14.  Screening for Ovarian Cancer



RECOMMENDATION



Routine screening for ovarian cancer by ultrasound, the measurement of

serum tumor markers, or pelvic examination is not recommended. There is

insufficient evidence to recommend for or against the screening of

asymptomatic women at increased risk of developing ovarian cancer. 



Burden of Suffering



Ovarian cancer is the fifth leading cause of cancer deaths among U.S.

women and has the highest mortality of any of the gynecologic cancers.1

It accounted for an estimated 26,600 new cases and 14,500 deaths in

1995.1 The lifetime risk of dying from ovarian cancer is 1.1%.1a The

overall 5-year survival rate is at least 75% if the cancer is confined to

the ovaries and decreases to 17% in women diagnosed with distant

metastases.2,3 Symptoms usually do not become apparent until the tumor

compresses or invades adjacent structures, ascites develops, or

metastases become clinically evident.4 As a result, two thirds of women

with ovarian cancer have advanced (Stage III or IV) disease at the time of

diagnosis.2,5,6 Carcinoma of the ovary is most common in women over age

60.7 Other important risk factors include low parity and a family history

of ovarian cancer.8-10 Less than 0.1% of women are affected by

hereditary ovarian cancer syndrome, but these women may face a 40%

lifetime risk of developing ovarian cancer.11



Accuracy of Screening Tests



Potential screening tests for ovarian cancer include the bimanual pelvic

examination, the Papanicolaou (Pap) smear, tumor markers, and ultrasound

imaging. The pelvic examination, which can detect a variety of gynecologic

disorders, is of unknown sensitivity in detecting ovarian cancer. Although

pelvic examinations can occasionally detect ovarian cancer,12,13 small,

early-stage ovarian tumors are often not detected by palpation,14,15 due

to the deep anatomic location of the ovary. Thus, ovarian cancers detected

by pelvic examination are generally advanced7,16-18 and associated with

poor survival.16 The pelvic examination may also produce false positives

when benign adnexal masses (e.g., functional cysts) are found.16,19 The

Pap smear may occasionally reveal malignant ovarian cells,20 but it is not

considered a valid screening test for ovarian carcinoma.16-18,21 Studies

indicate that the Pap smear has a sensitivity for ovarian cancer of only

10-30%.16 



Serum tumor markers are often elevated in women with ovarian cancer.

Examples of these markers include carcinoembryonic antigen, ovarian

cystadenocarcinoma antigen, lipid-associated sialic acid, NB/70K, TAG

72.3, CA15-3, and CA-125. CA-125 is elevated in 82% of women with

advanced (Stage III or IV) ovarian cancer,22 and it is also elevated,

although less frequently, in women with earlier stage disease.23 In

studies of women with known or suspected ovarian cancer, the reported

sensitivities of CA-125 in detecting Stage I and Stage II cancers are 29-

75% and 67-100%, respectively.24-30 These cases may not be

representative of asymptomatic women in the general population,

however. In screening studies, including a recent study of more than

22,000 women, the reported sensitivity was 53-85%.13,31 Evidence is

limited on whether tumor markers become elevated early enough in the

natural history of occult ovarian cancer to provide adequate sensitivity

for screening. Studies of stored sera have found that about one half of

women who developed ovarian cancer had elevated CA-125 levels (>35

U/mL) 18 months23 to 3 years32 before their diagnosis. Further research

is needed, however, to provide more reliable data on the sensitivity of

this and other tumor markers in detecting early-stage ovarian cancer in

asymptomatic women. 



Tumor markers may have limited specificity. It has been reported that CA-

125 is elevated in 1% of healthy women, 6-40% of women with benign

masses (e.g., uterine fibroids, endometriosis, pancreatic pseudocyst,

pulmonary hamartoma), and 29% of women with nongynecologic cancers

(e.g., pancreas, stomach, colon, breast).22,33 Reported specificity in

screening studies is about 99%.13,31 It may be possible to improve the

specificity of CA-125 measurement by selective screening of

postmenopausal women,34 modifying the assay technique,35 adding other

tumor markers to CA-125,36 requiring a higher concentration or

persistent elevation of CA-125 levels over time, or combining CA-125

measurement with ultrasound (see below). Prospective studies involving

asymptomatic women are needed, however, to provide definitive data on

the performance characteristics of these techniques when used as

screening tests. 



Ultrasound imaging has also been evaluated as a screening test for ovarian

cancer, since it is able to estimate ovarian size, detect masses as small

as 1 cm, and distinguish solid lesions from cysts.17,37 Transvaginal

color-flow Doppler ultrasound can also identify vascular patterns

associated with tumors.38,39 In screening studies, the reported

sensitivity and specificity of transabdominal or transvaginal ultrasound

are 50-100% and 76-97%, respectively,3,14,15,40-43 but small sample

sizes, limited follow-up, and outdated techniques may limit the validity

of the data. Studies have shown that routine ultrasound testing of

asymptomatic women has a low yield in detecting ovarian cancer and

generates a large proportion of false-positive results that often require

diagnostic laparotomy or laparoscopy. In one study, ultrasound screening

of 805 high-risk women led to 39 laparotomies, which revealed one

ovarian carcinoma, two borderline tumors, one cancer of the cecum, and

five cystadenomas.40 A transvaginal ultrasound study of 600 patients

with previous breast cancer revealed 18 patients with complex cysts or

enlarged ovaries. Laparotomy was performed on 21 patients, four of whom

had ovarian cancer (positive predictive value of 22%); the use of color-

flow imaging appeared to increase the positive predictive value.44



In a larger study, ultrasound was performed routinely on 5,678

asymptomatic female volunteers over age 45 or with a history of previous

breast or gynecologic cancer.44a Two Stage I ovarian cancers were

detected in a total of 6,920 scans performed over 2 years. Another report

from the same center indicated that 14,356 ultrasound examinations

performed over 3 years on 5,489 asymptomatic women over age 45

detected five ovarian cancers.45 Although the sensitivity and specificity

of the test were excellent (100% and 94.6%, respectively), the positive

predictive value in this low-risk study population was only 2.6% and

follow-up was of short duration. It has been calculated from these results

and other data that ultrasound screening of 100,000 women over age 45

would detect 40 cases of ovarian cancer, but at a cost of 5,398 false

positives and over 160 complications from diagnostic laparoscopy.46



It may be possible to improve accuracy by combining ultrasound with

other screening tests, such as the measurement of CA-125. This approach

has been examined as a method of discriminating between benign and

malignant adnexal masses in preoperative patients.47 Further research is

needed, however, to determine the sensitivity, specificity, and positive

predictive value of performing these tests in combination to screen

asymptomatic women. One prospective study12 screened 1,010

asymptomatic postmenopausal women over age 45 with pelvic

examination and CA-125 measurement; those with abnormal results

received an ultrasound examination. Although one ovarian cancer was

detected (all three screening tests were positive in this woman), the

study demonstrated poor positive predictive value with each of the three

screening tests. No abnormality was discovered in 28 of the 31 women

with elevated CA-125. Fibroids and benign cysts were responsible for over

half of the 28 abnormal pelvic examinations. There were 13 abnormal

ultrasound examinations; 12 of these women consented to laparotomy,

which revealed six benign ovarian cysts, two fimbrial cysts, two women

with no surgical findings, one woman with adhesions, and the ovarian

cancer. A more recent report from the same center found that the

combination of abdominal ultrasound and sequential CA-125

measurements had a sensitivity of 58-79%, a specificity of about 100%,

and a positive predictive value of 27%.31 Another program that screened

597 women with transvaginal color-flow Doppler ultrasound and CA-125

measurements detected abnormalities in 115 patients, only one of whom

had ovarian cancer.48



Effectiveness of Early Detection



There is no direct evidence from prospective studies that women with

early-stage ovarian cancer detected through screening have lower

mortality from ovarian cancer than do women with more advanced disease.

A large body of indirect evidence, however, suggests that this is the case.

Although lead-time and length biases may be responsible, it is known that

survival from ovarian cancer is related to stage at diagnosis. The 5-year

survival rate is 89% for localized disease, 36% for women with regional

metastases, and 17% for women with distant metastases.1 Studies have

shown that the most important prognostic factor in patients with

advanced ovarian cancer is the size of residual tumor after treatment.4,7

Surgical debulking and chemotherapy for ovarian cancer appear to be more

effective in reducing the size of residual tumor when ovarian cancer is

detected early.4 Although these observations provide suggestive evidence

that early detection may be beneficial, conclusive proof will require

properly conducted prospective studies comparing long-term mortality

from ovarian cancer between screened and nonscreened cohorts. A large

clinical trial to obtain this evidence has recently been launched by the

National Cancer Institute.49 Under the most optimistic assumptions

(100% sensitivity, 30% reduction in 5-year mortality with screening, no

lead-time bias), annual pelvic examinations of 40-year-old women would

reduce 5-year mortality from ovarian cancer in the population by less than

0.0001%.50 Modeling studies that have examined annual CA-125 testing or

a single screening with transvaginal ultrasound and CA-125 measurement

have found that either approach would increase life expectancy by an

average of less than 1 day per woman screened.51,52



Recommendations of Other Groups



There are no official recommendations to screen routinely for ovarian

cancer in asymptomatic women by performing ultrasound or serum tumor

marker measurements. The American College of Physicians (ACP),53 the

Canadian Task Force on the Periodic Health Examination,54 and the

American College of Obstetricians and Gynecologists55 recommend

against such screening. A National Institutes of Health Consensus

Conference on Ovarian Cancer recommended taking a careful family

history and performing an annual pelvic examination on all women.56 The

pelvic examination, including palpation of the adnexae, is mentioned in a

recommendation on Pap testing issued by the American Cancer Society,

National Cancer Institute, American College of Obstetricians and

Gynecologists, American Medical Association, American Nurses

Association, American Academy of Family Physicians, and the American

Medical Women's Association.57 Specifically, the pelvic examination (and

Pap smear) is recommended annually for all women who are or have been

sexually active or have reached age 18. Although Pap testing may be

performed less frequently once three annual smears have been normal, the

American Cancer Society specifies that the pelvic examination be

performed with the Pap test every 1-3 years in women aged 18-40 years

and annually thereafter.58



The NIH Consensus Conference concluded that women with presumed

hereditary cancer syndrome should undergo annual pelvic examinations,

CA-125 measurements, and transvaginal ultrasound until childbearing is

completed or at age 35, at which time prophylactic bilateral

oopherectomy was recommended.56 The ACP recommends counseling high-

risk women about the potential benefits and harms of screening.53 The

Canadian Task Force on the Periodic Health Examination found insufficient

evidence to recommend for or against screening for ovarian cancer in

high-risk women.54



Discussion



The sensitivity and specificity of available screening tests for ovarian

cancer in asymptomatic women are uncertain and require further study.

Although various tests can detect occasional asymptomatic tumors, there

is currently no evidence that routine screening will improve overall health

outcomes. The large majority of women with abnormal screening test

results do not have cancer, yet will require invasive procedures

(laparoscopy or laparotomy) to rule out malignancy. Given the risks,

inconvenience, and substantial costs of follow-up testing, and the current

lack of evidence that screening reduces morbidity or mortality from

ovarian cancer, routine screening cannot be recommended. Trials to

determine the benefits and risks of ovarian cancer screening are under

way. There is also no evidence to support routine screening in women with

a history of ovarian cancer in a first-degree relative. Although such

women are at increased risk and stand to benefit more from interventions

that reduce ovarian cancer mortality, the effectiveness of screening has

yet to be determined for any group of women. Referral to a specialist may

be appropriate for women whose family history suggests hereditary

ovarian cancer syndrome, due to the very high risk of cancer in this

disorder.



CLINICAL INTERVENTION



Screening asymptomatic women for ovarian cancer with ultrasound, the

measurement of serum tumor markers, or pelvic examination is not

recommended ("D" recommendation). There is insufficient evidence to

recommend for or against the screening of asymptomatic women at

increased risk of ovarian cancer ("C" recommendation).



The draft update of this chapter was prepared for the U.S. Preventive

Services Task Force by Steven H. Woolf, MD, MPH, based in part on a paper

prepared for the Clinical Efficacy Assessment Panel of the American

College of Physicians by Karen J. Carlson, MD, et al. See relevant

background paper: Carlson KJ, Skates SJ, Singer DE. Screening for ovarian

cancer. Ann Intern Med 1994;121:124-132.



REFERENCES



  1. Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA Cancer J Clin

1995;45:8-30.



 1a. Ries LAG, Miller BA, Hankey BF, et al, eds. SEER cancer statistics

review, 1973-1991: tables and graphs. Bethesda: National Cancer

Institute, 1994. (NIH Publication no. 94-2789.)



  2. Pettersson F, ed. Annual report on the results of treatment of

gynecologic cancer. Int J Gynecol Obstet 1991;36(suppl):238-277.



  3. Goswamy RK, Campbell S, Whitehead MI. Screening for ovarian cancer.

Clin Obstet Gynecol 1983;10:621-643.



  4. Slotman BJ, Rao BR. Ovarian cancer: etiology, diagnosis, prognosis,

surgery, radiotherapy, chemotherapy and endocrine therapy. Anticancer

Res 1988;8:417-434.



  5. Richardson GS, Scully RE, Nikrui N, et al. Common epithelial cancer of

the ovary. N Engl J Med 1985;312:415-424.



  6. Young RC. Ovarian cancer treatment: progress or paralysis. Semin Oncol

1984;11:327-329.



  7. Young JL, Percy CL, Asire AJ, eds. SEER Program: incidence and

mortality, 1973-1977. National Cancer Institute, Monograph 57.

Washington, DC: Government Printing Office, 1981:75.



  8. Whittemore AS, Harris R, Itnyre J, et al. Characteristics relating to

ovarian cancer risk: collaborative analysis of 12 US case-control studies.

II. Invasive epithelial ovarian cancers in white women. Am J Epidemiol

1992;136: 1184-1203.



  9. Kerlikowske K, Brown JS, Grady DG. Should women with familial

ovarian cancer undergo prophylactic oopherectomy? Obstet Gynecol

1992;80:700-707.



 10. Amos CI, Struewing JP. Genetic epidemiology of epithelial ovarian

cancer. Cancer 1993;71:566-572.



 11. Biesecker B, Boehnke M, Calzone K. Genetic counseling for families

with inherited susceptibility to breast and ovarian cancer. JAMA

1993;269:1970-1974.



 12. Jacobs I, Stabile I, Bridges J, et al. Multimodal approach to screening

for ovarian cancer. Lancet 1988;1:268-271.



 13. Einhorn N, Sjovall K, Knapp RC, Hall P, Scully RE, Bast RC, Zurawski

VR. Prospective evaluation of serum CA 125 levels for the early detection

of ovarian cancer. Obstet Gynecol 1992;80:14-18.



 14. Van Nagell JR, DePriest PD, Puls NE, Donaldson ES, Gallion HH, Pavlik

EJ, et al. Ovarian cancer screening in asymptomatic postmenopausal

women by transvaginal sonography. Cancer 1991;68:458-462.



 15. Andolf E, Jorgensen C, Astedt B. Ultrasound examination for detection

of ovarian carcinoma in risk groups. Obstet Gynecol 1990;75:106-109.



 16. Smith LH, Oi RH. Detection of malignant ovarian neoplasm: a review of

the literature. 1. Detection of the patient at risk; clinical, radiological and

cytological detection. Obstet Gynecol Surv 1984;39:313-328.



 17. Lynch HT, Albano WA, Lynch JF, et al. Surveillance and management of

patients at high genetic risk for ovarian carcinoma. Obstet Gynecol

1982;59:589-596.



 18. Hall DJ, Hurt WG. The adnexal mass. J Fam Pract 1982;14:135-140.



 19. Griffiths CT. Carcinoma of the ovary and fallopian tube. In: Holland JF,

Frei E, eds. Cancer medicine. Philadelphia: Lea & Febiger, 1982:1958-1969.



 20. Graham JB, Graham RM, Schueller EF. Preclinical detection of ovarian

cancer. Cancer 1964;17:1414.



 21. Rubin P, Bennett JM. Ovarian cancer. In: Bakeman RP, ed. Clinical

oncology for medical students and physicians: a multidisciplinary

approach. 5th ed. New York: American Cancer Society, 1978:114-120.



 22. Bast RC, Klug TL, St John E, et al. A radioimmunoassay using a

monoclonal antibody to monitor the course of epithelial ovarian

carcinoma. N Engl J Med 1983;309:883-887.



 23. Zurawski VR Jr, Orjaseter H, Andersen A, et al. Elevated serum CA 125

levels prior to diagnosis of ovarian cancer neoplasia: relevance for early

detection of ovarian cancer. Int J Cancer 1988;42:677-680.



 24. Zurawski VR Jr, Knapp RC, Einhorn N, et al. An initial analysis of

preoperative serum CA 125 levels in patients with early stage ovarian

carcinoma. Gynecol Oncol 1988;30:7-14.



 25. Patsner B, Mann WJ. The value of preoperative serum CA 125 levels in

patients with a pelvic mass. Am J Obstet Gynecol 1988;159:873-876.



 26. Mogensen O, Mogensen B, Jakobsen A. CA 125 in the diagnosis of pelvic

masses. Eur J Cancer Clin Oncol 1989;25:1187-1190.



 27. Cruickshank DJ, Fullerton WT, Klopper A. The clinical significance of

pre-operative serum CA 125 in ovarian cancer. Br J Obstet Gynaecol

1987;94:692-695.



 28. Zanaboni F, Vergadoro F, Presti M, Gallotti P, Lombardi F, Bolis G.

Tumor antigen CA 125 as a marker of ovarian epithelial carcinoma.

Gynecol Oncol 1987;28:61-67.



 29. Brioschi PA, Irion O, Bischof P, Bader M, Forni M, Krauer F. Serum CA

125 in epithelial ovarian cancer: a longitudinal study. Br J Obstet Gynaecol

1987;94:196-201.



  30. Schilthuis MS, Aalders JG, Bouma J, et al. Serum CA 125 levels in

epithelial ovarian cancer: relation with findings at second-look operations

and their role in the detection of tumour recurrence. Br J Obstet Gynaecol

1987;94:202-207.



  31. Jacobs I, Davies AP, Bridges J, et al. Prevalence screening for ovarian

cancer in postmenopausal women by CA 125 measurement and

ultrasonography. BMJ 1993;306:1030-1034.



 32. Helzllsouer KJ, Bush TL, Alberg AJ, Bass KM, Zacer H, Comstock GW.

Prospective study of serum CA125 levels as markers of ovarian cancer.

JAMA 1993;269:1123-1126.



 33. Di-Xia C, Schwartz P, Xinguo L, et al. Evaluation of CA 125 levels in

differentiating malignant from benign tumors in patients with pelvic

masses. Obstet Gynecol 1988;72:23-27.



 34. Zurawski VR Jr, Broderick SF, Pickens P, et al. Serum CA 125 levels in

a group of nonhospitalized women: relevance for the early detection of

ovarian cancer. Obstet Gynecol 1987;69:606-611.



  35. Klug TL, Green PJ, Zurawski VR Jr, et al. Confirmation of a false-

positive result in CA 125 immunoradiometric assay caused by human anti-

idiotypic immunoglobulin. Clin Chem 1988;34:1071-1076.



 36. Jacobs IJ, Oram DH, Bast RC. Strategies for improving the specificity

of screening for ovarian cancer with tumor-associated antigens CA125,

CA15-3, and TAG 72.3. Obstet Gynecol 1992;80:396-399.



 37. Campbell S, Goessens L, Goswamy R, et al. Real-time ultrasound for

determination of ovarian morphology and volume: a possible early

screening test for ovarian cancer? Lancet 1982;1:425-426.



 38. Bourne T, Campbell S, Steer C, Whitehead MI, Collins WP. Transvaginal

colour flow imaging: a possible new screening technique for ovarian

cancer. BMJ 1989;299:1367-1370.



  39. Kurjak A, Zalud I, Alfirevic Z. Evaluation of adnexal masses with

transvaginal color ultrasound. J Ultrasound Med 1991;10:295-297.



 40. Andolf E, Svalenius E, Astedt B. Ultrasonography for early detection of

ovarian carcinoma. Br J Obstet Gynaecol 1986;93:1286-1289.



 41. Campbell S, Royston P, Bhan V, Whitehead MI, Collins WP. Novel

screening strategies for early ovarian cancer by transabdominal

ultrasonography. Br J Obstet Gynaecol 1990;97:304-311.



 42. Rodriguez MH, Platt LD, Medearis AL, Lacarra M, Lobo RA. The use of

transvaginal ultrasonography for evaluation of postmenopausal size and

morphology. Am J Obstet Gynecol 1988;159:810-814.



 43. Bourne TH, Campbell S, Reynolds KM, et al. Screening for early

familial ovarian cancer with transvaginal ultrasonography and colour flow

imaging. BMJ 1993;306:1025-1029.



 44. Weiner Z, Beck D, Shteiner M, et al. Screening for ovarian cancer in

women with breast cancer with transvaginal sonography and color flow

imaging. J Ultrasound Med 1993;12:387-393.



44a. Goswamy RK, Campbell S. Screening for ovarian cancer. IARC Sci Publ

1986;76:305-309.



 45. Campbell S, Bhan V, Royston J, et al. Screening for early ovarian

cancer. Lancet 1988;1:710-711.



 46. Jacobs I. Screening for early ovarian cancer. Lancet 1988;2:171-172.



 47. Finkler NJ, Benacerraf B, Lavin PT, et al. Comparison of serum CA 125,

clinical impression, and ultrasound in the preoperative evaluation of

ovarian masses. Obstet Gynecol 1988;72:659-664.



 48. Karlan BY, Raffel LJ, Crvenkovic G, et al. A multidisciplinary approach

to the early detection of ovarian carcinoma: rationale, protocol design, and

early results. Am J Obstet Gynecol 1993;169:494-501.



 49. Kramer BS, Gohagan J, Prorok PC, Smart C. A National Cancer Institute

sponsored screening trial for prostatic, lung, colorectal, and ovarian

cancers. Cancer 1993;71:589-593.



 50. Eddy DM. Annual pelvic examination. Ann Intern Med 1990;113:803.



 51. Skates SJ, Singer DE. Quantifying the potential benefit of CA125

screening for ovarian cancer. J Clin Epidemiol 1991;44:365-380.



 52. Schapira MM, Matchar DB, Young MJ. The effectiveness of ovarian

cancer screening: a decision-analysis model. Ann Intern Med

1993;118:838-843.



 53. American College of Physicians. Screening for ovarian cancer. Ann

Intern Med 1994;121:141-142.



 54. Canadian Task Force on the Periodic Health Examination. Canadian

guide to clinical preventive health care. Ottawa: Canada Communication

Group, 1994:869-881.



 55. American College of Obstetricians and Gynecologists. Routine cancer

screening. Committee Opinion no. 128. Washington, DC: American College

of Obstetricians and Gynecologists, 1993.



 56. National Institutes of Health. Ovarian cancer: screening, treatment,

and follow-up. National Institutes of Health Consensus Conference

Statement, April 5-7, 1994.



 57. Fink DJ. Change in American Cancer Society checkup guidelines for

detection of cervical cancer. CA Cancer J Clin 1988;38:127-128.



 58. American Cancer Society. Guidelines for the cancer-related checkup:

an update. Atlanta: American Cancer Society, 1993.