INTRODUCTION — Ovarian cancer is the second most common gynecologic malignancy and the most common cause of death among females with gynecologic cancer . This poor prognosis is due, in large part, to the fact that most patients are diagnosed at an advanced stage, while early stages of the disease are potentially curable. Unfortunately, attempts to develop screening programs for epithelial ovarian cancer using pelvic imaging or tumor markers have not yet been successful. The identification of epithelial ovarian cancer symptoms to aid early detection has become a focus of clinical research.
Epithelial carcinoma of the ovaries, fallopian tubes, and peritoneum are clinically similar. Evidence suggests that these diseases have a common pathogenesis, and may be initiated in the fallopian tubes. The term ovarian cancer will be used in this topic to refer to disease of any of these three sites.
Early detection of epithelial ovarian cancer through symptom recognition is reviewed here. Screening and diagnosis of epithelial ovarian cancer are discussed separately. (See "Screening for ovarian cancer" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis".)
EVIDENCE REGARDING EARLY SYMPTOMS
Presence of early symptoms — Historically, epithelial ovarian cancer was called the "silent killer" because symptoms were not thought to occur until very late in the course of the disease . Advanced epithelial ovarian cancer typically presents with abdominal distention, nausea, anorexia, or early satiety due to the presence of ascites and omental or bowel metastases; dyspnea is occasionally present due to a pleural effusion. However, studies have found that symptoms occur in many patients even at early stages of the disease [3-9].
Most patients with epithelial ovarian cancer have pelvic or abdominal symptoms prior to their diagnosis. This was demonstrated in a meta-analysis that included 21 mostly retrospective studies (one study was prospective) of patients with epithelial ovarian cancer . The proportion of patients who reported symptoms differed by study design (7 percent were asymptomatic by patient interview or questionnaire; 23 percent according to medical records). This difference is likely due to recall bias in the patient report studies.
The symptoms that were most commonly reported by at least one-half of study subjects were: abdominal pain/discomfort and abdominal swelling/bloating. These symptoms may be attributed to many different conditions. It appears, though, that they are more common, recur more frequently, and are more severe in patients prior to a diagnosis of epithelial ovarian cancer than in other patients.
The rate of symptoms in patients with epithelial ovarian cancer compared with other patients was illustrated in three case control studies included in the meta-analysis. As an example, one study surveyed 128 patients with pelvic masses prior to undergoing surgery (44 were ultimately diagnosed with epithelial ovarian cancer) and 1011 of whom presented to a primary care clinic for a problem visit . Patients with epithelial ovarian cancer had a higher rate of the following symptoms compared with those with benign masses and with the primary care patients, respectively: increased abdominal size (64 versus 56 and 19 percent); bloating (70 versus 49 and 38 percent); and urinary tract symptoms, particularly urgency (55 versus 31 and 32 percent). Pelvic pain, abdominal pain, abdominal mass, difficulty eating, and constipation were significantly more common in patients with epithelial ovarian cancer than in primary care patients, but not in those with pelvic masses.
The pattern and quality of symptoms appear to differ among patients with cancer. In the meta-analysis, compared with primary care patients, symptoms in patients with epithelial ovarian cancer recurred more frequently (20 to 30 times versus 2 to 3 times per month), were more severe, and had a shorter duration (less than three to six months versus one year or more) . In addition, epithelial ovarian cancer patients were more likely to have multiple symptoms (a triad of bloating, increased abdominal size, and urinary urgency was present in 44 versus 8 percent).
The increased likelihood of symptoms in patients with epithelial ovarian cancer was further supported by a study that compared Medicare claims linked to the California Surveillance, Epidemiology, and End Results cancer database for 1985 patients with epithelial ovarian cancer, 6024 patients with breast cancer, and over 10,000 patients without cancer . Epithelial ovarian cancer patients were more likely to have health care visits for abdominal swelling and gastrointestinal symptoms in the six months prior to diagnosis than age-matched breast cancer and noncancer controls. In another retrospective study evaluating a diverse community cohort of 540 patients with epithelial ovarian cancer, 85 percent of patients presented with symptoms and initial diagnosis occurred in the emergency department for 25 percent of patients . For patients with early-stage disease (190 patients), 74 percent were detected as a result of symptoms.
The duration of the onset of symptoms to time of diagnosis of ovarian cancer varies. A study of 1700 patients with ovarian cancer reported that 30 percent of patients had symptoms for 0 to 2 months, 35 percent for 3 to 6 months, 20 percent for 7 to 12 months, and 15 percent for greater than 12 months . Patients who felt that they had ignored their symptoms were more frequently found to have advanced stage disease; however, this question may be influenced by recall bias.
Use of symptom recognition may have the potential to identify patients with early stage disease. Patients with early stage epithelial ovarian cancer appear to have symptoms, but less frequently than those with late stage cancer (89 versus 97 percent in one study ) . Prospective studies are needed to determine whether recognition of epithelial ovarian cancer symptoms results in earlier diagnosis, and ultimately, in improved prognosis.
Role of early detection — The goal of early detection is to reduce epithelial ovarian cancer mortality by diagnosing the disease while it is confined to the ovary rather than at advanced stages, when the five-year survival rate is less favorable (table 1 and table 2). Unfortunately, however, almost 80 percent of patients have lymph node or distant metastases at the time of diagnosis . For this reason, early identification of symptomatic patients has become a goal of the current approach to this disease.
A secondary goal is detection and treatment of advanced disease as early as possible. Cure rates are twofold for patients in whom optimal cytoreduction (less than 1 cm of gross residual disease following surgery) can be achieved compared with those who do not have an optimal surgery (30 to 40 percent cure versus 15 to 20 percent) . The most significant factor associated with optimal cytoreduction is the volume of disease at the time of presentation . (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Surgical staging".)
Some evidence suggests that evaluation of ovarian cancer symptoms results in identification of more patients with completely resectable disease. The highest quality data regarding this are from the pilot phase of the Diagnosing Ovarian Cancer Early (DOvE) study, a prospective study in which 1455 patients age 50 or older with symptoms associated with ovarian cancer were evaluated with serum CA 125 and transvaginal ultrasound . At seven-month follow-up, 239 patients (16 percent) had an initial abnormal test result and underwent further evaluation and 11 patients (0.8 percent) were diagnosed with invasive ovarian, fallopian tube, or peritoneal cancers. Only one patient who underwent exploratory surgery was found to have benign rather than malignant disease. Among the patients with ovarian, fallopian tube, or peritoneal cancer, eight (72 percent) were completely resectable compared with 23 percent in a control group of patients with ovarian cancer who presented during the study period to gynecologic oncologists at the same institution.
It is hypothesized that if an association between specific patterns of symptoms and epithelial ovarian cancer can be identified, earlier detection of disease may be possible. At issue is whether diagnosing epithelial ovarian cancer three to six months earlier will improve prognosis. The potential impact of early detection depends upon how much time it takes to progress from disease confined to the ovary or fallopian tube to metastatic disease as well as how quickly metastases increase in volume.
There are no definitive data regarding the doubling time for ovarian cancer. In one study, the average time to develop port site metastasis after laparoscopy in ovarian cancer was 17 days . A modelling study calculated that ovarian tumors may spend more than four years as stage I or II and one year as stage III or IV until they become clinically apparent . In recurrent ovarian cancer, the median doubling time of CA 125 (a surrogate for volume of disease) is 40 days but the range of doubling times is very wide and prognosis was significantly worse in those with quick doubling times compared with those with long doubling times .
Symptoms that are associated with epithelial ovarian cancer are often nongynecologic and, frequently, nonspecific (table 3) [4-7]. Patients and providers may not consider the possibility of epithelial ovarian cancer when these symptoms arise. Thus, another important clinical challenge is to identify which symptoms warrant further evaluation for epithelial ovarian cancer, without resulting in large-scale unnecessary testing.
CLINICAL APPROACH TO SYMPTOM RECOGNITION — The following discussion reviews our clinical approach to early detection of epithelial ovarian cancer through symptom recognition.
History — Risk assessment for ovarian cancer depends upon age and family history. It is probably most effective to focus attention on symptoms in patients who are at an increased risk (ie, over 40 years old or with a family history of ovarian or related cancer). (See "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Incidence and risk factors", section on 'Probable risk factors'.)
Patients may present with symptoms suggestive of epithelial ovarian cancer or such symptoms can be elicited during a routine review of symptoms [4-9]:
●Urinary urgency or frequency
●Difficulty eating or feeling full
●Abdominal or pelvic pain
Patients who complain of these symptoms should be further evaluated with a thorough history to assess for other potential symptoms of epithelial ovarian cancer and to gain additional information about each symptom (eg, frequency, severity). Symptoms that are of new onset, coexist with other symptoms, occur almost daily, and are more severe than expected warrant further evaluation. For example, persistent rather than fluctuating abdominal distension was associated with epithelial ovarian cancer in one small observational study .
A population-based study in the United Kingdom found that a clinical algorithm was able to predict the risk of a diagnosis of ovarian cancer within two years based upon family history of ovarian cancer or a set of symptoms (eg, abdominal distension, abdominal pain) . In the two-year study period, 63 percent of the ovarian cancers were diagnosed among the 10 percent of patients with the highest predicted risk. The top predictive factors were: abdominal distention, family history of ovarian cancer, postmenopausal bleeding, and appetite loss. This algorithm is not available for clinical use.
Symptom index — A symptom index has been developed to aid clinicians in evaluating patients for early symptoms of epithelial ovarian cancer. Further validation studies are needed for this index, and it is not yet recommended for routine clinical use. The symptom index is considered to be positive if a patient reports any of the following symptoms that are: (1) new to the patient within the past year and (2) occur more than 12 times per month :
●Pelvic or abdominal pain
●Increased abdominal size or abdominal bloating
●Difficulty eating or feeling full quickly
Follow-up for a positive index includes the standard steps used to evaluate a patient with suspected epithelial ovarian cancer: assessment of risk factors, pelvic imaging, serum CA 125 concentration, and possible referral to a gynecologic oncologist. Decisions regarding surgical exploration should not be made based upon a positive symptom index alone.
The initial study to develop the epithelial ovarian cancer symptom index was a case control study in which 149 patients with epithelial ovarian cancer, 255 patients enrolled in an epithelial ovarian cancer screening program, and 233 patients referred for pelvic/abdominal ultrasound were surveyed . The cases and controls were divided randomly into two groups, and in the initial phase of the study, the symptom index was developed by evaluating the cases and controls in one group. Pelvic/abdominal pain, increased abdominal size/bloating, and difficulty eating/feeling full were the symptoms that were most significantly associated with epithelial ovarian cancer when they were present for less than one year and occurred for more than 12 days per month. These results were then used as the reference standard to determine the performance of the index in the other part of sample. By disease stage, sensitivity of the index for early stage was 57 and for late stage was 80 percent. According to patient age, sensitivity and specificity for patients <50 years were both 87 percent and for patients ≥50 years were 67 and 90 percent.
Since the prevalence of epithelial ovarian cancer is low, the utility of the symptom index in an average risk population has been questioned. A case control study compared 812 patients with epithelial ovarian cancer with 1313 patients from the general population . Sensitivity for epithelial ovarian cancer in stage I/II was 62 percent and for stage III/IV was 70 percent; the specificity was 95 percent for all stages. For different age groups, the sensitivity and specificity for ages 55 to 74 were 66 and 96 percent and for ages 35 to 54 were 69 and 94 percent. Using this average risk study population for comparison, the positive predictive value of the symptom index was 0.8 to 1.1 percent for all ovarian cancers and 0.2 to 0.5 for stage I/II disease. From a clinical perspective, the symptom index is best utilized when it is the first step in a sequential process that includes measurement of CA 125 and ultrasound imaging for patients with a positive symptom index .
Combined use of CA 125 and the symptoms index for epithelial ovarian cancer may have better diagnostic performance than either test alone. In a prospective study, 75 patients with pelvic masses who were subsequently diagnosed with epithelial ovarian cancer and 254 high risk controls were evaluated with the symptom index and a serum CA 125 . The symptom index had lower sensitivity and specificity for epithelial ovarian cancer than an abnormal CA 125 (64 and 88 versus 79 and 95 percent); 11 percent of patients with ovarian cancer had a positive symptom index and negative CA 125 . The combination of either a positive CA 125 or symptom index had a higher sensitivity, but a lower specificity than either test alone (89 and 84 percent). The combination of these tests needs to be evaluated in an average risk population.
Many media sources and survivor groups have suggested that patients keep symptom diaries and report them to physicians, but the safety of this approach has not been evaluated and there are concerns that a systematic focus on symptoms could lead to unnecessary surgery. A pilot study of over 1200 patients who were screened with a symptom index followed by reflexive CA 125 and transvaginal ultrasound in symptom index positive patients resulted in no major (laparoscopy or laparotomy) unindicated procedures .
Physical examination — Patients with symptoms suggestive of epithelial ovarian cancer should be evaluated with a physical examination, including an abdominal, pelvic, and rectovaginal examination as well as palpation of groin and supraclavicular lymph nodes. Findings suggestive of epithelial ovarian cancer include:
●A mass in the mid to left upper abdomen, which may represent an omental cake
●Groin or supraclavicular lymphadenopathy
If the physical examination is normal, then, depending upon the clinical situation, we may wait two to four weeks to see if symptoms resolve or can be explained by another disorder. If they do not, we obtain an ultrasound examination of the pelvis.
Laboratory and imaging studies — If the findings on physical examination are abnormal or symptoms are persistent, then we evaluate patients with a transvaginal and transabdominal ultrasound examination to evaluate the ovaries and check for ascites . Occasionally, abdominal or pelvic computed tomography (CT) is needed to help clarify ultrasound findings. (See "Adnexal mass: Ultrasound categorization".)
We also suggest measuring the serum CA 125 concentration. This tumor marker used alone does not perform well for diagnosis or exclusion of epithelial ovarian cancer in premenopausal patients. Moreover, one-half of patients with stage I epithelial ovarian cancer have a normal CA 125 level. Nevertheless, a very high level is suggestive of epithelial ovarian cancer and a baseline value is useful in monitoring patients who are subsequently diagnosed with epithelial ovarian cancer. (See "Screening for ovarian cancer", section on 'Cancer antigen 125 (CA 125)'.)
Recommendations from expert groups — Expert panels endorse the use of symptoms as a prompt for evaluation for epithelial ovarian cancer [27-29]. The Gynecologic Cancer Foundation, American Cancer Society, and Society of Gynecologic Oncologists issued a consensus statement regarding early symptoms in 2007 (table 4) . In addition, since 2008, the National Comprehensive Cancer Network has included symptoms associated with epithelial ovarian cancer without other obvious source of malignancy as an indication for a work-up to exclude epithelial ovarian cancer .
REFERRAL TO A GYNECOLOGIC ONCOLOGIST — The American College of Obstetricians and Gynecologists (ACOG) has published guidelines to help predict when ovarian or adnexal masses are likely to be malignant . ACOG recommends referral to a gynecologic oncologist in the following settings:
●Postmenopausal patients with an elevated CA 125 level, ultrasound findings suggestive of cancer, ascites, a nodular or fixed pelvic mass, or evidence of abdominal or distant metastasis.
●Premenopausal patients with a very elevated CA 125 level, ultrasound findings suggestive of cancer, ascites, a nodular or fixed pelvic mass, or evidence of abdominal or distant metastasis.
●Premenopausal or postmenopausal patients with an elevated score on a formal risk assessment test (eg, multivariate index assay, risk of malignancy index, risk of ovarian malignancy algorithm) or one of the ultrasound-based scoring systems from the International Ovarian Tumor Analysis group.
This recommendation is based on consistent evidence from studies showing that surgical treatment by nongynecologic oncologists, and by low volume providers, contributes to suboptimal surgical management and shorter median survival. The guidelines are summarized in the table (table 5). (See "Approach to the patient with an adnexal mass", section on 'When to refer to a gynecologic oncologist'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ovarian and fallopian tube disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Ovarian cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Screening for ovarian cancer (Beyond the Basics)" and "Patient education: Ovarian cancer diagnosis and staging (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The goal of early detection of epithelial ovarian cancer is to improve prognosis by diagnosing the disease while it is confined to the ovary or when the disease volume is low. (See 'Role of early detection' above.)
●Most patients with epithelial ovarian cancer have abdominal symptoms prior to their diagnosis. These symptoms are often gastrointestinal or urinary, rather than gynecologic. (See 'Presence of early symptoms' above.)
●Bloating, increased abdominal size, urinary urgency or frequency, difficulty eating or feeling full, and abdominal or pelvic pain occur in many gastrointestinal disorders, but are also common in patients with epithelial ovarian cancer. In particular, epithelial ovarian cancer should be suspected when these symptoms coexist with other symptoms, occur almost daily, and are more severe than expected. (See 'Presence of early symptoms' above.)
●A symptom index has been developed to aid clinicians in evaluating patients for early symptoms of epithelial ovarian cancer. Further validation studies are needed for this index, and it is not yet recommended for routine clinical use. (See 'Symptom index' above.)
●We suggest physical examination, pelvic ultrasound examination, and measurement of serum CA 125 for further evaluation of patients with persistent symptoms that are suggestive of epithelial ovarian cancer. (See 'Laboratory and imaging studies' above.)
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