By Jessica L. Crull, MSN, FNP-BC; Deborah K. Mayer, PhD, RN, AOCN, FAAN; and Ann N. Jessup, PhD, RN, FNP-BC

The authors searched and synthesized the literature to identify current recommendations for early detection of ovarian cancer, the female reproductive cancer with the highest mortality rate. After providing background information regarding risk factors for ovarian cancer and discussing the challenges of detecting this disease at an early stage, the authors list the most recent clinical guidelines from a variety of sources.

Key words: ovarian cancer, early detection, risk factors, screening

Among all female reproductive cancers, ovarian cancer has the highest mortality rate.^1-3 Although the incidence of ovarian cancer isrelatively low, overall survival is only 35%.¹ In 2013, 22,240 new cases of ovarian cancer were diagnosed and 14,030 women died of the disease,⁴ making it the fifth leading cause of cancer death in females, behind lung, breast, colon and pancreatic cancers.⁵ Whereas earlier stage at diagnosis has been linked to an increased survival rate (70%-90%), ovarian cancer is commonly found at more advanced stages, resulting in a 5-year survival rate of only 15%.2,^6-9 Mortality reduction may be possible with earlier detection.¹⁰

The purpose of this article is to synthesize the literature and identify current recommendations regarding early detection of ovarian cancer. The authors searched the PubMed and CINAHL databases for primary, peer-reviewed studies reported between 2005 and 2013. This review-and-synthesis is based on 47 articles and 11 relevant clinical guidelines identified in the search.

Risk factors

Although no evidence-based ovarian cancer screening recommendations exist for women in the general population,¹¹ study findings indicate that women at higher risk for ovarian cancer need to be evaluated differently. Three areas of increased risk are age, personal history, and genetics.

Age—Age is the single most important risk factor for ovarian cancer. The incidence increases significantly after menopause (average age at diagnosis, 63 years).¹²Personal history—Some breast cancer survivors are at an increased risk for ovarian cancer; the risk is 12.7% in those with the breast cancer susceptibility gene 1 (BRCA1) mutation and 6.8% for those with the breast cancer susceptibility gene 2 (BRCA2) mutation.¹³ Ovarian cancer risk after breast cancer is also higher in women with a positive family history of breast cancer.⁵ Breast cancer-free women with a family history of breast or ovarian cancer but without the BRCA1/2 mutation have a risk closer to that in the general population.^14,15 Women diagnosed with hereditary non-polyposis colorectal cancer, also known as Lynch syndrome, have a 10%-36% risk of developing ovarian cancer.¹⁶ Other factors increasing ovarian cancer risk include endometriosis, nulliparity, infertility, early menarche, late menopause, and living in a Western industrialized nation.¹³ In addition, ovarian cancer has been associated with obesity, failure to follow a low-fat diet, use of fertility drugs or androgens, and use of unopposed estrogens after menopause, although no studies have proved causation in these cases.⁵Genetic risk and assessment—Approximately 10% of ovarian cancer cases are related to mutation of the BRCA1/2 gene, which can be inherited.¹³ In the general population, the risk of having either mutation is 1:300 to 1:800.¹³ Women of Ashkenazi Jewish descent have a 10-fold higher risk of having either mutation.¹³ If a woman has a BRCA1/2 mutation, her lifetime risk of developing ovarian cancer is 65%-74%, placing her in a high-risk category.¹³ The term hereditary breast and ovarian cancer syndrome (HBOCS) is used to describe the tendency to develop breast and/or ovarian cancer because of an inherited BRCA1/2 gene mutation. The American Congress of Obstetricians and Gynecologists (ACOG) has issued specific referral guidelines for women with HBOCS.¹³

The National Cancer Center Network and the Society of Gynecological Oncology (SGO) recommend that women at risk for reproductive cancer-related genetic mutations be referred for formal genetic counseling.^17,18 Despite this advice, Levy et al¹⁹ have reported that few primary care practitioners (PCPs) follow these referral guidelines.

Challenges of early ovarian cancer detection

Early ovarian cancer detection is challenging because symptoms are often vague, leading to misdiagnosis.²⁰ Screening is not recommended for the general population because of the lack of effective screening methods in this population.¹¹ Despite the availability of triage and referral guidelines, many women’s complaints are not fully investigated or appropriately referred by the PCP.^19,21,22Symptoms—More than two-thirds of all ovarian cancers are diagnosed at a later stage (III or IV), when the disease has already spread to other intra-abdominal organs.^7,8 Factors contributing to late diagnosis include vague symptoms and lack of a definitive precursor lesion.⁸ Many women report symptoms to their PCP a few months before diagnosis,² yet they are misdiagnosed 70%-75% of the time.²⁰ Contrary to previous thought, ovarian cancer can present with symptoms.⁷ In fact, gastrointestinal, urinary, or gynecologic symptoms are common; complaints often include abdominal bloating, a pelvic mass, pain, or malaise.^3,7,9,23

Usefulness of the presence of symptoms as a trigger for early screening has been evaluated. Goff et al¹ developed a symptom index based on the presence of pelvic/abdominal pain, an increase in abdominal size, bloating, and difficulty eating or early satiety. In terms of identifying early ovarian cancer, the Goff symptom index was found to have a sensitivity of 56.7%, as well as a specificity of 90% for women older than 50 years and of 86.7% for women younger than 50 years. Although several symptom indexes are being studied, evidence-based screening tools are still lacking at this time.

Screening tests—Although many screening tests for early detection of ovarian cancer meet many of the World Health Organization (WHO) guiding principles for early disease detection (Table 1),^24,25 certain challenges exist. These screening methods must also have high sensitivity, specificity, and positive predictive value (PPV).²⁵ With regard to ovarian cancer, screening tests need to have a sensitivity of ?75% and a specificity of >99.6% to yield a PPV of ?10%.^24,26 (The specificity requirement is high because of the low prevalence of ovarian cancer in the general population.) Effective screening would result in 10 exploratory surgeries for every detected cancer case, which is the minimum accepted screening requirement determined by statistical estimates.^24,26

The low specificity, sensitivity, and PPV of bimanual pelvic examination, imaging, and tumor markers, used independently in the general population, lead to the possibility of unnecessary exploratory surgery and/or patient stress,²⁷ posing the risk that harm will outweigh benefits.11 The United States Preventive Services Task Force (USPSTF) recently reviewed the evidence for ovarian cancer screening and did not recommend screening for women at average risk.¹¹ However, women with increased risk related to BRCA 1/2 mutations, Lynch syndrome, or a family history of ovarian cancer should be considered for genetic counseling to further evaluate their risk.¹¹Triage techniques—Several studies have suggested improved survival if women with possible ovarian cancer are managed by a gynecologic oncologist.²⁸ ACOG and the SGO have issued referral guidelines: Women of all ages with ascites, evidence of metastasis, or a first-degree relative with breast or ovarian cancer should be referred to a gynecologic oncologist.^12,29 Premenopausal women should be referred only if they have a CA-125 level >200 U/mL, whereas postmenopausal women should be referred
if they have any elevation in CA-125 or a nodular or fixed pelvic mass.^12,29

Delay in diagnosis is a problem in ovarian cancer. One study showed that the median interval from first symptom to diagnosis was 74.5 days.²¹ In addition, PCPs were not consistent in terms of the specialist to whom they referred patients; among the 92% of patients who were referred, only 31% were referred to a gynecologist.₂₁ One study showed that as a woman’s age increases, the likelihood that her complaint was investigated or that she was referred decreased, contributing further to a delay in diagnosis.²²

Discussion

Studies examining the effectiveness of various screening strategies, alone or combined with each other, are ongoing, and several clinical assessment tools are being evaluated for the earlier assessment of ovarian cancer. Each of these methods used in early detection of ovarian cancer is subject to WHO screening criteria (ie, sensitivity ?75% and specificity >99.6% to yield a PPV of ?10%).^24,26 Although many detection methods meet some of these criteria, few fulfill all requirements for non-high-risk women. Therefore, this review supports the USPSTF conclusion that sufficient evidence is lacking to recommend ovarian cancer screening for the general population.¹¹ Existing guidelines are outlined in Table 2.

Despite the USPSTF conclusion, certain specific situations place women in high-risk categories that may still benefit from early detection measures.^13,30 Nurse practitioners should be aware of what constitutes higher risk for ovarian cancer (e.g., certain genetic mutations, family history). If a woman has familial and other risk factors, NPs should offer her the option of genetic counseling.¹⁸ Current imaging standards support the use of transvaginal ultrasonography for initial evaluation of ovarian masses.¹² Other modalities, such as computed tomography and magnetic resonance imaging, are used by specialists to evaluate an ovarian mass pre-operatively. NPs should know that an elevation of CA-125 has more clinical significance in postmenopausal women than in premenopausal women.

Conclusion

Ovarian cancer is not always silent, and may manifest with gastrointestinal or other vague symptoms. Although screening the general population is not recommended, NPs need to know what places a woman at high risk for ovarian cancer and keep ovarian cancer on the differential diagnosis list in such a case. For primary care NPs, this type of triage may
result in shorter delay in referral to a gynecologic oncology specialist.

Jessica L. Crull is a family nurse practitioner with Carolinas Healthcare System, Concord, North Carolina. Deborah K. Mayer is an associate professor and Ann N. Jessup is a clinical assistant professor, both at the University of North Carolina–Chapel Hill School of Nursing. The authors state that they do not have a financial interest in or other relationship with any commercial product named in this article.

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