The Effectiveness of Ovarian Cancer Screening: A Decision Analysis Model

An important issue in the preventive health care of women is screening for gynecologic malignancies. The role of cervical cancer screening is well established, but an effective approach to ovarian cancer screening is still being sought. Ovarian cancer is the leading cause of death among gynecologic malignancies (not including breast cancer) and the fifth leading cause of all cancer deaths in women [1]. In 75% of cases, the disease is detected in the late stage when 5-year survival is poor [1]. Developing an effective screening test is an attractive strategy for improving survival. There are several problems, however, with an ovarian cancer screening approach. A low annual incidence, 13.8/100 000 means that many people must be screened to find only a few cases of disease. In addition, an invasive procedure is needed to evaluate a positive screening test. This places a high financial, physical, and emotional cost on false-positive screening tests. Given the complexity of the decision and the absence of a randomized, controlled trial to evaluate screening strategies for ovarian cancer, we turned to decision analysis to examine this issue. This allowed quantification of the effect of relevant factors and specification of test characteristics required for an effective screening strategy. The specific question we pose is, will a one-time screen improve the average life expectancy in a cohort of 40-year-old women? Natural History of Ovarian Cancer Incidence, Risk, and Prognostic Factors The annual incidence of ovarian cancer in the United States is 13.8/100 000 with an annual incidence of death of 8.5/100 000 [2]. Its cause remains unknown, and survival rates have been relatively stable in the past 35 years [3]. The strongest risk factor for the disease is increasing age. Other risk factors are family history of ovarian cancer, residence in a Western industrialized country, and nulliparity [4]. Established protective factors are multiparity and oral contraceptive use [5]. The most important prognostic factor for ovarian cancer is stage of disease at diagnosis [6]. The present staging system for ovarian cancer was devised by the International Federation of Gynecology and Obstetrics. The system defines stage I as disease limited to the ovaries, stage II as disease limited to the true pelvis, stage III as disease that involves intraperitoneal spread, and stage IV as disease with distant metastasis. Other independently prognostic factors are the size of residual tumor remaining after a surgical debulking procedure and the histologic grade of the tumor [6]. Clinical Presentation and Disease Course Ovarian cancer is often silent in the early stages of disease, yet aggressive and resistant to treatment late in its course when most cases become clinically apparent. Ovarian cancer first spreads locally with metastasis to the contralateral ovary, the uterus, and the fallopian tubes. Further dissemination occurs through the peritoneum to involve the omentum, bowel, and retroperitoneal lymph nodes. Hematogenous spread is rare but can result in distant metastasis. As the disease progresses, gastrointestinal and urinary tract obstruction are common. These late complications are often resistant to effective medical or surgical intervention because of the extensive amount of disease. Most deaths occur within 5 years of diagnosis [7]. Early diagnosis of ovarian cancer is difficult because symptoms are often vague and nonspecific. Presenting symptoms include abdominal swelling and pain, abnormal uterine bleeding, and gastrointestinal and urinary complaints [8]. A retrospective study of 277 patients with primary ovarian cancer reports the average patient delay in seeking medical evaluation after the onset of symptoms to be 9.1 months and the average physician delay in performing pelvic examination in symptomatic patients to be 9.6 months [9]. The clinical significance of these delays is not known. Available Screening Tests The optimal characteristics of a screening test include ease of performance, patient acceptability, limited expense, lack of complications, and high sensitivity and specificity. Sensitivity is defined as the proportion of patients with the target disorder who have a positive test result. Specificity is defined as the proportion of patients without the target disorder who have a negative test result[10]. Screening tests that have been proposed for ovarian carcinoma include manual pelvic examination, cytologic detection, serologic testing with monoclonal antibodies, abdominal ultrasound, and transvaginal sonography (TVS). Of these, the monoclonal antibody to the CA 125 antigen and TVS are the most promising because of their high specificity and reproducibility and ease of performance. The test characteristics of these modalities are described below. Pelvic Examination and Cytologic Detection No evidence exists that annual pelvic examinations for detecting cervical cancer in asymptomatic women have increased case finding for early ovarian cancer. Compared with abdominal ultrasonography, the pelvic examination reportedly detects 34% of adnexal masses and over-reads 8% [11]. The cervical Papanicolaou smear, which is an effective test for the early detection of cervical cancer, is not a good screening test for ovarian carcinoma. In a population of 164 patients diagnosed with ovarian carcinoma, only 11% had a positive Papanicolaou smear [12]. Peritoneal and cul-de-sac lavage have also been investigated as possible screening tests for ovarian cancer but are cumbersome to perform and have poor test performance [13, 14]. Abdominal Ultrasonography Abdominal ultrasonography has been evaluated extensively as a screening test for ovarian cancer. Uncontrolled screening trials have provided information on test characteristics but have failed to show a convincing benefit in terms of the detection of early-stage disease. The specificity of abdominal ultrasound scans in the detection of ovarian cancer was estimated to be 97.7% (95% CI, 96.4% to 99.0%) in a study of 5000 asymptomatic women aged 18 to 78 years (mean age, 52 years) who were screened with abdominal ultrasound for 3 consecutive years [15]. The sensitivity of abdominal ultrasound scan to detect a pelvic mass was found to be 90% in a study of 72 women with a diagnosis of pelvic mass who subsequently had laparotomy [16]. Abdominal ultrasonography has the disadvantages of being time consuming and expensive and requiring significant patient preparation. Transvaginal Sonography The use of TVS has been proposed as an alternative to abdominal ultrasound in ovarian cancer screening. Transvaginal sonography was developed to improve the resolution of abdominal ultrasound and provides detailed imaging of the ovary and masses confined to the true pelvis. It is easy to perform, well accepted by patients, and shows strong interobserver interpreter agreement [17, 18]. In premenopausal women, a normal ovary is defined as having a volume of 18 cm3 or less and being uniformly hypogenic or entirely cystic. If the ovary is enlarged but the structure is normal, the scan is repeated 1 week after menses. If the scan remains abnormal, the test is considered positive. In postmenopausal women, a normal ovary is defined as having a volume of 8 cm3 or less and a uniformly hypogenic internal structure. Any ovary that exceeds this volume or shows complex or solid areas on sonography is defined as abnormal. The specificity of TVS for ovarian carcinoma was found to be 98.1% (CI, 97.4% to 98.8%) in a study of 1300 asymptomatic postmenopausal women who underwent screening with TVS [17]. The sensitivity of TVS in the detection of an ovarian mass was found to be 90% in a study of postmenopausal women undergoing elective surgery for reasons unrelated to adnexal disease [19]. Transvaginal sonography with color flow imaging is under investigation as a screening modality [20]. This test can detect intraovarian vascular changes and measure impedance to blood flow in ovarian masses as potential indices of early malignancy. This technique may increase the specificity of conventional ultrasound examinations. Monoclonal Antibodies The development of monoclonal antibodies reactive to tumor-specific antigens has been applied to the diagnosis and management of ovarian cancer. The most promising monoclonal antibody with respect to ovarian cancer screening is 0C 125, which reacts to the CA 125 antigen. It was originally reported that serum CA 125 was greater than 35 U/mL in 83% of patients with epithelial ovarian cancer and 1% of presumably healthy blood donors [21]. CA 125 was also found to be elevated in nongynecologic carcinomas and benign abdominal disorders such as pancreatic pseudocyst, uterine fibroids, and endometriosis [21]. The sensitivity of CA 125 for ovarian cancer increases with the clinical stage at diagnosis, 50% for stage I and II neoplasms and 90% for stage III and IV neoplasms [22, 23]. The specificity of CA 125 for ovarian cancer was determined to be 97.6% in a prospective study of 5550 women ages 40 years or older who were screened with CA 125. In the study, an elevated level of CA 125 was followed with physical examination, abdominal ultrasound, and serial CA 125 levels, with further management based on clinical and sonographic findings [24]. Methods The Decision Analysis Model We designed a decision tree to test the strategy of a one-time screen versus no screen for a population of healthy 40-year-old women (Figure 1). We modeled the use of CA 125 and TVS as individual and combined screening tests. When used in combination, an abnormal test was required of both modalities to define a positive screen. A decision tree is a diagram that describes a clinical decision and possible outcomes of that decision. The tree begins with a decision node that represents an active choice that is to be made by the patient or physician. Each point of uncertainty is represented by a chance node. Branches of chance nodes