Definition of Ovarian Cancer

Ovarian cancer includes cancers of the ovary, fallopian tubes, and peritoneum due to the origination from similar tissue types and similar clinical management and treatment.¹ Epithelial ovarian cancer is classified into five subtypes, based on histology to identify the origin and degree of differentiation: high-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, low-grade serous carcinoma, and mucinous carcinoma.² Most ovarian cancers are included in these subtypes, with the remainder being rare non-carcinoma types include germ cell tumors, sarcomas, sex cord-stromal tumors. The most common subtype is serous carcinoma, and this subtype comprises the majority of advanced stage cancers.³ The staging of ovarian cancer follows National Cancer Institute definitions describing the extent of tissue involvement and spread with the terms in situ, localized, regional, distant (outside the peritoneum), and unknown.⁴ Detailed staging categories for ovarian cancer established by the International Federation of Gynecology and Obstetrics (FIGO) describe the specific characteristics used to assign stages I through IV, as well as staging within these levels.^{3, 5} As understanding of ovarian tumor pathogenesis has deepened, distinctions between type I and type II ovarian cancers have been outlined.^{6, 7} Type I ovarian cancers tend to be early stage low grade tumors that generally arise through a progression from benign precursor lesions, tending to remain indolent or slowly progressive. The majority of cases are classified as type II ovarian cancers, characterized by rapid metastatic progression and accounting for the overwhelming majority of ovarian cancer deaths.⁶

Prevalence and Burden

Ovarian cancer is the fifth most common cause of cancer death in U.S. women and the leading cause of gynecologic cancer deaths despite having low incidence.⁸ Approximately 22,440 ovarian cancer cases and 14,080 deaths are estimated to occur in 2017.⁹ According to data from the Surveillance, Epidemiology, and End Results Program (SEER) and National Program of Cancer Registries, the average annual age-adjusted incidence of ovarian cancer in the U.S. was 11.4 cases per 100,000 women for 2010-2014 with a mortality rate of 7.4 per 100,000 women. The incidence of ovarian cancer has declined slightly since the mid-1970s with an average of 1.9 percent a year over the last 10 years.^{2, 10-12} The majority of women diagnosed with ovarian cancer are over age 45 (88%), with a median age of diagnosis of 63 years. The average age-adjusted (2010-2014) annual incidence of ovarian cancer varies by race and ethnicity, occurring most frequently in white women (11.8 per 100,000) followed by Hispanic women (10.3 per 100,000). Rates are similar for black women (9.2 per 100,000 women), Asian/Pacific Islander (9.1 per 100,000), and lowest for American Indian/Alaska Native women (8.3 per 100,000), although estimates are less precise for this subpopulation.^{8, 10}

Etiology and Natural History

Ovarian cancers can originate from ovarian, fallopian, or other tissue types (e.g., endometrium, peritoneum).^{2, 13} Historically, ovarian carcinomas were assumed to derive from the ovarian surface epithelium; however, evidence increasingly indicates that high-grade intraepithelial lesions in the fallopian tubes may become malignant and spread to the ovarian epithelium and peritoneum.⁶ Two broad categories defined by shared clinical features have been developed to better represent distinct models of epithelial ovarian carcinogenesis.¹⁴ Type I tumors include low-grade, generally indolent tumors, that are often associated with somatic mutations in a number of genes (e.g., KRAS, BRAF, ERBB2) and develop from benign extra-ovarian lesions implanted on the ovary.^{6, 15, 16} Type II tumors are more likely to derive from the fallopian tube or ovarian surface epithelium. These cancers are generally high grade and are genetically unstable, including high rates of TP53 and BRCA mutations.^{6, 14}

Overall, mortality from ovarian cancer is high, with fewer than half (46%) of women surviving for at least 5 years following an ovarian cancer diagnosis.⁸ By comparison, overall 5-year survival rates for cancers of the breast (90%), endometrium (80%), and cervix (70%) are much higher. The aggressive nature and commonly advanced stage at diagnosis translates to a poorer prognosis for type II ovarian cancers, with 30 percent of patients surviving at 5 years, compared to 55 percent of patients with type I cancers.¹⁴ Non-Hispanic black women have the lowest 5-year survival rates, and the second-highest mortality rates (7 per 100,000), slightly lower than the mortality rates observed among non-Hispanic white women (8 per 100,000).¹⁷ Ovarian cancer mortality increases with age at diagnosis with the highest rates of death among women 65 to 74 and a median age of death of 70 years.⁸

Risk Factors

Multiple modifiable and nonmodifiable factors have been associated with an increased risk for developing ovarian cancer including: increasing age, family history of ovarian cancer, inherited genetic mutations (e.g., BRCA1/BRCA2), obesity, nulliparity, use of hormone replacement therapy, and increased numbers of lifetime ovulatory cycles.^{2, 18} Most risk factors show significant heterogeneity across ovarian cancer subtypes.¹⁹ Approximately 20 percent of ovarian cancers are familial, with the presence of cancer in multiple first- or second-degree relatives being an indicator of inherited cancer syndrome.¹ Inherited mutations are associated with 5 to 15 percent of all ovarian carcinomas. The most common high-risk genetic syndromes include hereditary breast and ovarian cancer (i.e., BRCA1 and BRCA2), Lynch, and Peutz-Jeghers syndromes.^{2, 20-24} In addition, genome-wide association studies have identified as many as 17 common low-penetrance alleles associated with ovarian cancer.^{2, 25-30} Women with a greatly increased risk for developing ovarian cancer, defined by the presence of germline genetic mutations, may benefit from risk-reducing surgery or chemoprevention. For these women genetic counseling is recommended, including a discussion of the risks and benefits of prevention.^31-33

Several factors have been identified that are associated with a decreased risk of ovarian cancer. Among the most well established is the use of oral contraceptives, with an estimated 20 percent decrease in the risk of ovarian cancer for every 5 years of use.^{2, 34} This protective effect may be due to the suppression of ovulation and the associated hormonal and inflammatory process which may be associated with the etiology of ovarian carcinomas.^{2, 34} Parity also has a protective effect, with estimates of a 30 to 40 percent decrease in the risk of cancer associated with a first pregnancy, and 10 to 15 percent decrease in each subsequent pregnancy.^{2, 35} Breastfeeding is also associated with decreased risk.^{2, 36-39} However, these identified lifestyle and hormonal risk factors as mainly associated with a decreased risk of the less lethal Type I ovarian cancers with more modest effects on the prevention of Type II cancers (e.g., high-grade serous-carcinoma).^{2, 40}

Risk-prediction models have been developed to identify women at increased risk of developing ovarian cancer based on personal and family history. To date, for women at average genetic risk, these tools have not been found to have a strong predictive performance, likely due to the relative rarity of ovarian cancer and the modest effect size of known risk factors.^{2, 41-44}

Prevention

Risk-reducing surgery, such as bilateral salpingo-oopherectomy (BSO), has generally been advocated for women at high genetic risk,^{2, 45} and some evidence^{46, 47} from observational studies suggests that it may also be associated with a decreased risk of ovarian cancer for women at average or unknown genetic risk. The risk reduction conferred, however, is not 100 percent, and has been associated with side effects and potential risks including: early menopause, osteoporosis, cardiovascular disease, and increased overall mortality.^{2, 48} Bilateral salpingectomy, even with ovarian retention, may be effective in preventing ovarian cancer as there are subtypes postulated to arise in the fallopian tubes. Salpingectomy may allow high-risk women to delay removal of the ovaries, and when performed during a planned hysterectomy, may reduce risk for average-risk women.^{2, 49, 50} Based on evidence of the distal fallopian tube epithelium as the site of origin for at least some cancers the Society for Gynecologic Oncology (SGO) and the American Congress of Obstetricians and Gynecologists (ACOG) have issued statements recommending consideration of opportunistic bilateral salpingectomy to reduce ovarian cancer mortality in the general population.^{2, 51, 52} Tubal ligation and hysterectomy have also been associated with reduced risk of ovarian cancer; however, no groups have recommended these procedures as prevention strategies.^{2, 53}

In addition to surgical intervention, hormone-modulating prescription drugs such as oral contraceptives have been investigated for prevention of ovarian cancer.^{2, 34} The SGO has stated that appropriate counseling about side effects and contraindications for oral contraceptive use can allow patients to weigh the risks and benefits of their use for cancer prevention.⁵⁴ Of note, a 2013 systematic review for the AHRQ Effective Healthcare Program did not find sufficient evidence to recommend oral contraceptive use for the sole purpose of ovarian cancer prevention.⁵⁵

Diagnosis and Treatment

Definitive diagnosis and staging of ovarian cancer requires surgery.^{1, 2, 32} Most women with newly diagnosed ovarian cancer undergo primary staging and debulking surgery to remove as much of the visible tumor as possible. This surgery may include hysterectomy, BSO, and omentectomy.^{1, 32} Younger patients with early (stage I or II) and/or low-risk tumors who wish to preserve fertility may opt for unilateral salpingo-oophorectomy.¹ Survival is improved for women with complete tumor resection. In cases where total resection is not possible or contraindicated, neoadjuvant chemotherapy can reduce tumor size and facilitate later resection. Most women respond well to initial treatment; however, the majority will experience recurrence of the disease, requiring a cycle of repeated surgeries and chemotherapy cycles.^{1, 2} Care delivered within high-volume hospitals and by gynecologic oncologists has been associated with guideline-adherent treatment and improved survival.^{2, 56-58}

Rationale for Screening

The high mortality and low 5-year survival among all women diagnosed with ovarian cancer is largely due to challenges detecting the disease at an early stage. Only 15 percent of cases are diagnosed at the local stage, when 5-year survival is favorable at 92 percent. Over 60 percent of cases are diagnosed after the cancer has distant metastases. With distant spread, the 5 year survival drops to 29 percent.⁸ Thus, screening for early-stage disease has been a focus of research. Screening women for symptoms of ovarian cancer poses challenges; symptoms are often nonspecific, including bloating, pelvic or abdominal pain, urinary symptoms, vaginal discharge, increased vaginal bleeding, or gastrointestinal problems.^{1, 2} These symptoms are often not seen as symptoms of serious illness by women or providers.² As many as 95 percent of all women in primary care report one of the symptoms of ovarian cancer in the previous year, with 72 percent of women having recurring symptoms, most commonly back pain, fatigue, indigestion, urinary tract problems, constipation, and abdominal pain.⁵⁹ While women found to have ovarian cancer appear to have symptoms more frequently and with a higher severity, the frequency of reported symptoms in unaffected women poses a challenge for clinical detection.⁵⁹ Efforts to generate clinical decision tools based on the presence of combinations of symptoms, such as the Ovarian Cancer Screening Index,⁶⁰ have been found to have a higher sensitivity than individual symptoms; however, estimates for the accuracy of these tools indicate that they are not sufficiently specific for implementation in clinical practice.⁶¹ Because of the lack of specific symptoms, research has investigated the use of other strategies for early detection, including the use of biomarkers and imaging technologies.

Screening Strategies

The most widely tested screening approaches, with reasonable test performance characteristics, have broadly focused on identifying abnormalities in the physical structure of the ovary or detecting increased CA-125 levels or trends. The most complex screening strategies involve algorithms that use CA-125 levels measured over time to compute the likelihood of ovarian cancer and determine surveillance and surgical investigation protocols at different risk thresholds.^{2, 62-65} Transvaginal ultrasound (TVU) is the most widely used imaging technique for gynecologic symptoms and pathologies, but the majority of adnexal masses identified by TVU are benign.^{2, 66}

Elevated CA-125 levels have been noted in women with an advanced ovarian carcinoma at diagnosis, leading to its proposed use as a biomarker for early detection.² Some limitations with regard to the assay's specificity and sensitivity have been recognized, as CA-125 may be markedly elevated in patients with a variety of benign or non-ovarian malignant conditions. In addition, serum CA-125 has been found to be significantly elevated in only half of women diagnosed with stage I or II ovarian cancer.^{2, 67} Efforts to improve the performance of screening with CA-125 led to development of the Risk of Ovarian Cancer Algorithm (ROCA™ [Abcodia]). The algorithm uses sequential CA-125 measures taken at annual screening visits to evaluate the trajectory of CA-125 serum over time following a baseline age-adjusted CA-125 measurement.⁶⁸

Another screening strategy that continues to be practiced⁶⁹ but is not supported by clinical evidence is ovarian palpation with bimanual pelvic examination. The accuracy of this screening examination (sensitivity 5.1%)⁷⁰ does not support its use.^{71, 72} The practice has been discouraged⁷¹ or recognized as lacking evidence to recommend⁷² as a routine screening examination for ovarian cancer due to its high false positive rate, low positive predictive value^{73, 74} and potential physical and psychological harms in the absence of benefits.

Research continues into the discovery of other biomarkers and the use of alternative imaging strategies for the early identification of ovarian cancer; however, no other markers have been implemented and tested in an ovarian cancer screening trial.²

Current Clinical Practice in the United States

No organizations currently recommend screening for ovarian cancer in the general population. Several groups have issued guidelines that do not recommend screening in asymptomatic, average-risk women, including the American Academy of Family Physicians,⁷⁵ American Cancer Society,^{76, 77} American College of Radiology,⁷⁸ and American Congress of Obstetricians and Gynecologists.⁷³ Nonetheless, a 2012 nationally representative sample of over 1,000 family physicians, general internists, and obstetrician/gynecologists found that over one-third of physicians believed that ovarian cancer screening was effective and up to one-fourth routinely offered TVU and/or CA-125 screening to asymptomatic women.⁷⁹ Additionally, a 2014 survey of 1,555 U.S. family physicians, general internists, and obstetrician-gynecologists found that 27 percent of physicians overestimated the ovarian cancer risk among women at the same risk as the general population and 65 percent underestimated ovarian cancer risk among women at much higher risk than the general population.⁸⁰

In 2016 the United States Food and Drug Administration (FDA) released a recommendation against using tests marketed for ovarian cancer screening. The FDA stated that there are no ovarian cancer screening tests approved by the FDA and no published clinical information to demonstrate that currently available tests are accurate and reliable in asymptomatic women. In particular the FDA stated that the ROCA algorithm has been marketed in the United States with no data to support its claims for ovarian cancer detection and improved cancer survival.⁸¹ Following this statement from the FDA the company marketing the ROCA test suspended its commercial availability in the United States.⁸²

Previous USPSTF Recommendation

In 2012, the U.S. Preventive Services Task Force (USPSTF) recommended against screening for ovarian cancer in women (D recommendation).⁷⁴ This recommendation applies to asymptomatic women without a known genetic mutation that increases their risk for ovarian cancer (e.g., BRCA mutations). There was adequate evidence that annual screening with TVU and testing for CA-125 in women does not reduce ovarian cancer mortality. In addition, the disease occurs infrequently enough that most women with a positive screening test results will have a false positive result; therefore, screening for ovarian cancer can lead to important harms, including major surgical interventions and complications in women who do not have cancer. The USPSTF concluded that there was at least moderate certainty that the harms of screening for ovarian cancer outweighed the benefits.