Ovarian Cancer in Canada (October 1999) Breast Cancer in Canada (April 1999) Cervical Cancer in Canada (March 1998)

Ovarian Cancer in Canada

• 2,600 new cases and 1,500 deaths estimated for 1999
• Incidence and mortality rates increase with advancing age
• 5-10% of all ovarian cancers may result from hereditary predisposition
• Factors leading to reduced risk include reproductive factors such as term pregnancy, breast feeding, use of oral contraceptives, hysterectomy and tubal ligation

Ovarian cancer is both the fifth most diagnosed (accounting for 4% of all new cancers) and the fifth leading cause of cancer deaths (accounting for almost 5%) among Canadian women. In 1999, it is estimated that there will be 2,600 new cases and 1,500 deaths due to ovarian cancer ¹. Among gynaecologic cancers, it is the most lethal, largely due to the fact that it is often not diagnosed until late stage when symptoms develop due to invasion of other pelvic organs or from metastases. Symptoms initially tend to be vague and as the disease progresses may include abdominal distention or pain, alterations in bowel or bladder habits, and gynaecologic complaints such as pain on intercourse.

More than 90% of ovarian tumours arise from the epithelial cells that form the surface of the ovary. These are the same cells that line the peritoneal cavity and the outside of the bowel and urogenital systems. Tumours spread when there is local shedding into the peritoneal cavity followed by implantation into the peritoneum. Approximately 15% of tumours are of low malignant potential and are deemed to be borderline tumours. These tumours have an excellent prognosis².

TRENDS

Incidence and mortality rates for ovarian cancer have been relatively stable over time, though a modest decline in mortality has been observed¹ (Figure 1). To illustrate this, trends in age-specific incidence and mortality rates are shown in Figure 2. Both rates increase with advancing age. The largest proportion of new cases of ovarian cancer (35%) was reported from women 65 to 79 years of age. Women in the age group 50 to 64 had the next highest incidence with 28% of new cases and those 35 to 49 years old accounted for 18%. This distribution reflects not only the risk of developing ovarian cancer in a particular age group, but also the number of women who are in an age group. Interprovincial comparison of incidence and mortality fail to reveal any geographic patterns although it appears that both of these rates are lower in some Atlantic provinces (Figure 3). Variations observed across Canada may reflect historic risk factor exposures or differences in diagnostic or cancer registry recording practices.

Figure 1
Age-Standardized Incidence and Mortality Rates for Ovarian Cancer, Canada, 1969-1999

Figure 2
Age-Specific Incidence and Mortality Rates for Ovarian Cancer, Canada

Figure 3
Age-Standardized Incidence and Mortality Rates for Ovarian Cancer, Canada and Provinces

Incidence and mortality in the oldest age group increased in the 1960s and 1970s and stabilized above those of the 65-79-year-old group. The variations noted in the oldest group may reflect changes in diagnostic practices over time or differences in risk factor exposures, e.g., the number of pregnancies.

RISK FACTORS

The causes of ovarian cancer are poorly understood; however, a number of risk factors have been associated with either an increased or decreased likelihood of developing the disease.

A number of factors have been identified providing potential reduction of risk from ovarian cancer. These include reproductive factors such as the use of oral contraceptives, hysterectomy, and tubal ligation³. A decreasing trend in the risk of ovarian cancer was observed among women with full term pregnancies. The estimated risk reduction was 40% with the first term pregnancy and ranged to 67% with a fifth pregnancy. Risk reduction was also observed with increasing duration of breast feeding, with a 19% reduction in risk for any breast feeding.

The same trend occurred with oral contraceptives; a 34% risk reduction was observed with any use, and this reduction increased to 70% with use for 6 or more years. This risk reduction appears to last at least 10 years after cessation⁴.

A number of studies have been conducted to examine the effects of tubal ligation and hysterectomy on the risk of developing ovarian cancer^3–6. In a population-based study, a 41% reduction in ovarian cancer risk was found in women who had undergone tubal ligation, while a statistically non-significant reduction was seen in women who had undergone hysterectomy ³.

Family history of the disease in a first degree relative is associated with an increased risk of ovarian cancer but it is an imperfect predictor for mutation status⁸. It is estimated that between 5% to 10% of all ovarian cancer cases result from hereditary predisposition ⁹. Hereditary breast-ovarian cancer (HBOC) syndrome is thought to account for 65% to 75% of all hereditary ovarian cancer cases. Approximately 75% of HBOC families are linked to either one of the tumour suppressor genes: BRCA1 and BRCA2⁹. Women with an altered suppressor gene are at an increased risk for both breast and ovarian cancer (Table 1).

Table 1: Risk of Breast and Ovarian Cancer in Presence of BRCA Genes ⁴

Studies which investigated the effects of infertility drugs¹⁰, talc exposure ^4,11,12 and diet ^4,13 on risk of ovarian cancer were inconclusive.

PREVENTION

Specific recommendations for the prevention of ovarian cancer are hampered because of uncertainty surrounding the origin and risk factors of the disease.

The use of oral contraceptives has been associated with a reduced risk of ovarian cancer. Although this association has been less clear in women with hereditary ovarian cancer, a pre- liminary case-control study in women with hereditary ovarian cancer demonstrated a 50% reduction in risk with oral contraceptive use¹⁴.

Prophylactic oophorectomy has also been suggested as a possible preventative measure in women from families with hereditary ovarian cancer syndromes. The reduction of risk with this procedure has yet to be proven and the morbidity and mortality associated with the surgery, risks of early menopause, need for long-term hormone replacement therapy and the incomplete prevention of ovarian cancer must be weighed against the potential benefit. Currently there is insufficient evidence, either for or against, to recommend prophylactic oophorectomy; however, it has been suggested that women with BRCA1 mutation should be counselled that this is an option available to them¹⁵.

EARLY DETECTION

Because survival rates are much higher when ovarian cancer is diagnosed in an early or localized stage, screening has been considered with the hope of being able to detect women in the asymptomatic stage of disease. However, there is currently no evidence that screening for ovarian cancer will reduce mortality.

Pelvic exams generally detect ovarian cancer that is at an advanced stage of disease. Two tests that have been considered for use as a screening tool are the measurement of serum CA-125 and ultrasound. Serum levels of CA-125 are elevated in approximately half of patients with Stage I disease and 90% of patients with Stage II disease ¹⁶. It is important to note that elevated levels can also occur in other conditions such as endometriosis, pregnancy, and non-gynaecologic malignancies. The use of ultrasound as a screening tool has been associated with a high number of false positives and resulted in unnecessary surgery to some women in these studies ¹⁷.

Because there are no proven methods to detect pre-cancerous lesions, The Canadian Task Force on Preventive Health Care and the US Preventive Services Task Force both recommended against screening asymptomatic women^18,19.

There are currently three randomized controlled trials¹⁷ under way to evaluate the effectiveness of screening in the general population; results from these trials are expected by the year 2004.

TREATMENT

Prognosis is largely determined by stage at diagnosis, although factors such as younger age, cell type, grade, smaller disease volume prior to surgical debulking (reducing as much of the tumour as possible), and residual tumour following debulking do have an impact on prognosis^20,21. Ovarian cancer staging encompasses four domains that reflect the spread of cancer. Stage 1 disease is defined as tumours that are confined to one or both ovaries. Ovarian cancer is classified as Stage II when cancer has spread from one or both ovaries to other parts within the pelvis, e.g. uterus, fallopian tubes. Stage III involves spread to lymph nodes or parts within the abdomen, and Stage IV involves spread outside the abdomen or to the liver. Stage-specific survival data on ovarian cancer are not available for Canada. Data from the United States Surveillance, Epidemiology and End Results (SEER) Program use extent of disease for staging. Table 2 illustrates the dramatic drop off in survival rates at later stages of diagnosis ²². Unfortunately, 70% of tumours have spread regionally or to distant sites at diagnosis.

Table 2: Ovarian Cancer Stage at Diagnosis and 5-year Relative Survival ²⁰

Accurate staging is required to determine appropriate treatment. This may be difficult to achieve due to the potential for occult metastases in the upper abdomen and lymph nodes. Surgery is the primary treatment for women with localized (Stage 1) disease, although other therapy such as chemotherapy may also be offered²³. Treatment for women with advanced ovarian cancer will, for the most part, delay symptomatic relapse. This treatment includes surgery to debulk the tumour to further reduce it to a state of minimal disease.

Trials are ongoing to determine the optimal treatment for the various stages of ovarian cancer.

REFERENCES

1. National Cancer Institute of Canada. Canadian cancer statistics 1999. Toronto, ON: National Cancer Institute of Canada 1999.

2. Weiss NS, Cook LS, Farrow DC, Rosenblatt KA. Ovarian cancer. In: Schottenfield D, Fraumeni JF, eds. Cancer epidemiology and prevention. 2nd ed. New York: Oxford University Press, 1996:1040.

3. Whittemore AS, Harris R, Itnyre J, et al. Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. Am J Epidemiol 1992;136:1184-1203.

4. Hankinson SE, Colditz GA, Hunter DJ, Spencer TL, Rosner B, Stampfer MJ. A quantitative assessment of oral contraceptive use and risk of ovarian cancer. Obstet Gynecol 1992;80:7088-114.

5. Hankinson SE, Hunter DJ, Colditz GA, Willett WC, et al. Tubal ligation, hysterectomy, and risk of ovarian cancer: a prospective study. JAMA 1993;270:2813-18.

6. Godard B, Foulkes WD, Provencher D, Brunet JS, et al. Risk factors for familial and sporadic ovarian cancer among French Canadians: a case-control study. Am J Obstet Gynecol 1998;179:403-10.

7. Miracle-McMahill HL, Calle EE, Kosinski AS, Rodriguez C, et al. Tubal ligation and fatal ovarian cancer in a large prospective cohort study. Am J Epidemiol 1997;145:349-57.

8. Rubin SC. Chemoprevention of hereditary ovarian cancer. N Engl J Med 1998;339:469-71.

9. Penson RT, Shannon KE, Sharpless NE, Seiden MV. Ovarian cancer: an update on genetics and therapy. Comp Ther 1998;24:477-87.

10. Daly MB, Bookman MA, Lerman CE. Female reproductive tract: cervix, endometrium, ovary. In: Greenwald P, Kramer BS, Weed DL, eds. Cancer prevention and control. New York: Marcel Kekker Inc, 1995.

11. Harlow BL, Cramer DW, Bell DA, Welch WR. Perineal exposure to talc and ovarian cancer risk. Obstet Gynecol 1992;80:19-26.

12. Chang S, Risch HA. Perineal talc exposure and risk of ovarian carcinoma. Cancer 1997;79:2396-2401.

13. Kushi LH, Mink PJ, Folsom AR, Anderson KE. Prospective study of diet and ovarian cancer. Am J Epidemiol 1999;149:21-31.

14. Narod SA, Risch H, Moslehi R, Dorum A, et al. Oral contraceptives and the risk of hereditary ovarian cancer. N Engl J Med 1998;339:424-28.

15. Burke W, Daly M, Garber J, Botkin J, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. JAMA 1997;277:997-1003.

16. Berek JS, Thomas GM, Ozols RF. Ovarian cancer. In: Holland JF, Frei E III, Bast RC Jr., Kufe DW, Morton DL, Weichselbaum RR, eds. Cancer medicine. 4th ed. Baltimore: Williams & Wilkins, 1997:2289-2326.

17. MacDonald ND, Rosenthal AN, Jacobs IJ. Screening for ovarian cancer. Ann Acad Med Singapore 1998;27:676-82.

18. US Preventive Services Task Force. Guide to clinical preventive services. 2nd ed. Baltimore: Williams & Wilkins, 1996.

19. Canadian Task Force on the Periodic Health Examination. Canadian guide to preventive health care. Ottawa: Canada Communications Group, 1994.

20. Neijt JP, tenBokkel Huinink WW, van der Burg MEL, van Oosterom AT, et al. Long-term survival in ovarian cancer. Eur J Cancer 1991;27:1367-72.

21. Omura GA, Brady MF, Homesley HD, Yordan E, et al. Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the gynecologic oncology group experience. J Clin Oncol 1991;9:1138-50.

22. National Cancer Institute. SEER cancer statistics review, 1973-1995. Bethesda, MD: National Cancer Institute, 1997.

23. National Cancer Institute.
PDQ_treatment:ovarian epithelial cancer. 1999. (Http://cancernet.nci.nih.gov/clinpdq/SOa/
ovarian_epithelial_cancer_physician.html)

Contributors: Brent Moloughney, Judy Snider and Laura Villeneuve.

Acknowledgement

Data were provided to Health Canada from the Canadian Cancer Registry, formerly the National Cancer Incidence Reporting System, at Statistics Canada. The cooperation of the provincial and territorial cancer registries which supply the data to Statistics Canada is gratefully acknowledged.

The Cancer Bureau is part of the Laboratory Centre for Disease Control,
Health Protection Branch, Health Canada.