[16,17] A retrospective cohort study of women evaluated for infertility observed an increased risk of invasive or borderline malignant ovarian tumors associated with prolonged use of clomiphene.[18]

Other risk factors have been suggested for ovarian cancer, such as peritoneal exposure to talc due to powder application to the perineum and a high-fat diet, although the exact relationship remains unclear. No cohort studies investigating the exposure to talc and the increased consumption of fat have been reported. An analysis of 6 papers that address the subject of peritoneal exposure to talc and risk of ovarian cancer found a statistically significant increase in risk (OR = 1.3, 95% CI 1.1-1.6). Conceptually, talcum powder placed on the perineum may gain access to the ovaries by ascension through the vagina, cervix, uterus, and fallopian tubes, acting as a cocarcinogen in the development of ovarian cancer.[19]

Dietary Factors

The major dietary differences between industrialized and nonindustrialized nations primarily involve the intake of meat and animal fat and may explain the increased age-adjusted annual ovarian cancer incidence among industrialized countries. A significant dose-response relationship between the intake of fat from animal sources and the risk of developing ovarian cancer has been reported.[20] A population-based case-control study observed an increased risk of ovarian cancer associated with saturated fat consumption and a decreased risk associated with vegetable fiber consumption.[21] The association between serum cholesterol levels and the risk of ovarian cancer has been examined prospectively in 2 studies,[22,23] but findings are inconsistent. One study observed an increased risk with increasing cholesterol levels,[22] but no association was observed in another study.[23] A protective association was also observed between serum selenium levels and the risk of ovarian cancer.[22] This finding differs from a report by the Nurses' Health Study, which failed to find an association between serum selenium levels and ovarian cancer.[24] Because of the small number of prospective studies and inconsistencies among case-control studies, these findings should be replicated. Other case-control studies have shown a relationship between the consumption of milk, a primary source of dietary fat and lactose (a component of milk), and an increased risk for the development of ovarian cancer.[25,26] Another study, however, did not observe an association between consumption of lactose or free galactose and the risk of ovarian cancer.[27]

References:

  1. Hankinson SE, Colditz GA, Hunter DJ, et al.: A quantitative assessment of oral contraceptive use and risk of ovarian cancer. Obstetrics and Gynecology 80: 708-714, 1992.
  2. Lee NC, Wingo PA, Gwinn ML, et al.: The reduction in risk of ovarian cancer associated with oral-contraceptive use: the Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. New England Journal of Medicine 316: 650-655, 1987.
  3. Narod SA, Risch H, et al. for the Hereditary Ovarian Cancer Clinical Study Group: Oral contraceptives and the risk of hereditary ovarian cancer. New England Journal of Medicine 339(7): 424-428, 1998.
  4. Garg PP, Kerlikowske K, Subak L, et al.: Hormone replacement therapy and the risk of epithelial ovarian carcinoma: a meta-analysis. Obstetrics and Gynecology 92(3): 472-479, 1998.
  5. Rodriguez C, Patel AV, Calle EE, et al.: Estrogen replacement therapy and ovarian cancer mortality in a large prospective study of US women. JAMA: Journal of the American Medical Association 285(11): 1460-1465, 2001.
  6. Hankinson SE, Hunter DJ, Colditz GA, et al.: Tubal ligation, hysterectomy, and risk of ovarian cancer: a prospective study. JAMA: Journal of the American Medical Association 270(23): 2813-2818, 1993.
  7. Grimes DA: Primary prevention of ovarian cancer. JAMA: Journal of the American Medical Association 270(23): 2855-2856, 1993.
  8. Schrag D, Kuntz KM, Garber JE, et al.: Decision analysis: effects of prophylactic mastectomy and oophorectomy on life expectancy among young women with BRCA1 or BRCA2 mutations. New England Journal of Medicine 336(20): 1465-1471, 1997.
  9. Tobacman JK, Tucker MA, Kase R, et al.: Intra-abdominal carcinomatosis after prophylactic oophorectomy in ovarian cancer-prone families. Lancet 2(8302): 795-797, 1982.
  10. Struewing JP, Watson P, Easton DF, et al.: Prophylactic oophorectomy in inherited breast/ovarian cancer families. Journal of the National Cancer Institute Monographs 17: 33-35, 1995.
  11. Piver MS, Jishi MF, Tsukada Y, et al.: Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. Cancer 71(9): 2751-2755, 1993.
  12. Trimble EL, Karlan BY, Lagasse LD, et al.: Diagnosing the correct ovarian cancer syndrome. Obstetrics and Gynecology 78(6): 1023-1026, 1991.
  13. Genetic risk and screening techniques for epithelial ovarian cancer. ACOG Committee Opinion: Committee on Gynecologic Practice. Number 117--December 1992. International Journal of Gynecology and Obstetrics 41(3):321-3, 1993.
  14. Kerlikowske K, Brown JS, Grady DG: Should women with familial ovarian cancer undergo prophylactic oophorectomy? Obstetrics and Gynecology 80: 700-707, 1992.
  15. Whittemore AS, Harris R, Itnyre J: Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies: II. Invasive epithelial ovarian cancers in white women: Collaborative Ovarian Cancer Group. American Journal of Epidemiology 136(10): 1184-1203, 1992.
  16. Parazzini F, Negri E, LaVecchia C, et al.: Treatment for infertility and risk of invasive epithelial ovarian cancer. Human Reproduction 12(10): 2159-2161, 1997.
  17. Mosgaard BJ, Lidegaard O, Kjaer SK, et al.: Ovarian stimulation and borderline ovarian tumors: a case-control study. Fertility and Sterility 70(6): 1049-1055, 1998.
  18. Rossing MA, Daling JR, Weiss NS, et al.: Ovarian tumors in a cohort of infertile women. New England Journal of Medicine 331(12): 771-776, 1994.
  19. Harlow BL, Cramer DW, Bell DA, et al.: Perineal exposure to talc and ovarian cancer risk. Obstetrics and Gynecology 80(1): 19-26, 1992.
  20. Shu XO, Gao YT, Yuan JM, et al.: Dietary factors and epithelial ovarian cancer. British Journal of Cancer 59(1): 92-96, 1989.
  21. Risch HA, Jain M, Marrett LD, et al.: Dietary fat intake and risk of epithelial ovarian cancer. Journal of the National Cancer Institute 86(18): 1409-1415, 1994.
  22. Helzlsouer KJ, Alberg AJ, Norkus EP, et al.: Prospective study of serum micronutrients and ovarian cancer. Journal of the National Cancer Institute 88(1): 32-37, 1996.
  23. Hiatt RA, Fireman BH: Serum cholesterol and the incidence of cancer in a large cohort. Journal of Chronic Diseases 39(11): 861-870, 1986.
  24. Garland M, Morris JS, Stampfer MJ, et al.: Prospective study of toenail selenium levels and cancer among women. Journal of the National Cancer Institute 87(7): 497-505, 1995.
  25. Mettlin CJ, Piver MS: A case-control study of milk-drinking and ovarian cancer risk. American Journal of Epidemiology 132(5): 871-876, 1990.
  26. Cramer DW, Harlow BL, Willett WC, et al.: Galactose consumption and metabolism in relation to the risk of ovarian cancer. Lancet 2(8654): 66-71, 1989.
  27. Risch HA, Jain M, Marrett LD, et al.: Dietary lactose intake, lactose intolerance, and the risk of epithelial ovarian cancer in southern Ontario (Canada). Cancer Causes and Control 5: 540-548, 1994.
Date Last Modified: 11/2002

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