Screening for ovarian cancer: what we know, what we need to know

The majority of women with ovarian cancer present with advanced-stage disease. Women with early-stage ovarian cancer have a much better chance of achieving a cure than do women with late-stage disease. This difference makes screening for ovarian cancer, with the hope of detecting it in its presymptomatic state, an attractive concept. Unfortunately, efforts to demonstrate that screening for ovarian cancer in the general population can decrease mortality have been disappointing. Current screening techniques do not have high enough sensitivity and specificity to be applied to the general population, because the low prevalence of the disease in the general population leads to very low positive predictive values for the available screening tests. However, applying current screening strategies to certain high-risk populations (women who carry mutations in the BRCA1 or BRCA2 genes, or with strong family histories of breast/ovarian cancer) is a reasonable approach and may result in acceptably high positive predictive values. This article discusses the results of screening studies using serum CA-125, sonography, other serum markers, and combinations of these tests. Screening for women of average risk is not recommended, although such women should be encouraged to participate in clinical trials whose end points are either the demonstration of the impact of screening on mortality, or the development of novel screening strategies. Screening with twice yearly transvaginal sonography and serum CA-125 testing is recommended for women at high risk for ovarian cancer, although prospective data are needed regarding the impact of such screening on stage of cancer detected, quality of life, and psychological distress, as well as the costs--both personal and societal--of screening.     

Ovarian cancer screening with annual transvaginal sonography: findings of 25,000 women screened

BACKGROUND: Ovarian cancer has the highest mortality rate of all gynecologic malignancies, and most women present with advanced-stage disease. The current investigation was performed to determine the efficacy of annual transvaginal sonography (TVS) as a screening method for ovarian cancer. METHODS: Annual TVS screening was performed on 25,327 women from 1987 to 2005. Asymptomatic women aged>or=50 years and women aged>or=25 years who had a family history of ovarian cancer were eligible for participation in this trial. RESULTS: Among 364 patients (1.4%) with a persisting ovarian tumor on TVS who underwent exploratory laparoscopy or laparotomy with tumor removal, 35 primary invasive ovarian cancers, 9 serous ovarian tumors of low malignant potential, and 7 cancers metastatic to the ovary were detected. Stage distribution was as follows: 28 patients had stage I disease, 8 patients had stage II disease, and 8 patients had stage III disease. Four patients died of disease, 2 patients died of other causes, and 38 patients were alive and well from 0.5 years to 15.8 years after diagnosis (mean, 5.3 years). Nine women developed ovarian cancer within 12 months of a negative screen (false-negative results), and 3 of these patients died of disease. TVS screening had a sensitivity of 85.0%, specificity of 98.7%, positive predictive value of 14.01%, and negative predictive value of 99.9%. After 107,276 screening years, there have been 7 ovarian cancer deaths in the annually screened population and 3 ovarian cancer deaths among women who were noncompliant. Excluding patients with nonepithelial or borderline ovarian malignancies, the survival of patients with ovarian cancer in the annually screened population was 89.9%+/-10.1% at 2 years and 77.2%+/-22.8% at 5 years. CONCLUSIONS: TVS screening, when it was performed annually, was associated with a decrease in disease stage at detection and with case-specific ovarian cancer mortality, but it was not effective in detecting ovarian cancers in women who had normal ovarian volume.     

Development of an ovarian cancer screening decision model that incorporates disease heterogeneity: implications for potential mortality reduction

BACKGROUND:

Pathologic and genetic data suggest that epithelial ovarian cancer may consist of indolent and aggressive phenotypes. The objective of the current study was to estimate the impact of a 2‐phenotype paradigm of epithelial ovarian cancer on the mortality reduction achievable using available screening technologies.

METHODS:

The authors modified a Markov model of ovarian cancer natural history (the 1‐phenotype model) to incorporate aggressive and indolent phenotypes (the 2‐phenotype model) based on histopathologic criteria. Stage distribution, incidence, and mortality were calibrated to data from the Surveillance, Epidemiology, and End Results Program of the US National Cancer Institute. For validation, a Monte Carlo microsimulation (1000,000 events) of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) multimodality prevalence screen was performed. Mortality reduction and positive predictive value (PPV) were estimated for annual screening.

RESULTS:

In validation against UKCTOCS data, the model‐predicted percentage of screen‐detected cancers diagnosed at stage I and II was 41% compared with 47% (UKCTOCS data), and the model‐predicted PPV of screening was 27% compared with 35% (UKCTOCS data). The model‐estimated PPV of a strategy of annual population‐based screening in the United States at ages 50 to 85 years was 14%. The mortality reduction using annual postmenopausal screening was 14.7% (1‐phenotype model) and 10.9% (2‐phenotype model). Mortality reduction was lower with the 2‐phenotype model than with the 1‐phenotype model regardless of screening frequency or test sensitivity; 68% of cancer deaths are accounted for by the aggressive phenotype.

CONCLUSIONS:

The current analysis suggested that reductions in ovarian cancer mortality using available screening technologies on an annual basis are likely to be modest. A model that incorporated 2 clinical phenotypes of ovarian carcinoma into its natural history predicted an even smaller potential reduction in mortality because of the more frequent diagnosis of indolent cancers at early stages. Cancer 2011. © 2010 American Cancer Society.     

Biology of epithelial ovarian cancer: implications for screening women at high genetic risk.

PURPOSE: Our aim was to analyze the clinicopathologic features of screen-detected ovarian cancers identified in women, either at general population risk or high genetic risk of ovarian cancer, who have participated in screening studies. METHODS: Studies published between 1988 and April 2003 were categorized by the population screened and the primary screening modalities used. Each report was examined with reference to the histologic type, stage, and grade of screen-detected cancers. Reports of studies of prophylactically removed ovaries from women at high risk of ovarian cancer were also reviewed. RESULTS: Of the stage I tumors detected by screening women at population risk, almost half were borderline ovarian tumors, granulosa-cell tumors, or germ-cell tumors, which is disproportionate to their frequency. Furthermore, of the stage I invasive epithelial cancers diagnosed in women at population risk, the majority were endometrioid, clear-cell, and mucinous histologic subtypes. Most ovarian cancers that occur in women at high genetic risk are high-grade serous cancers, and these are infrequently screen detected at an early stage. CONCLUSION: The clinicopathologic features of screen-detected ovarian cancers suggest that screening may not reduce mortality in women at increased genetic risk. Prospective screening studies are required in genetically high-risk populations to answer this important question. Women electing surveillance should be aware of the lack of proven benefit and the low likelihood of detecting early stage serous cancers. Bilateral salpingo-oophorectomy appears to be the most effective approach to decrease the risk of ovarian cancer and thereby reduce mortality in high-risk women.     

Women at risk of ovarian cancer: attitudes towards and expectations of the familial ovarian cancer clinic

Familial ovarian cancer clinics are a recent development and little is known about the characteristics of women who attend. One hundred and ninety-seven women with a family history of ovarian cancer completed a questionnaire prior to their initial attendance at the Familial Ovarian Cancer Clinic in Edinburgh. Issues relating to screening procedures were the most commonly cited barriers to attendance, with a proportion finding gynaecological examination embarrassing (17.0%) or uncomfortable (18.0%). Expectations of the clinic were high in terms of access to resources and information. The vast majority of women would prefer to have regular screening (94.7%) and genetic testing (93.2%) if it were available. Attitudes to prophylactic surgery and chemoprevention were more diverse, but would be considered by 54.3% and 43.9% of respondents respectively. Although the current screening procedure for ovarian cancer is of unproven efficacy, a high proportion of women believed in its ability to reduce mortality (77.9%) and to detect tumours at an early stage (65.8%). There was a trend for women to believe this more strongly at follow-up. This study highlights the need to make women more aware of the limitations of current ovarian cancer screening techniques, particularly where the alternative management strategy of prophylactic surgery might otherwise be dismissed.     

卵巢癌一级预防研究进展

卵巢癌是严重危害女性健康的恶性肿瘤之一，其死亡率居妇科恶性肿瘤首位。目前遗传易感是卵巢癌较明确的高危因素，其他可能的因素包括激素使用、疾病/生殖相关因素及生活方式等。根据卵巢癌发生的不同风险等级，可将人群分为高风险人群和普通人群，本文就两个人群的筛查策略、干预措施两方面分别进行研究进展追踪。常规筛查不能提高普通人群卵巢癌的检出率，也无法提高卵巢癌生存。加强卵巢癌高风险人群肿瘤预防意识，进行有效筛查及干预，是降低卵巢癌发病率及死亡率的重要手段。     

Compliance of average- and intermediate-risk women to semiannual ovarian cancer screening.

OBJECTIVE: To report rates of compliance with an ovarian cancer screening protocol using serum CA125 and transvaginal sonography (TVS), performed semiannually on an alternating schedule, among participants at average or intermediate risk for developing ovarian cancer. METHODS: Two hundred ninety-two women at average or intermediate risk for developing ovarian cancer were randomly assigned to arms of a controlled clinical trial in which they received ovarian cancer screening consisting of serum CA125 alternating with TVS performed semiannually over 18 months, either alone or in combination with ovarian cancer risk education. A computerized tracking system generated screening appointment reminder letters and monitored adherence to scheduled screening. Participants overdue for scheduled screens received follow-up telephone calls consisting of up to four reminder messages left at 1-week intervals, and one to two interim attempts to reach participants between messages. The compliance rate for each screen was calculated as a ratio of the number of participants successfully completing the screen relative to the number expected to attend. Compliance rate by screen was: screen 1 (CA125) (97.3%), screen 2 (TVS) (82.5%), screen 3 (CA125) (79.0%), and screen 4 (TVS) (64.5%). One hundred seventy-two women completed all four screens and were classified as adherent to the screening protocol. Analysis by screening modality suggests that participants were more compliant to screens involving CA125. Age, educational background, distance from screening center, personal or family history of cancer, perceived risk of ovarian cancer, pre-enrollment ovarian cancer screening behavior, receiving an abnormal screen test result, and participation in ovarian cancer risk education sessions were not associated with adherence to the screening protocol or compliance to any of the screens. CONCLUSIONS: Despite extensive follow-up, compliance of average- and intermediate-risk women to an ovarian cancer screening protocol requiring semiannual screening diminishes rapidly. We propose that a semiannual ovarian cancer screening protocol, particularly one including TVS, may be too intensive for use in this population.     

The Status of Ultrasound and Color Doppler Imaging for the Early Detection of Ovarian Carcinoma

Noninvasive imaging techniques such as ultrasound and color doppler imaging have been evaluated during the last decdefor their ability to detect organ-confined curable ovarian cancer. While sensitivities approaching 100% can be achieved by these techniques, their specificities and the frequent invasive procedures required to confirm the abnormal sonographic findings have led to caution regarding the widespread use of ultrasound screening for ovarian cancer. These data are reviewed, as well as the NIH Consensus Panel on ovarian cancer's recommendation that routine screening for ovarian carcinoma should not be carried out at this time. Hereditary ovarian cancer syndromes account for approximately 5-10% of the cases. Many of the genes responsible for these syndromes have recently been elucidated. Due to the significant increase in the risk of ovarian cancer in these families, many screening studies have focused on this patient population. Findings from these trials, as well as studies on the psychological impact of screening are presented.     

Ovarian cancer screening: are we making any progress?

Given the burden of suffering associated with the development of ovarian cancer and the clear survival gradient related to the stage of disease at diagnosis, there is much enthusiasm for the development of effective screening strategies aimed at early detection. To date, no evidence exists to justify mass population screening; however, emphasis on subpopulation screening, identification of novel serologic markers, and multimodality screening designs have provided hope that these refinements may eventually translate into a reduction in ovarian cancer mortality.     

Large prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined by menopausal status

Previous screening trials for early detection of ovarian cancer in postmenopausal women have used the standard CA125 cut-point of 35 U/mL, the 98th percentile in this population yielding a 2% false positive rate, whereas the same cut-point in trials of premenopausal women results in substantially higher false positive rates. We investigated demographic and clinical factors predicting CA125 distributions, including 98th percentiles, in a large population of high-risk women participating in two ovarian cancer screening studies with common eligibility criteria and screening protocols. Baseline CA125 values and clinical and demographic data from 3,692 women participating in screening studies conducted by the National Cancer Institute-sponsored Cancer Genetics Network and Gynecologic Oncology Group were combined for this preplanned analysis. Because of the large effect of menopausal status on CA125 levels, statistical analyses were conducted separately in pre- and postmenopausal subjects to determine the impact of other baseline factors on predicted CA125 cut-points on the basis of 98th percentile. The primary clinical factor affecting CA125 cut-points was menopausal status, with premenopausal women having a significantly higher cut-point of 50 U/mL, while in postmenopausal subjects the standard cut-point of 35 U/mL was recapitulated. In premenopausal women, current oral contraceptive (OC) users had a cut-point of 40 U/mL. To achieve a 2% false positive rate in ovarian cancer screening trials and in high-risk women choosing to be screened, the cut-point for initial CA125 testing should be personalized primarily for menopausal status (50 for premenopausal women, 40 for premenopausal on OC, and 35 for postmenopausal women).     

Surveillance of women at high risk for hereditary ovarian cancer is inefficient

To determine the effectiveness of annual gynaecological screening (pelvic examination, transvaginal ultrasound, and CA-125), a prospective cohort study of women at high risk for hereditary ovarian cancer was conducted. Women were offered DNA analysis followed by either annual screening or prophylactic bilateral salpingo-oophorectomy (BSO). Study population consisted of 512 high-risk women (median follow-up 2.07 years, range 0-9.4 years): 265 women (52%) had a BRCA mutation. Persisting abnormalities indicated diagnostic surgery in 24 women resulting in one primary ovarian cancer FIGO stage IIIc was found. The effectiveness of screening was studied by calculating the probability of finding ovarian cancers in the BRCA-1 and BRCA-2 carrier group and comparing this to the identified number of ovarian cancers. The number of ovarian cancer patients found at surveillance was in accordance with the predicted number of ovarian cancers. A total number of 169 women underwent prophylactic BSO: one ovarian cancer stage IIb was found. In conclusion, the surveillance programme for hereditary ovarian cancer does identify patients with ovarian cancer but is very inefficient considering the high number of surveillance visits and the advanced stage of ovarian cancer in the identified patient. For prevention of advanced stage ovarian cancer, prophylactic BSO from age 35-40 years is a more efficient alternative.     

Screening for gynaecological cancers.

BACKGROUND: The role of screening in gynaecological cancers is under evaluation. With mass screening proven effective in significantly reducing cervical cancer mortality, there is an interest in developing other screening methods to detect gynaecological malignancies early. This review covers advances in cervical cancer screening, strategies being investigated in ovarian cancer screening and the lack of justification in screening for endometrial, vulval and vaginal cancers. METHODS: A Medline based literature search was performed for articles relating to screening for different gynaecological malignancies. Additional original papers cited in those identified by the initial search were also reviewed. RESULTS: Advances in cervical cancer screening include liquid-based cytology and HPV testing. Results of ongoing trials are awaited before these can be fully implemented. The results of the two large, multicentre, randomised controlled trials being conducted in the United Kingdom and United States (UKCTOCS and PLCO study, respectively) to assess impact of screening on ovarian cancer mortality will shed some light on the need to implement screening for ovarian cancer in the general population. Novel markers, serum proteomic profiles and Doppler are some of the other technologies being explored. Currently, screening for endometrial cancer is not advocated as most women present with symptoms in early disease with good survival outcomes. Vulval and vaginal cancers are too rare to justify mass screening. CONCLUSION: Methods to screen for various gynaecological malignancies need further evaluation before implementation in the general population. Results of large multicentred trials are awaited. Presently, screening for endometrial, vaginal and vulval cancers is not justified.     

Personalizing CA125 levels for ovarian cancer screening

Screening trials for the early detection of ovarian cancer in the general population and in patients at a high risk for this disease have so far failed to show a reduction of ovarian cancer-specific mortality. Current screening modalities include pelvic examinations, transvaginal ultrasounds, and cancer antigen 125 (CA125) serum marker levels, which are associated with a high false-positive rate. The last decade has witnessed significant modifications in the interpretation of serum CA125 that extend beyond a static CA125 cutoff point. The Risk of Ovarian Cancer Algorithm (ROCA) incorporates changes of CA125 levels over time and an individual's age-specific risk. Ongoing screening trials have incorporated ROCA, but it is still unclear whether the algorithm will increase the sensitivity and specificity of early ovarian cancer diagnosis. A very recent study analyzed baseline CA125 serum marker levels from high-risk patients included in ovarian cancer screening trials conducted by the Cancer Genetics Network and the Gynecologic Oncology Group. The findings show that the distribution of CA125 serum marker levels in this population is significantly affected by various demographic and clinical factors, in particular menopausal status and oral contraceptive use in premenopausal patients. The data suggest that CA125 cutoff points might have to be stratified for subgroups of patients to reduce false-positive results. These intriguing observations will need to be validated in future screening trials for ovarian cancer.     

Future directions in the management of epithelial ovarian cancer

Epithelial ovarian cancer can be a difficult malignancy to manage, partially owing to its heterogenous biology. Whilst desirable, screening designed to reduce mortality has not yet proven effective, though results of ongoing studies are awaited. In this brief review, we attempt to highlight some important issues in the current management of primary and recurrent ovarian cancer, and to place these issues in the context of cutting-edge approaches to targeted therapy and its combination with chemotherapy, as well as other novel treatment strategies. It is hoped that this will lead to further improvements in progression-free and overall survival for patients with ovarian cancer, whilst maintaining their quality of life for as much of the disease journey as possible.     

Inherited risk of ovarian cancer and the implications for screening

Epithelial ovarian cancer is a disease normally diagnosed at late stages, when survival rates are particularly poor. Diagnostic screening strategies are currently ineffective at detecting diseases at the earliest most treatable stages. This is confounded by the relative rarity of the disease. Stratifying the population according to genetic, lifestyle, and/or epidemiological risk factors could improve early-stage screening approaches by enriching the population for individuals at greatest disease risk. If lifetime risks are substantial, surgical interventions such as laparoscopic salpingo-oophorectomy could be offered to women to eliminate altogether their risks of primary cancer of the ovary. There have been significant recent advances in characterizing genetic risk factors for a multitude of cancers, including ovarian cancer. This research has been driven by technological advances that enable very high throughput DNA scanning approaches in tens of thousands of subjects. This article summarizes the progress in identifying genetic alleles for ovarian cancer in the population and the implications for clinical intervention strategies based on identifying the proportion of the population at greatest risk of disease.     

Screening for ovarian cancer]

In recent years, ovarian cancer has been increasing in Japan. However, a mass-screening system for ovarian cancer is not yet established. For this reason, detection of early ovarian cancer is very difficult. 1. Due to the low frequency of ovarian cancer detection, a mass-screening system is not cost-effective. 2. There is no accurate method for the detection of ovarian cancer, as with cytology or colposcopy for the detection of uterine cancer. We describe some methods for the detection of ovarian cancer by mass screening, and point out some problems. Tumor marker is not always useful because of its low sensitivity for early ovarian cancer. It is most important to determine whether or not an ovarian tumor is present. We attempted to detect ovarian tumors at the time of uterine cancer mass screening by ultrasonography (transvaginal proof). Three early ovarian cancers were detected in 10,294 women.     

Multiple biomarker panels for early detection of ovarian cancer

Ovarian cancer is the eighth most common cause of cancer mortality in women. It is diagnosed in more than 20,000 women in the USA each year and approximately 15,000 women die of the disease annually. The majority of patients are diagnosed with advanced-stage ovarian cancer, as this deadly disease causes minimal and nonspecific symptoms until late in the course of the disease. No standardized screening test exists to reliably detect ovarian cancer. Cancer antigen (CA)-125 is a protein antigen found at abnormally high levels in the blood of many women with ovarian cancer. Most healthy women have CA-125 levels of below 35 units/microl of blood serum. However, a number of noncancerous conditions can cause elevated CA 125 levels, and many women with early-stage ovarian cancer have normal CA-125 levels. Owing to these limitations, this test is not recommended for routine screening in women who are not at high risk or who do not have specific symptoms of the disease. Currently, many researchers are focusing on simultaneous examination of multiple markers to increase sensitivity of the screening test for early detection of ovarian cancer. Analysis of the current literature shows that combining several biomarkers dramatically improves sensitivity of CA-125 in ovarian cancer patients. This article provides a comprehensive overview of existing studies in the area of multimarker panel development for the early detection and monitoring of ovarian cancer. Our literature review demonstrates that a multimarker approach for the generation of a prototype assay for early detection of ovarian cancer has a great potential to lead to the development of a screening test for this disease.     

The potential for risk stratification in the management of ovarian cancer risk

Invasive epithelial ovarian cancer (EOC) is the most fatal malignancy of the female reproductive tract, causing more deaths than all other gynecologic cancers combined. Most cases are diagnosed at an advanced stage, and 5-year survival with EOC is less than 50%. Screening for EOC in the general population has not been found to be effective, with the recently reported results from the Prostate, Lung, Colorectal and Ovarian trial showing that there was no shift in the stage at diagnosis among the screen-detected cases and no reduction in mortality. Targeting screening at those at highest risk may prove to be more effective. An alternative approach to risk management is prophylactic surgery, which may be a useful option for women in the highest risk groups. In this article, I will summarize the current state of knowledge about ovarian cancer genetics and discuss how this knowledge may be used to target primary or secondary prevention in ovarian cancer.     

Gynecologic malignancies in older women

The aging of the population is a social phenomenon that will present a challenge to clinical practice in the 21st century. Women constitute a majority of the elderly population as they outlive males by 5 to 7 years. Ovarian, endometrial, and vulvar cancers are diseases seen more commonly in postmenopausal and elderly women. Cervical cancer continues to be a significant problem in the elderly and is usually detected at a later stage in that population than in younger patients. Accordingly, primary care clinicians ought to possess a thorough knowledge of gynecologic malignancies and should refer women who present with these disorders to a gynecologic oncologist. Ovarian cancer patients treated by a gynecologic oncologist are more likely to undergo proper surgical staging, leading to optimal debulking surgery and improved survival. Age, by itself, should not alter the diagnostic and therapeutic approach to gynecologic malignancy. Elderly patients can safely undergo radical pelvic surgery. Multiagent chemotherapy is also possible in the elderly without excess morbidity, and without compromise of response rates. Radiation therapy for cervical cancer appears to be as effective and is generally well tolerated. The Papanicolaou (Pap) test continues to be the primary screening tool for cervical cancer. Although transvaginal ultrasound seems to be useful in detecting early-stage ovarian cancer, its cost effectiveness for screening the general population remains to be demonstrated. The main considerations in the treatment of ovarian, endometrial, cervical, and vulvar cancer are discussed.     

Screening for ovarian cancer: old tools, new lessons

The early detection of ovarian cancer represents a clinical objective with an enormous potential for a meaningful improvement in our ability to treat and cure afflicted patients. The magnitude of this potential is matched by the challenges associated with attaining it. In addition to the well noted aspects of ovarian cancer which have thus far precluded the development a effective screening strategies, recent work regarding the differential pathogenesis and origins of the various histological subtypes of epithelial ovarian cancer have further revealed the challenges ahead. These findings are reviewed here with a particular focus on reports describing the early development of high-grade serous carcinomas, the most prevalent and aggressive disease subtype. The unique set of difficulties associated with the early detection of these tumors is discussed in depth. An update on findings stemming from several large randomized screening trials is provided. While the current state of ovarian cancer screening remains characterized by unmet needs, the ongoing evaluation of those needs is providing a strong basis for future advancement. This advancement will rely upon the refined application of currently available diagnostic tools based on lessons well learned.