Ovarian Cancer

Ovarian Cancer

Ovarian Cancer

Ovarian Cancer Focus on Female Cancers Ovarian Cancer

Ovarian Cancer

FocusonFemaleCancers • ACOG District II/NY • 1  Focus on Female Cancers: American College of Obstetricians and Gynecologists, District II 152Washington Avenue, Albany, NewYork 12210 Telephone: (518) 436-3461 • Fax: (518) 426-4728 E-mail: info@ny.acog.org •Website: www.acogny.org Ovarian CancerTask Force: GINGER GARDNER, MD, FACOG, Chair CHRISTINE COMPTON, MD, MPH NEFERTITI DUPONT, MD, MPH MARY EIKEN RN, MS EILEEN FUSCO, NP KAREN GREENDALE, MA, CGC KATY IRANI, MD, FACOG SUSAN KLUGMAN, MD, FACOG LESLIE MORAN MARK B.

POCHAPIN, MD CLAIRE QU, MS MARIS SCHILLING JASONWRIGHT, MD Staff: DONNA MONTALTO, MPP KATHERINE CAMPBELL, MPH, CPH KATY STEVENSON, MPP ACOG District II would like to extend special thanks to their Medical Education Co-Chairs: Maureen Killackey MD, FACOG, FACS and Camille A. Clare MD, FACOG. ThisovariancancerchapterwasmadepossiblebytheNewYorkStateDepartmentofHealth OvarianCancerProgram,withfundingfromtheCentersforDiseaseControlandPreventio n (CooperativeAgreement#1U58DP000783-02).

Compiled June 2009 Ovarian Cancer

Ovarian Cancer

2 •FocusonFemaleCancers • ACOG District II/NY DearWomen’s Health Care Provider, O n behalf of the American College of Obstetricians and Gynecologists, District II (ACOG), we are pleased to provide you with the fourth chapter of Focus on Female Cancers, a resource guide offering relevant provider education on cancer in women. The content of this fourth chapter includes primary prevention and screening information, symptom recognition and evaluation techniques, and staging and surgical management of ovarian cancer, as well as guidance for counseling patients.

In the United States, ovarian cancer is the second most common type of gynecologic cancer, surpassed only by uterine cancer. In 2008, an estimated 21,650 new cases of ovarian cancer were diagnosed, accounting for 3% of all cancers in women, and 15,520 women died, making ovarian cancer the fifth leading cause of cancer deaths. Over 1,000 of these deaths or approximately 6% occurred in NewYork State. In an effort to reduce the impact of this disease, significant focus has been given to primary prevention, screening and symptom recognition.

We would like to extend our appreciation to the task force of women’s health experts who offered their expertise throughout the creation of this resource guide chapter.

Their knowledge and dedication to the initiative were invaluable during the guide’s development. The ovarian cancer chapter is the fourth chapter in a series of comprehensive educational resources on cancer in women. Additional chapter topics include cervical cancer, hereditary breast and ovarian cancer and cancer survivorship. A fifth chapter regarding colorectal cancer will be distributed in the coming months.

If you have any questions regarding the resource guide or ACOG’s cancer initiatives, please contact the ACOG District II office at info@ny.acog.org or (518) 436-3461. Sincerely, Scott D. Hayworth, MD, FACOG Ginger Gardner, MD, FACOG Chair, ACOG District II Chair, Ovarian CancerTask Force

Ovarian Cancer

FocusonFemaleCancers • ACOG District II/NY • 3  Introduction Project Overview I n 2008, ACOG District II formed a task force of women’s health experts to create this educational chapter focusing on ovarian cancer. Initial provider surveys helped guide the creation of learning objectives and content.

The chapter content focuses on recognizing common signs, symptoms and risk factors for ovarian cancer, appropriate referral techniques for utilizing a gynecologic oncologist, as well as increasing awareness of community resources for both the provider and the patient.

Obstetrician-gynecologists play a critical role in the early diagnosis of ovarian cancer. Recent studies focus on the importance of symptom recognition by both the patient and her physician. When diagnosed early, while still confined to the ovary, the five-year survival rate is 92%. However, only 19% of ovarian cancers are localized or stage I when first diagnosed. For the majority of patients (those diagnosed with advanced disease), recent studies have shown that optimal front-line therapy can now yield a median overall survival greater than five years. As new technologies emerge to combat this disease, ACOG will continue promoting education to ensure women in NewYork State are receiving the current standard of care.

The content of this chapter was developed by a panel of nationally recognized experts in the field of women’s health, and provides basic knowledge about ovarian cancer diagnosis and management. As medical information evolves, the content of the guide will be adjusted to reflect new developments and changes in practice standards. On-going evaluation of this chapter and the cancer resource guide as a whole will help ACOG District II continue to provide medical education that targets the needs of women’s health care providers’in NewYork State. This document serves to guide best practices. However, the most essential best practices are recognizing the need to evaluate each patient individually and always utilizing sound clinical judgment.

With this in mind, these evidence- based guidelines provide a foundation from which women’s health care providers can achieve optimal quality in patient care.

❙❙ In the United States, ovarian cancer is the second most common type of gynecologic cancer.

Ovarian Cancer

4 •FocusonFemaleCancers • ACOG District II/NY Resource Guide Overview Table of Contents I. Primary Prevention and Screening:The Asymptomatic Patient . . 5 II. Symptom Recognition and Evaluation . . 13 III. Disease Classification, Staging and Surgical Management . . 21 IV. Chemotherapy . . 29 V. Recurrent Disease Management . . 35 VI. Counseling the Patient / Resources . . 43 Appendix: Future Directions in Ovarian Cancer Screening and Management . . 51 Objectives This guide is designed to enable participants to: • Recognize common signs, symptoms and risk factors for ovarian cancer; • Appreciate new developments in the management of ovarian cancer; • Determine who should be referred to a gynecologic oncologist based on a high-risk profile, symptoms, or a newly diagnosed adnexal mass; • Understand, regardless of referral barriers, that utilizing a gynecologic oncologist when possible can improve outcomes for patients with ovarian cancer; and • Increase awareness of cancer resources (including ovarian cancer-specific resources) available in your area.

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Ovarian Cancer

I. Primary Prevention & Screening: The Asymptomatic Patient FocusonFemaleCancers • Primary Prevention and Screening:The Asymptomatic Patient • 5 Overview BACKGROUND Ovarian cancer is the deadliest gynecologic cancer, taking the lives of over 15,000 women annually in the United States. Although the length of survival after diagnosis has increased over past decades with advances in treatment, the overall mortality has shown little improvement. In an effort to reduce the impact of this disease, significant focus has been given to both primary prevention and screening, particularly in the high-risk patient population.

WHATYOU SHOULD KNOW PrimaryPrevention:The goal of primary prevention is to prevent disease from developing. • Risk factors for ovarian cancer include: o Age • Incidence of ovarian cancer increases with age; almost 70% of ovar- ian cancer occurs after the age of 50 o Inherited mutations • Women with Hereditary Breast and Ovarian Cancer (HBOC) Syn- drome (inherited mutations of the BRCA1 and BRCA2 genes) have up to a 45% lifetime risk of ovarian cancer. Approximately 10% of epithelial ovarian cancer is due to BRCA1 or 2 mutations • Women with Hereditary Non-Polyposis Colorectal Cancer (HNPCC) also known as Lynch II Syndrome have up to a 12% lifetime risk of ovarian cancer.

Mutations of the mismatch repair genes associated with this syndrome are primarily MSH2, MLH1, and MSH6 o Family history • Women who have one first degree relative with ovarian cancer have a 3-5% lifetime risk of developing the disease o Other factors that are associated with an increased risk of developing ovarian cancer include: • Infertility • Endometriosis • Low parity • Early menarchal age • Late menopausal age • Living in aWestern industrialized country • Protective factors for ovarian cancer include: o Oral contraceptive use o Pregnancy o Prophylactic bilateral salpingo-oophorectomy (BSO) in high-risk women can reduce the risk of ovarian cancer by approximately 90% o Other factors that are associated with a decreased risk of developing ovarian cancer include: • Tubal ligation • Hysterectomy • Breast feeding Almost 70% of ovarian cancer occurs after the age of 50.

Ovarian Cancer

6 •FocusonFemaleCancers • ACOG District II/NY • Prevention Strategies o Risk management strategies include chemoprevention (oral contraceptives) and prophylactic BSO when appropriate (prophylactic BSO is generally not recommended for women without a known BRCA mutation who have only one relative with ovarian cancer or in women at average risk) Screening:The purpose of a screening test is to detect patients in the asymptomatic, preclinical phase of disease, which is the time between the pathological onset of disease and the development of clinically detectable symptoms.

• The American College of Obstetricians and Gynecologists (ACOG) and the United States Preventive ServicesTask Force (USPSTF) recommend AGAINST routine screening for ovarian cancer • In the United States, 1 in 70 women will be diagnosed with ovarian cancer in her lifetime • The five-year survival rate for localized ovarian cancer is 92%.

The five-year survival rate for advanced ovarian cancer is 30%. However, only 19% of ovarian cancer cases are localized when diagnosed • Finding an effective screening strategy that would shift diagnosis to the early, most treatable stage should improve outcomes and decrease mortality from ovarian cancer • A screening program should be: o Cost-effective o Convenient o Acceptable to most patients o Relatively free of risks or discomfort o Able to correctly identify individuals who have preclinical disease and those who do not o Feasible, which is primarily determined by the positive predictive value (PPV) of the test o Able to reduce the disease-specific mortality in the screened population (considered the best measure of screening benefit) • Challenges of screening for ovarian cancer include: o Low prevalence of disease o No tests currently available with adequate sensitivity, specificity or PPV to effectively screen for ovarian cancer o High number of false positive tests, which would result in an unacceptable number of women who would be subjected to invasive procedures o Screening has not been shown to reduce mortality from ovarian cancer, even in high-risk patients • Currently available tests for ovarian cancer screening include CA 125 and transvaginal ultrasound (TVS) o CA 125 is not sensitive for early disease and is elevated in a number of benign conditions, even in older women o TVS is not reliable in distinguishing benign from malignant tumors and its use in the asymptomatic patient can lead to unnecessary surgery o Either test alone is not as effective as using a multimodal approach, although this also does not achieve adequate sensitivity, specificity or PPV WHATYOU SHOULD DO • Routine screening for ovarian cancer should not be performed in the asymptomatic patient.

Emphasize to patients the high number of false positive tests and the associated risks of unnecessary surgery • Routinely perform a risk assessment with all patients, specifically asking about a family history of ovarian cancer as well as other cancers including breast, colorectal and endometrial cancers • Refer to a genetic counselor when appropriate • When counseling patients on birth control options, highlight the significant decrease (up to 60%) in risk of ovarian cancer associated with oral contraceptive pill use • Encourage patients to adopt a healthy lifestyle • Review the Hereditary Breast and Ovarian Cancer (HBOC) chapter of this resource guide, and the April 2009 ACOG Practice Bulletin on HBOC Syndrome for more information on screening and prevention in the high-risk patient

Ovarian Cancer

FocusonFemaleCancers • Primary Prevention and Screening:The Asymptomatic Patient • 7  ❙❙ Ovarian cancer accounts for approximately 15,000 deaths in the United States annually. Although the length of survival after diagnosis has increased over the past decades with advances in treatment, the overall mortality has shown little improvement. In an effort to reduce the public health impact of this disease, significant focus has been given to both primary prevention and screening. Prevention, by definition, takes place at three different levels, depending on the stage of the disease continuum targeted.

Primary prevention targets the pre-disease stage and reduces disease incidence by eliminating the causes of the disease or by increasing the body’s resistance to disease. Secondary prevention targets asymptomatic disease and seeks to diagnose disease at an earlier stage, when treatment is potentially more effective. Screening tests, followed by appropriate diagnostic tests and treatment when needed, are considered secondary prevention strategies. Tertiary prevention targets symptomatic disease and aims to halt or slow disease progression and limit resulting impairment and disability. This applies to most medical and surgical care provided by clinicians.

This section will focus on primary and secondary prevention of ovarian cancer.

Primary Prevention To prevent disease from developing, it is important to have a basic understanding of the underlying physiologic pathways and the associated risk factors and protective factors related to disease development in order to make informed recommendations. EtiologyofOvarianCancer To date, the etiology of ovarian cancer is not well understood. Several hypotheses have been proposed to explain the events leading to the development of ovarian cancer. These hypotheses include the following: • Incessant Ovulation Hypothesis: During ovulation, the surface epithelium of the ovary is damaged when the follicle ruptures and undergoes subsequent repair.

This hypothesis posits that increased cell division which accompanies the repeated repair process increases the opportunity for developing and propagating spontaneous mutations that promote carcinogenesis • Gonadotropin Hypothesis:This hypothesis posits that overstimulation of the ovarian surface epithelial cells by gonadotropins, Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) causes increased cell division and mutations that promote carcinogenesis • Hormonal Stimulation:This hypothesis suggests that high concentrations of androgens in the tumor environment promote carcinogenesis while progestins decrease risk • Inflammation Hypothesis: Ovulation is accompanied by the release of inflammatory mediators and an inflammatory response that“stresses”the ovarian surface epithelial cells and can promote malignant transformation.

Exposure to other inflammatory agents or conditions can also increase the risk of cancer • Gene Environment Interaction:This hypothesis suggests that family members can inherit a mutation that makes them more susceptible to certain environmental factors putting them at increased risk for disease No single hypothesis is adequate to explain all the known risk and protective factors associated with ovarian cancer. Ovarian surface epithelial cells are influenced by a host of factors and the exact mechanism of disease onset is yet to be identified.

RiskFactors Epidemiologic studies have identified a number of factors associated with an increased risk of developing ovarian cancer. These factors are listed below. Please seeTable 1 for a summary of risk factors. • Age: Incidence increases with age, occurring most frequently in women aged 50-79 years, with a median age at diagnosis of 63. Over 70% of ovarian cancer occurs after the age of 50 • Family history:Women who have one first degree relative with ovarian cancer have a 3-5% lifetime risk of developing the disease o The risk further increases if two or more relatives are affected, if the patient is of Ashkenazi Jewish descent, or if there is any family history of breast, male breast, pancreas, colon or uterine cancer o Women with hereditary ovarian cancer syndromes have an inherited genetic mutation that confers a significantly increased risk of developing ovarian cancer and other cancers • The majority of women with hereditary ovarian cancer have mutations in the BRCA1 and BRCA2 tumor suppressor genes.

The lifetime risk for ovar- ian cancer in BRCA1 mutation carriers is 36-45% and in BRCA2 carriers is 10-27%. About 10% of epithelial ovarian cancer is due to a BRCA1 or BRCA2 mutation • Another hereditary ovarian cancer is HNPCC, also referred to as Lynch II Syndrome. HNPCC involves mutations in the mismatch repair genes and accounts for about 2% of epithelial ovarian cancer. Women with HNPCC have a 10-12% lifetime risk of ovarian cancer. They also have an increased risk of early-onset colorectal, endometrial, urothelial and stomach cancer • Infertility: Infertility has been associated with an increased risk of ovarian cancer Primary Prevention and Screening: The Asymptomatic Patient

• Obesity: Evidence for the effect of obesity on the risk of ovarian cancer has been mixed. A recent study suggests that the risk of ovarian cancer increases modestly with increasing Body Mass Index (BMI). Women who were obese had 1.3 times the risk of women with a normal BMI of developing ovarian cancer. Women who were overweight had 1.2 times the risk of developing ovarian cancer, which was marginally significant. Being obese or overweight in early adulthood (17-20 years) also increased the risk of ovarian cancer 1.2 times that of women with a normal BMI. It has been suggested that the increase in ovarian cancer may be linked to a number of possible hormonal mechanisms associated with obesity, including elevated estrogen, elevated insulin and insulin-like growth factor and reduced progesterone • Hormone ReplacementTherapy (HRT): A recent meta-analysis suggests that the use of HRT is associated with an increased risk of ovarian cancer.

Women who had ever used HRT had a 24% increased risk of ovarian cancer compared to women who never used HRT. However, risk was not related to the duration of prior use. Those who were current users had a 28% increased risk, which increased to 47% for current users of more than five years duration. The risk of ovarian cancer was noted to be higher in women using estrogen only therapy (RR: 1.51) compared to estrogen- progestin therapy (RR: 1.24). Women should weigh the risks against the potential benefits on an individual basis and make an informed decision before starting HRT • Endometriosis: Ovarian cancer has been reported in association with some cases of endometriosis • Early menarche and/or late menopause: Findings are inconsistent.

If there is an increased risk it is very small • Race and Geographic Area:The incidence of ovarian cancer is highest in white women and inWestern industrialized nations. Women of Ashkenazi Jewish descent have a higher incidence of BRCA1 and 2 mutations. Refer to the HBOC chapter of this resource guide for more details • Smoking: Current smokers have twice the risk of mucinous ovarian cancer than women who have never smoked. However, there is no significant increase in risk for other histological types Table1: SummaryofRiskFactorsforOvarianCancerbyStrengthofEvidence Established risk factors Possible risk factors Suspected risk factors Age Early age at menarche Hormone replacement therapy Family history/ Mutation status Late age at menopause Obesity Nulliparity Infertility Sedentary lifestyle Oral contraceptive use (protective) Lactation (protective) Low vegetable intake Oophorectomy (protective) Tubal ligation (protective) Cigarette smoking Hysterectomy (protective) Permuth-WeyJ,SellersTA.Epidemiologyofovariancancers.MethodsofMolecularBiolo gy,Cancer Epidemiology.2009;472:413-437.

ProtectiveFactors Epidemiologic studies have identified a number of factors associated with a decreased risk of developing ovarian cancer.These factors include the following: • Prophylactic bilateral salpingo-oophorectomy (BSO): In high-risk women, prophylactic BSO reduces the risk of ovarian cancer by at least 90% • Pregnancy: Pregnancy has consistently been associated with a decreased risk of ovarian cancer. A single pregnancy confers a 20-40% reduction in risk. Each additional pregnancy decreases the risk another 10-15% • Oral Contraceptive Pills (OCPs):The use of OCPs reduces the risk of developing ovarian cancer, and the longer women take OCPs the greater the reduction in risk.

A woman can decrease her risk of ovarian cancer by as much as 60% with OCP use alone. The protection afforded by OCP use appears to last for decades and remains significant more than 30 years after last pill use. Protection also appears to be independent of the estrogen content in the pill and is similar for different pill formulations used over time. It has been estimated that 200,000 incident cases and 100,000 deaths from ovarian cancer could have been prevented in the past 50 years by oral contraceptive use. OCP use has standard associated side effects including a potential short-term increased risk of breast cancer, however, this risk declines with time since last pill use • Hysterectomy andTubal Ligation:These surgical procedures reduce the risk of ovarian cancer by 30-40%.

The postulated mechanism is preventing potential carcinogens from ascending to the ovary or reduced blood flow to the ovary • Lactation: Most studies show a slight decrease in ovarian cancer risk in women who breastfeed • Healthy lifestyle: A recent literature review suggests that vegetables and whole grains may reduce risk; however studies are inconsistent. The relationship between physical activity and ovarian cancer remains unclear, although some studies suggest that sedentary behavior may increase risk PrimaryPreventionStrategies In developing prevention strategies it is particularly important to identify those women who have the highest risk of developing ovarian cancer; women with hereditary cancer syndromes or with a strong family history.

The women’s health care provider should routinely perform a risk assessment with all patients, specifically asking about a family history of ovarian cancer as well as other cancers including breast, colorectal and endometrial cancer. Patients with a suggestive family history should be considered for genetic counseling and possible genetic testing. The HBOC chapter of this resource guide clearly outlines how to perform a risk assessment, identify patients who should be referred for further genetic evaluation and guidelines for the recommended preventive measures.

Prophylactic Bilateral Salpingo-oophorectomy Patients that have been identified to have a genetic predisposition for ovarian cancer can be advised on appropriate preventive measures including prophylactic 8 •FocusonFemaleCancers • ACOG District II/NY

bilateral salpingo-oophorectomy (BSO). Prophylactic BSO reduces the risk of ovarian cancer more than any other measure. This procedure is utilized in high- risk patients once childbearing is complete. In women undergoing abdominal surgery for other indications such as benign uterine disease, the physician may consider whether to also remove the ovaries at the time of surgery.

This decision must be made with the patient on an individual basis with a full discussion regarding the associated risks and benefits. In premenopausal women one must be particularly aware of the risks associated with premature menopause, including cardiovascular disease, osteoporosis and sexual side effects. In high-risk women undergoing a prophylactic BSO, early ovarian cancer (occult disease) can be identified on final pathology. Therefore, it is important to have the pathologist perform complete, serial sectioning of the bilateral tubes and ovaries and perform a microscopic examination for occult cancer.

Additional sections of the fimbriated tubal end have also been recommended by some studies. The provider should verify the extent of pathology processing performed within their institution for prophylactic cases, and may consider referring the patient to a gynecologic oncologist (gyn-onc) for this procedure. From a surgical stand point, it is imperative that all tissue from the ovaries and fallopian tubes be removed during the procedure. The infundibulopelvic ligament should be isolated and transected, fully clear of the adnexa. Thorough visualization of the peritoneal surfaces and pelvic washings should be performed.

Any suspicious areas should be biopsied.

Women with BRCA mutations who have had a prophylactic BSO have a 1-6% residual lifetime risk of developing primary peritoneal cancer. Peritoneal cancer can present with symptoms similar to ovarian cancer. Some have advocated serial CA 125 levels to screen for peritoneal cancer after prophylactic BSO, but this practice is not currently supported by evidence. Oral Contraceptive Pills (OCPs) An important preventive measure is the use of OCPs. When counseling patients regarding birth control options, the health care provider should highlight the protective effect of OCPs which have been associated with a significantly reduced risk for ovarian cancer.

Up to a 60% reduction of risk for ovarian cancer can be achieved with OCP use. The protective effect of OCPs increases with the duration of their use and this effect is sustained and continues long after a patient stops taking them. This information can be discussed with the patient as part of the counseling about benefits and side effects of contraceptive options. The HBOC chapter of this resource guide discusses OCP use in the high-risk population. Lifestyle When identifying potentially modifiable factors that may reduce risk for a given patient, lifestyle choices can be considered. Patients often want to know what they can do to improve their health and they value the recommendations of their health care provider.

This can be a valuable opportunity to promote a healthy lifestyle, which will contribute to overall health and well-being. Encourage patients to maintain a healthy weight, eat a healthy diet including plenty of vegetables and whole grains, get regular physical activity and avoid smoking. Screening If ovarian cancer is detected in the earliest stage, when it is localized to the ovary, the five-year survival rate is 92%. However, only 19% of ovarian cancers are localized when first detected. Most women are diagnosed with either regional or distant disease and the five-year survival rate is 71% and 30%, respectively.

Finding an effective screening strategy for the general population that would shift diagnosis to an earlier stage is still under investigation. ScreeningFundamentals The purpose of a screening test is to detect patients in the asymptomatic, preclinical phase of disease, which refers to the time between the pathological onset of disease and the development of clinically detectable symptoms. A screening test differentiates those likely to have disease from those who do not. A positive screening test is followed by a diagnostic test to establish the presence (or absence) of disease, and then allow for the appropriate treatment for confirmed cases.

A screening program consists of the screening test as well as the confirmatory diagnostic steps and subsequent treatment. Disease Characteristics In general, a disease must have certain characteristics to be appropriate for screening: • The disease must be serious with significant consequences • Available treatment must be more effective at an earlier stage • The disease must have a detectable preclinical phase (DPCP) and the DPCP must be of sufficient length • The disease should not be too rare Clearly, ovarian cancer is a serious disease and treatment of early stage disease is associated with higher survival outcomes.

However, the natural history of ovarian cancer is poorly understood. There is currently no clearly defined premalignant lesion and the DPCP is not well characterized. One longitudinal screening trial estimates the DPCP for ovarian cancer to be 1.9 +/- 0.4 years. If accurate, this should be adequate for annual screening. However, not all ovarian cancers behave the same. It is possible that biologically more aggressive tumors, which may contribute significantly to mortality, have a much shorter DPCP and are less likely to be detected by a periodic screening test. In addition, the prevalence of ovarian cancer in the general population is low, which makes screening an even greater challenge.

What Constitutes an Effective Screening Program? An effective screening program requires a screening test that is: • Convenient • Acceptable to most people FocusonFemaleCancers • Primary Prevention and Screening:The Asymptomatic Patient • 9

• Relatively free of risks or discomfort • Valid, meaning it can correctly distinguish individuals who have preclinical disease from those who do not • Cost effective Validity includes measures of both the sensitivity and the specificity of the test. Finding tests with adequate sensitivity and specificity is a challenge when screening for ovarian cancer.

Definitions of these terms are below: • Sensitivity:The probability that a test correctly classifies as positive those individuals with disease. A test with low sensitivity will miss many cases of disease, falsely labeling them as negative • Specificity:The probability that a test correctly classifies as negative those who do not have disease. A test with low specificity will incorrectly identify individuals without disease as having disease, also called false positives Positive PredictiveValue The feasibility of a screening program is measured primarily by looking at the positive predictive value (PPV) of the screening test.

The PPV is the proportion of those who test positive who actually have disease. A high PPV is important for a successful program because this indicates that a positive test is identifying a high proportion of actual cases and the number of false positive tests is low. When a screening test is positive, whether it is a true positive or a false positive, the patient must undergo a diagnostic test, which is often invasive and costly. If the PPV is low there will be an unacceptably large number of women with false positive tests who will require unnecessary follow-up evaluations, which pose potential harm to the patient and utilize limited resources.

The PPV of a screening test depends on the sensitivity and specificity of the test as well as the prevalence of the disease in the population. The prevalence of ovarian cancer in the post-menopausal population is only 1 per 2,500 women. Given this low prevalence, a screening test would need at least 75% sensitivity and 99.6% specificity to achieve a PPV of 10%. This means that for every 100 women who test positive, only 10 will have ovarian cancer. Therefore, 10 surgical evaluations would be conducted for each cancer detected.

Outcome Measures The success of a screening program is evaluated through specific outcome measures including: • Survival • A shift towards an earlier stage of disease in the screened population • Disease-specific mortality The "survival" endpoint refers to the number of people alive at a certain point in time, as measured from the time of diagnosis, such as five-year survival.This measurement is often used to compare the effectiveness of different treatment modalities. When survival measures are applied to screening, they must be interpreted with caution because they are inherently biased.

Survival may appear longer in the screened population, even if those screened do not actually live any longer. This is called lead-time bias, and refers to the period of time from when disease is detected by a screening test to when it would have presented based on symptoms. A screening test will detect disease earlier. Since survival is measured from the time of diagnosis, even if there is no change in the time of death, survival will appear to be increased (biased) by the length of the lead- time.

A screening program must reduce the disease-specific mortality in the screened population (this is considered the best measure of screening benefit). Screening for ovarian cancer in the general population has not been shown to improve overall survival and is therefore not recommended. CurrentlyAvailableScreeningModalities CA 125 and ultrasound have been the main focus of research efforts to date. However, with advances in scientific discovery, particularly in the areas of genomics and proteomics, new approaches to screening are being evaluated. The goal is to find a suitable test or combination of tests for a screening program that will reduce the mortality from ovarian cancer.

CA 125 CA 125 is a glycoprotein isolated from the serum of patients in a variety of clinical situations, including ovarian cancer. In the normal adult, CA 125 is found in the mesothelial cells of the pleura, pericardium and peritoneum, and in the epithelial cells of the female reproductive tract lining the tubes, endometrium and endocervix. CA 125 has been used in patients with ovarian cancer to monitor response to treatment as well as detect disease recurrence. However, its usefulness as a screening test is less clear. CA 125 lacks the sensitivity and specificity needed to function alone as a screening test.

Although 80% of women with advanced disease have elevated levels of CA 125 (> 35 U/ml), only 50% of women with early disease have elevated levels. Therefore, CA 125 is not sensitive enough to identify early stage disease. In addition, CA 125 is not specific to ovarian cancer such that women without ovarian cancer can have elevated levels due to a number of other conditions including: • Other malignancies: o Breast o Lung o Liver o Pancreas o Bladder • Non-malignant gynecologic and non-gynecologic conditions: o Diverticulitis o Cirrhosis o Hepatitis o Pancreatitis o Uterine fibroids 10 •FocusonFemaleCancers • ACOG District II/NY

o Endometriosis o Ovarian cysts o Tuboovarian abscess o Salpingitis • Menstruation • Pregnancy In an attempt to improve the utility of CA 125, efforts have been made to combine it with other screening tests, including other serum biomarkers and transvaginal ultrasound (TVS). Ultrasound Ultrasound is able to detect morphologic changes in the ovary, some of which could reflect ovarian malignancy. TVS is preferred over abdominal ultrasound because it gives a much better view of the ovaries. TVS is safe, efficient and generally well tolerated by patients, all of which are characteristics important for a screening test.

Information available fromTVS includes the volume of the ovary, presence of any abnormal lesions, evaluation of blood flow in an ovarian mass and presence of ascites. Median ovarian volume decreases with age from 1.25 cm3 for women aged 55-59 years to 1.0 cm3 for those aged 65-69 years. Although there are no recognized standard indices for evaluating ovarian tumors, increased ovarian volume, cystic ovarian tumors with papillary projections, and complex cysts with wall abnormalities or solid components are associated with ovarian cancer. TVS appears to have good sensitivity and is able to detect abnormalities in the ovary but the specificity is not good and it is often difficult to distinguish benign from malignant tumors, which leads to a relatively low PPV.

Attempts have been made to improve the specificity ofTVS, which would reduce the number of false positive tests. However, there are no current data suggesting TVS is appropriate for general population based screening. For more information regardingTVS studies currently being conducted, please see the Appendix: Future Directions in Ovarian Cancer Screening and Management. Multimodal Screening (MMS) Single modality screening with either CA 125 orTVS has not proven to be adequate given the inherent limitations of both tests. Therefore various efforts have been made to combine the tests and to refine the way the tests are used to improve screening utility.

Several studies conducted by Ian Jacobs in the United Kingdom in the late 1980s and early 1990s using CA 125 as an initial screening test followed by pelvic ultrasound suggested that this multimodal approach could achieve a high specificity and PPV in postmenopausal women. Subsequently, Jacobs et al. conducted the first randomized trial in ovarian cancer screening using this multimodal screening (MMS) strategy. The results were encouraging and laid the foundation for a larger randomized control trial using the multimodal approach. Further details of this study as well as a study evaluating the MMS approach with the Risk of Ovarian Cancer Algorithm (ROCA) andTVS can be found in the Appendix: Future Directions in Ovarian Cancer Screening and Management at the end of this chapter.

Current Studies At present two large randomized trials are being conducted, one in the United States and the other in the United Kingdom, each using both CA 125 andTVS to screen for ovarian cancer. Both studies have the stated objective of determining whether screening can decrease mortality due to ovarian cancer. Before general population based screening for ovarian cancer can be recommended, its efficacy in reducing mortality should be demonstrated. In the Prostate, Lung, Colorectal and Ovarian Cancer ScreeningTrial (PLCO), over 30,000 women aged 55 to 74 have been screened with an annual CA 125 and TVS.

Though the initial results have been discouraging, the effect of screening on mortality will not be available until the final results of the PLCO are reported. In the UK CollaborativeTrial of Ovarian Cancer Screening (UKCTOCS), almost 100,000 postmenopausal women have been screened with either annual CA 125 using the ROCA followed byTVS when indicated (MMS) or annualTVS alone (ultrasound screening). This unique design allows the direct comparison of two screening strategies. Results from the initial screen have been promising; however, the effect on mortality of this screening trial will not be available until 2014.

Further details regarding both of these trials, as well as other new developments in screening can be found in the Appendix: Future Directions in Ovarian Cancer Screening and Management. High-Risk Populations The feasibility of a screening test is improved when the prevalence of disease in the target population is increased. Given the increased prevalence of ovarian cancer in the high-risk population, screening methods should theoretically be more effective. Women considered at high-risk for the disease include those with a family history of ovarian cancer and those with known hereditary genetic mutations.

Screening recommendations for this population are discussed in the HBOC chapter of this resource guide.

Current Recommendations ACOG and the Society of Gynecologic Oncologists (SGO) recommend women get an annual gynecologic exam with an annual pelvic exam for routine preventive health care. It is important for patients to realize the importance of an annual well-woman visit. This visit is a yearly opportunity for examination and an appropriate time to discuss risk factors, prevention strategies and patient awareness regarding symptoms of ovarian cancer. FocusonFemaleCancers • Primary Prevention and Screening:The Asymptomatic Patient • 11 

The USPSTF, the American Cancer Society (ACS), ACOG and the National Institutes of Health (NIH) Consensus Panel all recommend against routine screening for ovarian cancer.

The USPSTF cited the low incidence of ovarian cancer, the low PPV of current screening methods, the high number of false positive tests generated, and the lack of evidence that screening reduces mortality from ovarian cancer as support for their recommendation. For women who are not considered high-risk and are interested in screening for ovarian cancer, it is important to emphasize the potential risks of random and unindicated screening, including the anxiety likely to be induced by false positive screening results and the likelihood of unnecessary surgery. References: Aschengrau A, Seage GR.

Essentials of Epidemiology in Public Health. Massachusetts: Jones and Bartlett Publishers; 2008. Badgewell D, Bast RC. Early detection of ovarian cancer. Disease Markers. 2007;23: 397-410.

Berek JS, Hacker NF. Practical Gynecologic Oncology, 4th Ed. Philadelphia: LippincottWilliams andWilkins; 2005. Collaborative Group on Epidemiological Studies of Ovarian Cancer, BeralV, Doll R, Hermon C, et al. Ovarian cancer and oral contraceptives: Collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls.The Lancet. 2008;371:303-314. HoskinsWJ, Perez CA,Young RC, et al. Principles and Practices of Gynecologic Oncology, 4th Ed. Philadelphia: LippincottWilliams andWilkins; 2005. Jacobs IJ, Skates SJ, MacDonald N, et al.

Screening for ovarian cancer: A pilot randomized controlled trial.The Lancet. 1999;353:1207-1210. Jekyll JF, Katz DL. Elmore JG,Wild DM. Epidemiology, Biostatistics, and Preventive Medicine. Philadelphia: Saunders; 2007.

Menon MD, Gentry-Maharaj A, Hallet R, et al. Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: Results of the prevalence screen of the UK CollaborativeTrial of Ovarian Cancer Screening (UKCTOCS).The Lancet. 2009;10:327-340. Menon U, Skates SJ, Lewis S, et al. Prospective study using the risk of ovarian cancer algorithm to screen for ovarian cancer. J Clin Oncol. 2005;23(31):7919-7926. Munkarah A, Chatterjee M,Tainsky M. Update on ovarian cancer screening. Current Opinions in Obstet and Gynecol. 2007;19:22-26. Nezhat F, Datta S, HansonV, et al.The relationship of endometriosis and ovarian malignancy: A review.

Fertility and Sterility. 2008;90(5):1559-1570. NIH Consensus Conference. Ovarian cancer: Screening, treatment, and follow-up. JAMA 1995;273:491-497.

NossovV, Amneus M, Su F, Lang J et al.The early detection of ovarian cancer: From traditional methods to proteomics. Can we really do better than serum CA 125? Am J Obstet Gynecol. 2008:215-223. Olsen CM, Green AC,Whiteman DC, et al. Obesity and the risk of epithelial ovarian cancer: A systematic review and meta-analysis. European J Cancer. 2007;43:690-709. Partridge E, Kreimer AR, Greenlee RT, et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol. 2009;113(1):775-782. Permuth-Wey J, SellersTA. Epidemiology of ovarian cancers. Methods of Molecular Biology, Cancer Epidemiology.

2009;472:413-437. South SA,Vance H, Farrell C, et al. Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation-negative familial ovarian cancers. Cancer. 2009;115(2):324-333.

Ueland FR, DePriest PD, Pavlik EJ, Kryscio RJ, van Nagell JR. Preoperative differentiation of malignant from benign ovarian tumors:The efficacy of morphology indexing and Doppler flow sonography. Gynecol Oncol. 2003;91:46-50. Urban N. Specific keynote: Ovarian cancer risk assessment and the potential for early detection. Gynecol Oncol. 2003;88:S75-S79. Van Nagell JR, DePriest PD, Ueland FR, et al. Ovarian cancer screening with annual transvaginal sonography. Cancer. 2007;109(9):1887-1896. Walsh CS, Karlan BY. Contemporary progress in ovarian cancer screening. Current Oncology Reports. 2007;9:485-493.

Zhou B, Sun Q, Cong R, et al. Hormone replacement therapy and ovarian cancer risk: A meta-analysis. Gynecol Oncol. 2008;108:641-65. 12 •FocusonFemaleCancers • ACOG District II/NY

Overview II. Symptom Recognition and Evaluation FocusonFemaleCancers • Symptom Recognition and Evaluation •13 BACKGROUND The earlier the diagnosis of ovarian cancer is made, the better the chance of survival. At present there is no reliable screening tool to detect ovarian cancer in the asymptomatic phase. However, it has been recognized that certain symptoms are reported by most women with ovarian cancer for months prior to diagnosis.

Prompt recognition of symptoms predictive of ovarian cancer, followed by an appropriate evaluation, are key strategies that will enable the diagnosis to be made earlier.

WHATYOU SHOULD KNOW SymptomRecognition • Ovarian cancer is not a“silent killer”and almost all women experience symptoms which present several months to a year before diagnosis • Symptoms in women with ovarian cancer are more numerous, more severe, occur more frequently (20-30 times a month) and are of more recent onset than in women in the general population • The constellation of symptoms that are reported most often by women with ovarian cancer prior to diagnosis include: o Increase in abdominal size or“bloating” o Pelvic or abdominal pain o Difficulty eating or feeling full quickly o Urinary complaints (urgency or frequency) o Other commonly reported symptoms include fatigue, indigestion, constipation, and back pain • Diagnosis in symptomatic women is frequently delayed due to the following: o Women delay presentation to their health care provider, either ignoring their symptoms or attributing symptoms to less serious conditions o Health care providers may be misled by the nature of the symptoms o A pelvic examination including rectovaginal exam is not completed o Symptoms are diagnosed as stress, depression, or irritable bowel syndrome o Appropriate ancillary testing including a transvaginal ultrasound (TVS) or CA 125 is not obtained Evaluation • A woman who presents with symptoms or physical findings suspicious for ovarian cancer should have additional evaluation which usually includes: o Complete physical exam, including abdominal/pelvic exam (with rectal examination) o TVS o CA 125 level o Other laboratory tests may include complete blood count (CBC), chemistry profile with liver function tests The earlier the diagnosis of ovarian cancer is made, the better the chance of survival.

14 •FocusonFemaleCancers • ACOG District II/NY o Assess family history for breast, ovarian, endometrial and colorectal cancer, a hereditary cancer syndrome and Ashkenazi Jewish ancestry o If the gynecologic evaluation is normal, consider CT scan to evaluate for other abdominal pathology • The initial focus when evaluating a pelvic mass is to determine whether it is most likely benign or malignant. This will guide further management decisions • Specific indicators suspicious for malignancy include: o Physical Exam • Irregular, solid, fixed, or nodular pelvic mass • Presence of ascites • Palpable lymphadenopathy o TVS • Increased ovarian volume • Solid areas • Papillary projections • Wall abnormalities or thickening • Ascites o CA 125 • For menopausal women, an elevated CA 125 is suspicious for malignancy • For premenopausal women, CA 125 is elevated in many benign conditions.

However, highly elevated levels are suspicious for malignancy • Normal levels do not rule out malignancy o Other modalities • CT: Helpful to characterize extent of abdominal spread when cancer is suspected based on initial tests • MRI: Helpful to distinguish if tumors are benign when theTVS is indeterminate, particularly if the CA 125 is normal or slightly elevated • A woman with a suspicious adnexal mass requires surgical evaluation. In these circumstances, the National Institutes of Health (NIH), the American College of Obstetricians and Gynecologists (ACOG) and the Society of Gynecologic Oncologists (SGO) all recommend that a physician trained to appropriately stage and debulk ovarian cancer, such as a gynecologic oncologist (gyn-onc), should perform the operation.

ACOG and SGO have developed specific guidelines for clinicians to prompt referral to a gyn-onc WHATYOU SHOULD DO • Have a high index of suspicion for ovarian cancer in women who present with abdominal, pelvic or urinary complaints that are new or persistent • Recognize that increasing age is a risk factor for ovarian cancer • Perform a pelvic exam andTVS on women with abdominal, pelvic or constitutional complaints before labeling them as having only stress, depression or a gastrointestinal process • Educate patients about potential symptoms of ovarian cancer to help reduce delays in diagnosis.

Women who have suspicious symptoms almost daily for more than a few weeks should see their health care provider, preferably a gynecologist • Obtain a CA 125 in women with an adnexal mass prior to surgical evaluation • Offer women with an adnexal mass that is suspicious for malignancy a referral to a gyn-onc • Familiarize yourself with the ACOG/SGO Referral Guidelines for a Newly Diagnosed Pelvic Mass (seeTable 2, page 19.) Most women with ovarian cancer have new and persistent symptoms that have been present for several months to more than one year prior to diagnosis.

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