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Back To Vidyya Screening For Ovarian Cancer

Cancer Institute Information For Health Professionals

Summary of Evidence

There is insufficient evidence to establish that screening for ovarian cancer with serum markers such as CA 125 levels, transvaginal ultrasound, or pelvic examinations would result in a decrease in mortality from ovarian cancer.

Levels of Evidence: 4,5

Evidence obtained from multiple-time series with or without intervention

Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees

Significance

Ovarian cancer is the fifth leading cause of cancer death among U.S. women and has the highest mortality rate of all gynecologic cancers.1 It is projected that 23,100 new cases of ovarian cancer will be diagnosed and 14,000 women will die of the disease in 2000.1 The prognosis for survival from ovarian cancer is largely dependent upon the extent of disease at diagnosis. Women diagnosed with local disease are over 3 times more likely to survive 5 years than women with distant disease.2 However, only one fourth of women present with localized disease at diagnosis.2 The overall 5-year survival rate for ovarian cancer is less than 50%.2 Incidence has decreased only slightly from 1973 to 1995; whereas mortality has decreased by almost 9% in that same time period.2

The etiology of ovarian cancer is poorly understood. The median age at diagnosis is 63.2 A decreased risk of ovarian cancer is associated with increased parity, oral contraceptive use, and breast-feeding.3 A history of tubal ligation or hysterectomy with ovarian conservation is also associated with a decreased risk.4 Risk is increased in women with a family history of ovarian cancer 3,5,6 and among women who have used fertility drugs;3,7 however, this information has limited application in programs of selective screening due to the small number of women with these risk factors. Age at menarche, menopause, or first live birth are unrelated to the risk of ovarian cancer.3 Other factors, such as exposure to talcum powder,8,9 have also been suggested to increase risk. Although there have been suggestions that talcum powder is a risk factor for ovarian cancer, the evidence is conflicting and inconclusive.

Elevated serum CA 125 levels have been associated with an increased incidence of ovarian cancer in a prospective cohort study.10 About 9,320 postmenopausal women underwent an initial and an average of 2.8 yearly screens with the CA 125 assay and were followed for an average of 6.8 years. Forty- nine cancers were identified. A serum CA 125 concentration of at least 30 U/mL was associated with a relative risk of 35.9 (95% confidence interval (CI) 18.3- 70.4) during the first year after the screen, and a relative risk of 14.3 (95% CI 8.5-24.4) during the 5 years after the screen. At a CA 125 concentration of 100 U/mL, the relative risks were 204.8 and 74.5, respectively. Women with CA 125 levels below 30 U/mL had risks of 0.13 and 0.54, respectively.

References:

  1. Greenlee RT, Murray T, Bolden S, et al.: Cancer statistics, 2000. Ca-A Cancer Journal for Clinicians 50(1): 7-33, 2000.
  2. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review 1973-1995. Bethesda, Md: National Cancer Institute, 1998.
  3. 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.
  4. Hankinson SE, Hunter DJ, Colditz GA, et al.: Tubal ligation, hysterectomy, and risk of ovarian cancer: a prospective study. Journal of the American Medical Association 270(23): 2813-2818, 1993.
  5. Cramer DW, Hutchison GB, Welch WR, et al.: Determinants of ovarian cancer risk: I. Reproductive experiences and family history. Journal of the National Cancer Institute 71(4): 711-716, 1983.
  6. Stratton JF, Pharoah P, Smith SK, et al.: A systematic review and meta-analysis of family history and risk of ovarian cancer. British Journal of Obstetrics and Gynaecology 105(5): 493-499, 1998.
  7. Koch M, Gaedke H, Jenkins H: Family history of ovarian cancer patients: a case-control study. International Journal of Epidemiology 18(4): 782-785, 1989.
  8. Whittemore AS, Wu ML, Paffenbarger RS, et al.: Personal and environmental characteristics related to epithelial ovarian cancer: II. Exposures to talcum powder, tobacco, alcohol, and coffee. American Journal of Epidemiology 128(6): 1228-1240, 1988.
  9. Harlow BL, Cramer DW, Bell DA, et al.: Perineal exposure to talc and ovarian cancer risk. Obstetrics and Gynecology 80(1): 19-26, 1992.
  10. Jacobs IJ, Skates S, Davies AP, et al.: Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study. British Medical Journal 313(7069): 1355-1358, 1996.
Evidence of Benefit

Potential screening tests for ovarian cancer include bimanual pelvic examination, vaginal ultrasound, and CA 125 antigen as a tumor marker. The Pap test may occasionally detect malignant ovarian cells, but it is not very sensitive (reported sensitivity of 10%-30%) and has not been evaluated for the early detection of ovarian cancer.1 Another method of detection, cytologic examination of peritoneal lavage obtained by culdocentesis, is technically difficult, uncomfortable to the patient, has low sensitivity for detecting early stage disease, and has not been evaluated for screening.1,2

The sensitivity and specificity of pelvic examination for the detection of ovarian cancer is unknown. Generally, detection by this method reveals advanced disease.1,3

Ultrasonography may be useful in discriminating benign from malignant adnexal masses.4 Transvaginal ultrasonography has been proposed as a screening method for ovarian cancer because of its ability to reliably measure ovarian size and detect small masses.5 The benefit of ultrasonography for the early detection of ovarian cancer has not been evaluated in controlled studies. Estimates of the yield and false positive rate are available from several cohort studies of women offered periodic screening. In a cohort of 801 women aged 40 to 70 who had one or more risk factors for ovarian cancer, 163 (20%) had an abnormal abdominal ultrasound.6 Surgery was performed in 30 cases for a yield of 1 borderline ovarian tumor and 2 endometrial carcinomas.6 In another study, 5,479 self-referred, asymptomatic women underwent periodic screening with abdominal ultrasonography 7 with positive results obtained in 326 participants. After surgery, 5 women were diagnosed with stage IA or IB ovarian cancer; 4 women were diagnosed with metastatic ovarian cancer. Transvaginal ultrasonography was used in a study of 3,220 asymptomatic, postmenopausal women.8 Forty-four women (1.4%) had persistent abnormal scans and underwent exploratory laparotomy. Three were found to have a primary ovarian carcinoma, 2 with stage IA disease. In one other study, transabdominal and transvaginal ultrasonography were both used to screen 1,601 self-referred women with a first- or second-degree relative with ovarian cancer.9 Sixty- one had positive screening tests; 6 had ovarian cancer that was detected at surgery (5 of 6 had stage I disease). Five additional cases of cancer (3 ovarian and 2 peritoneal) were reported 2 to 44 months after the last ultrasound test.9

CA 125 is a tumor-associated antigen that has been used clinically to monitor patients with epithelial ovarian carcinomas.10,11 The measurement of CA 125 levels, usually in combination with other modalities such as bimanual pelvic examination and transvaginal ultrasonography,12 has been proposed as a method for the early detection of ovarian cancer. Elevated CA 125 levels are not specific to ovarian cancer and have been observed in patients with nongynecological cancers 11 and in the presence of certain other conditions, such as the first trimester of pregnancy 13,14 or endometriosis.15 The most commonly reported CA 125 reference value that designates a positive screening test is 35 U/mL. The sensitivity of CA 125 for the detection of ovarian cancer was estimated in 2 nested case-control studies using serum banks.16,17 The sensitivity for CA 125 levels of greater than or equal to 35 U/mL ranged from 20% to 57% for cases occurring within the first 3 years of follow-up; the specificity was 95%. A CA 125 screening program of 22,000 postmenopausal women with subsequent transabdominal ultrasound for those with elevated CA 125 levels (reference value of 30 U/mL) detected 11 of 19 cases of ovarian cancer occurring in the cohort for an apparent sensitivity of 58%.18 The specificity for this screening study was 99.9%. Three of the 11 cases detected on screening were stage I disease. In one prospective screening study, the specificity of CA 125 levels of 35 U/mL was 97.6%.19

The available evidence suggests that using CA 125 alone, particularly at a reference value of 35 U/mL, does not have a sufficiently high sensitivity to be recommended for routine screening of ovarian cancer. The use of multiple modalities including bimanual examination, transvaginal ultrasonography, and CA 125 serum levels may be a means to improve sensitivity and maintain an adequate level of specificity. The cost of tests such as ultrasonography, in addition to the risks and cost associated with subsequent surgical evaluation of false positive test results, is a potential impediment to routine screening. Reports from several ovarian cancer screening centers stress the difficulties of screening in high-risk populations.20,21 A decision analysis model used to evaluate the potential effect of ovarian cancer screening predicted little improvement in life expectancy as a result of mass screening.22

Whether measurement of CA 125 levels as a component of a multimodality screening program may be useful requires further evaluation in controlled clinical trials as none of these methods is of proven benefit for the early detection of ovarian cancer. A National Cancer Institute multicenter trial is ongoing to test the utility of transvaginal ultrasound and CA 125 measurement in reducing the mortality from ovarian cancer.23 A pilot randomized trial in the United Kingdom allocated 10,977 women to a control group and 10,958 women to a screened group in 1989.24 The primary screen was CA 125, followed by ultrasonography when CA 125 was elevated. Women were offered 3 annual screening rounds and both groups were followed for 7 years. Compliance was 70.7% for all 3 screenings and 85.5% for at least 1 screening. There were 20 ovarian cancers in the control group and 16 in the screened group, only 6 of which were detected by screening. There was a higher proportion of stage I/II cancers in the screened group (31.3% vs 10.0%). There were 18 ovarian cancer deaths in the control group and 9 in the screened group (relative risk = 2.0, 95% confidence interval 0.78-5.13). However, the outcome for women with ovarian cancer in the control group was unexpectedly poor. A larger trial is required to fully assess screening.

References:

  1. Smith LH, Oi RH: Detection of malignant ovarian neoplasms: a review of the literature: I. Detection of the patient at risk; clinical, radiological and cytological detection. Obstetrical and Gynecological Survey 39(6): 313-328, 1984.
  2. Keettel WC, Pixley EE, Buchsbaum HJ: Experience with peritoneal cytology in the management of gynecologic malignancies. American Journal of Obstetrics and Gynecology 120(2): 174-182, 1974.
  3. Hall DJ, Hurt WG: The adnexal mass. Journal of Family Practice 14(1): 135-140, 1982.
  4. Brown DL, Doubilet PM, Miller FH, et al.: Benign and malignant ovarian masses: selection of the most discriminating gray-scale and Doppler sonographic features. Radiology 208(1): 103-110, 1998.
  5. Higgins RV, van Nagell JR, Woods CH, et al.: Interobserver variation in ovarian measurements using transvaginal sonography. Gynecologic Oncology 39: 69-71, 1990.
  6. Andolf E, Jorgensen C, Astedt B: Ultrasound examination for detection of ovarian carcinoma in risk groups. Obstetrics and Gynecology 75(1): 106-109, 1990.
  7. Campbell S, Bhan V, Royston P, et al.: Transabdominal ultrasound screening for early ovarian cancer. British Medical Journal 299: 1363-1367, 1989.
  8. DePriest PD, van Nagell JR, Gallion HH, et al.: Ovarian cancer screening in asymptomatic postmenopausal women. Gynecologic Oncology 51(2): 205-209, 1993.
  9. Bourne TH, Campbell S, Reynolds KM, et al.: Screening for early familial ovarian cancer with transvaginal ultrasonography and colour blood flow imaging. British Medical Journal 306(6884): 1025-1029, 1993.
  10. Bast RC, Feeney M, Lazarus H, et al.: Reactivity of a monoclonal antibody with human ovarian carcinoma. Journal of Clinical Investigation 68(11): 1331-1337, 1981.
  11. Bast RC, Klug TL, St. John E, et al.: Radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. New England Journal of Medicine 309(15): 883-887, 1983.
  12. Jacobs I, Stabile I, Bridges J, et al.: Multimodal approach to screening for ovarian cancer. Lancet 1(8580): 268-271, 1988.
  13. Niloff JM, Knapp RC, Schaetzl E, et al.: CA125 antigen levels in obstetric and gynecologic patients. Obstetrics and Gynecology 64(5): 703-707, 1984.
  14. Haga Y, Sakamoto K, Egami H, et al.: Evaluation of serum CA125 values in healthy individuals and pregnant women. American Journal of the Medical Sciences 292(1): 25-29, 1986.
  15. Jacobs I, Bast RC: The CA 125 tumour-associated antigen: a review of the literature. Human Reproduction 4(1): 1-12, 1989.
  16. Zurawski VR, Orjaseter H, Andersen A, et al.: Elevated serum CA 125 levels prior to diagnosis of ovarian neoplasia: relevance for early detection of ovarian cancer. International Journal of Cancer 42: 677-680, 1988.
  17. Helzlsouer K, Bush TL, Alberg AJ, et al.: Prospective study of serum CA-125 levels as markers of ovarian cancer. Journal of the American Medical Association 269(9): 1123-1126, 1993.
  18. Jacobs I, Davies AP, Bridges J, et al.: Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. British Medical Journal 306(6884): 1030-1034, 1993.
  19. Einhorn N, Sjovall K, Knapp RC, et al.: Prospective evaluation of serum CA 125 levels for early detection of ovarian cancer. Obstetrics and Gynecology 80(1): 14-18, 1992.
  20. Muto MG, Cramer DW, Brown DL, et al.: Screening for ovarian cancer: the preliminary experience of a familial ovarian cancer center. Gynecologic Oncology 51(1): 12-20, 1993.
  21. Karlan BY, Raffel LJ, Crvenkovic G, et al.: A multidisciplinary approach to the early detection of ovarian carcinoma: rationale, protocol design, and early results. American Journal of Obstetrics and Gynecology 169(3): 494-501, 1993.
  22. Schapira MM, Matchar DB, Young MJ: The effectiveness of ovarian cancer screening: a decision analysis model. Annals of Internal Medicine 118(11): 838-843, 1993.
  23. Gohagan JK, Prorok PC, Kramer BS, et al.: Screening for ovarian cancer: epidemiological aspects, study design, and target population. In: Lawton FG, Neijt JP, Swenerton KD, Eds.: Epithelial Cancer of the Ovary. London: British Medical Journal Publishing Group, 1995, pp 59-67.
  24. Jacobs IJ, Skates SJ, MacDonald N, et al.: Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 353(9160): 1207-1210, 1999.

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