Transvaginal sonography (TVS) has been considered a primary imaging modality for diagnosing and evaluating adnexal masses. TVS has high specificity and sensitivity for detecting an adnexal mass based on a pattern recognition approach and morphological feature through gray-scale ultrasound. Table 4.2 is a summary of the findings of the four major ovarian cancer screening trials using TVS. These studies used gray-scale TVS as a primary screening modality [13, 14, 16, 17]. The percentage of the total number of stage I cases increased after the induction of screening (stage shift). It was not effective in detecting ovarian cancers in women who had normal ovarian volume. The use and role of Doppler ultrasonography as a screening technique are controversial. Color flow imaging for detection of ovarian cancer greatly improves specificity but at the expense of potential sensitivity in the triage of adnexal masses. Dr. van Nagell and his colleagues have reported some encouraging evidence of not only stage shift but also survival benefit by a single-arm prospective study, not a RCT [18]. A large-scale RCT is required for answering this question. Further, stringent quality control and quality assurance are necessary for TVS screening of asymptomatic postmenopausal women.

Several studies have assessed the diagnostic value of combinations of CA125 and imaging concurrently or sequentially to augment the specificity and sensitivity for screening. Clinicians and public health informants were in consensus that the key issue is to reduce mortality. Table 4.3 is a summary of the key conclusions from the five major ovarian cancer screening trials using CA125 and TVS.

First, Jacobs and coworkers studied a group of 1010 asymptomatic postmenopausal women, comparing the specificities of individual evaluation or a combination of CA125, TVS, and pelvic examination (the first London study) [19]. Their study showed a specificity of 99.8% and 99.0% for CA125 plus TVS and CA125 plus pelvic examination, respectively, indicating that the combination of CA125 with TVS achieved acceptable specificity.

In the second study (a pilot randomized controlled trial in the second London study) conducted in the UK by Jacobs and coworkers, the specificity of CA125 alone or in combination with abdominal ultrasound was evaluated in postmenopausal women 45 years of age or above [20]. The subjects were divided into a control group (10,977) and a screened group (10,985). A total of 16 and 21 cancers were detected in the screened and control group, respectively, during the same interval. Median survival in the screened group (72.9 months) was significantly greater than in the control group (41.8 months) [20].

Third, the original intention in the Shizuoka study (RCT with one screening strategy in study group) conducted in Japan by Kobayashi and coworkers was to offer women in the intervention group annual screens by gynecological examination (sequential TVS and serum CA125 test) [21]. Women with abnormal TVS findings and/or elevated CA125 values were referred for surgical investigation by a gynecological oncologist. Twenty-seven index cancers were detected in the 41,688 screened women. Eight cancers were diagnosed outside the screening program. Among the 40,779 control women, 32 women developed ovarian cancer. The detection rate of early-stage ovarian cancer was elevated in the screened group compared with the controls, which did not reach statistical significance (63% vs 38%, p = 0.2285). Interestingly, sub-analysis assessment identified that the Shizuoka screening favorably detected certain histotypes such as clear cell and endometrioid types that are more common, low-grade, and less aggressive tumors in Japan. Since the progression of endometriosis to cancer is usually slow, recognition of patients at early stages may improve survival.

Fourth, the prostate, lung, colon, and ovary (PLCO) screening trial in the USA aimed to conduct concurrent testing of CA125 and TVS in the low-risk asymptomatic women between 55 and 74 years of age to determine if screening could reduce mortality in these cancers [22]. This RCT of screening versus usual care was initiated in 1993 and has studied 78,216 women. Data from the PLCO trial has not shown mortality benefit [15, 22, 23].

Finally, the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) used the risk of ovarian cancer algorithm (ROCA) to interpret the impact of CA125, which has shown an encouraging sensitivity and specificity [15]. The mortality reduction was not significant in the primary analysis, but this trial may have the potential to make an impact on survival benefit when prevalent cases were excluded [24]. The survival data from the UKCTOCS study provide a modest degree of hope.

Given the paucity of randomized controlled trial data, at present there is no effective screening test for ovarian cancer. The previous RCT results are unable to provide the impact on clinical survival benefit. This allowed us to explore the impact of growing insights into disease etiology and biomarker discovery on future screening strategies. In an era of promising advances in ovarian cancer screening, researchers have to focus on detecting low-volume disease using cancer-specific markers and targeted imaging. More cost-effective approaches might utilize novel biomarkers alone or in combination with imaging modalities in a more limited number of women.

Hereditary breast and ovarian cancer (HBOC) syndrome accounts for 5%–10% of breast cancers and 15% of invasive ovarian cancers [26]. Mutations in two genes, BRCA1 and BRCA2, are associated with HBOC. The average lifetime risk of EOC in the general populations is 1.3%, but the risk is markedly increased in women who carry mutations of the BRCA1 or BRCA2 (40% and 18% risk, respectively, by age 70 years) or the mismatch repair genes of hereditary nonpolyposis colorectal cancer (Lynch) syndrome (12% lifetime risk) [27–29]. Women with BRCA mutations have a markedly increased risk of early-onset breast, ovarian, pancreatic, and other cancers when compared to the risks in the general population. EOC is a spectrum of several subtypes, with different clinicopathological characteristics, possibly separate pathways of progression, and different sets of genetic and epigenetic characteristic of familial versus sporadic tumors. Since the molecular biology of the known hereditary disease may differ from that of sporadic cancer, separate trials and screening strategies may be required to detect hereditary and sporadic ovarian cancer. The overall occult gynecological carcinoma has been detected in 9.1% of BRCA mutation carriers [30]. Clinical guidelines are available for HBOC, such as those published by the National Comprehensive Cancer Network (NCCN), which include breast and ovarian cancer screening (surveillance) and risk-reducing interventions (risk-reducing surgical and medical options) [30, 31]. Published guidelines adopt standardized surveillance strategies that limit medication side effects, medical/surgical exposure without compromising cancer control and unnecessary cost, as well as enhance overall clinical and economic outcomes.