Ovarian cancer: Recognizing early symptoms can make a difference
David Cohen, M.D.·Published 29 April 2008·14 min read
Key points
With no reliable screening tests available, ob/gyns have tried to use their clinical judgment and the patient's medical history to detect the disease in its early stages.
To successfully screen asymptomatic women for ovarian cancer, we have to overcome several obstacles.
Keep in mind, however, that USPSTF says there's fair evidence to justify screening and genetic counseling in women whose family history suggests an increased risk for deleterious mutations in BRCA1 or BRCA2.
Given that screening for average-risk women is currently not recommended for the general population, is there anything that clinicians can do to help make a diagnosis earlier, when chance of cure is improved?
With no reliable screening tests available, ob/gyns have tried to use their clinical judgment and the patient's medical history to detect the disease in its early stages. Recent studies have found, however, that a specific set of persistent signs and symptoms may signal emerging disease and warrant follow-up diagnostic testing.
No one has to remind an ob/gyn that ovarian cancer is the most deadly gynecologic malignancy. With over 15,000 deaths in the United States each year and over 70% of cases diagnosed in their advanced stages, it is one of the most frustrating diseases for clinicians to contend with.
Five-year survival rates for women with advanced stages are only 15% to 30% but if the disease is diagnosed in its early stages cure rates jump to 70% to 90%. Because survival is so much more likely when the disease is caught early on, extensive research has been done to find an effective screening strategy. But despite our best efforts, an effective screening test has yet to emerge.
Obstacles to a successful screening protocol
To successfully screen asymptomatic women for ovarian cancer, we have to overcome several obstacles.
First, and foremost, an in situ phase of the disease must exist, but it's possible that, unlike in cervical carcinoma, a precancerous detectable ovarian lesion may not exist.
Second, most ovarian cancers grow very quickly, and so the window of opportunity to make a diagnosis when the disease is still confined to the ovary may be very short.
Third, the incidence in the general population is only 40 per 100,000 women. With so few women developing the disease annually, even a screening test with a specificity of 99.6% would yield a positive predictive value (PPV) of only 10%. (Put another way, 10 women would need to undergo surgery for one case of ovarian cancer to be detected).
Fourth, false-positive screening results can cause some serious psychological and financial consequences.
Finally, since the only way to confirm a diagnosis of ovarian cancer is with a major surgical procedure, the morbidity and mortality of screening may outweigh the benefit of early detection (Table 1).
TABLE 1: Pitfalls when 'screening' for ovarian cancer
No doubt these are some of the reasons the American College of Obstetricians and Gynecologists recommends against population-based screening for ovarian cancer and the United States Preventive Services Task Force (USPSTF) has assigned routine screening for ovarian cancer a "D" grade, a designation that indicates there is fair evidence to recommend its exclusion from a periodic health examination.
Written and revised by
David Cohen, M.D.
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Keep in mind, however, that USPSTF says there's fair evidence to justify screening and genetic counseling in women whose family history suggests an increased risk for deleterious mutations in BRCA1 or BRCA2. However, women from high-risk families constitute only 5% to 10% of ovarian cancer cases. Most cases occur among women from families with no significant family history of disease, and who are considered at average risk. Interest in screening average-risk women for ovarian cancer is growing and studies are ongoing, but as we mentioned earlier, currently available tests are inadequate for such use.
{pagebreak}Why not screen women at average risk? - Ovarian cancer: Recognizing early symptoms can make a difference
One of the problems in screening average-risk women is that the currently available tests have shortcomings. Although transvaginal ultrasound (TVS) has sensitivity and specificity ratings as high as 100% and 98%, respectively, their PPV is approximately 1% when it is used alone. We also don't know how frequently TVS should be performed to be effective. For example, one research group evaluated TVS every 6 months in 4,526 women at high risk for ovarian cancer and found that 10 ovarian, primary peritoneal, or fallopian tube cancers were diagnosed - but all were already in advanced stages.
We also know that CA125 is elevated in women with advanced-stage ovarian cancer but is not reliably elevated among women with early-stage disease, being elevated above a standard cutoff of 35 U/mL in approximately 50% of such women. This marker may also be elevated in women with a variety of benign conditions, including endometriosis and pelvic inflammatory disease, which means a significant number of women will receive elevated abnormal test results in the absence of ovarian cancer
Although neither TVS nor CA125 has performed well enough to justify their use for routine screening of average-risk women, their performance when used in a bimodal strategy is currently being tested in two randomized controlled trials.
IN THE US, the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial is evaluating annual use of both TVS and CA125 in women aged 55 to 74. (CA125 is considered positive if it exceeds 35 U/mL in this study.) If either the TVS or CA125 test is positive, the woman is referred to her own physician for evaluation. This strategy maximizes sensitivity at a cost in specificity. Because a woman's screen is considered positive if either the CA125 or the TVS suggests a malignancy, this method may be effective at identifying cancer. But inadequate specificity may lead to an unacceptable low PPV. Preliminary analysis from this study found a PPV of 1.6% in high-risk populations and 0.7% in average-risk populations using this screening strategy.
IN THE UK, a trial involving 200,000 women is evaluating serial changes in CA125 followed by TVS, if abnormal. Preliminary reports have found only three ovarian cancers so far in the screened group. Evaluation of screening with ultrasound and/or CA125 in other studies of high-risk women have also been disapointing, finding that the majority of women are still being diagnosed with advanced-stage disease despite being screened. With these data in mind, prophylactic bilateral salpingo-oophorectomy may be the only currently available intervention for women that can effectively eliminate the threat of ovarian cancer in high- risk women.
Assessing symptoms may be our best hope
Given that screening for average-risk women is currently not recommended for the general population, is there anything that clinicians can do to help make a diagnosis earlier, when chance of cure is improved? Ovarian cancer has been called the "silent killer" because symptoms were not thought to occur until very late in the course of the disease. However, recent studies have refuted this myth and shown that even in early stages symptoms can occur.
TABLE 2: Common symptoms in ovarian cancer
A large retrospective survey that evaluated symptoms and diagnosis among 1,725 women with ovarian cancer found that 97% of women with advanced-stage and 89% of women with early-stage ovarian cancer had symptoms an average of 3 months before seeing a physician. The most common symptoms were abdominal and gastrointestinal (Table 2); gynecologic symptoms were the least common. A significant percentage of women were misdiagnosed with conditions like stress, irritable bowel syndrome, and depression prior to receiving a correct diagnosis and 30% were given medication for another condition prior to their ovarian cancer diagnosis. Although this study was an important contribution to understanding of symptoms in ovarian cancer, there was also legitimate criticism due to concerns of recall bias and lack of a control group.
A subsequent case–control study evaluated symptoms in 168 ovarian cancer patients and 251 controls (obtained through random digit dialing). This study found that ovarian cancer patients were significantly more likely to complain of bloating, lack of appetite, abdominal pain, urinary frequency, and constipation, when compared to controls. In women with early-stage disease, 89% complained of symptoms prior to diagnosis and these symptoms, even in early-stage disease, were significantly more common than in controls. This study was also criticized due to recall bias and the fact that the controls were not necessarily seeking medical care.
This led to another case–control study in which the symptoms typical of ovarian cancer were evaluated in 1,709 women seeking care at a primary-care clinic and compared to 128 women with pelvic masses who were surveyed prior to undergoing surgery, and before patients knew if they had ovarian cancer. Symptoms such as bloating, increased abdominal size, urinary symptoms, and pelvic and abdominal pain were found significantly more frequently in women with ovarian cancer than in those presenting to primary-care clinics. However, 72% of the clinic population did have recurring symptoms, with the most common being back pain, fatigue, and constipation. Interestingly, older women in the clinic control group reported fewer symptoms and most symptoms reported, except urinary symptoms, were less frequent and less severe in the older women.
This study also explored the presentation of symptoms in cancer patients versus controls. Cancer patients typically reported that their symptoms occurred 20 to 30 times per month as compared to two to three times for the clinic population. The severity of symptoms was also significantly higher, and symptoms were of more recent onset in cancer patients. The investigators noted that 44% of women with ovarian cancer had a triad of bloating, increased abdominal size, and urinary urgency, as compared to only 8% of clinic controls. While the types of symptoms that women with ovarian cancer experience are vague and frequently reported by women presenting to primary-care clinics, the important distinction between cases and controls appears to be the frequency, severity, and duration of the symptoms.
THE MOST RECENT STUDY evaluating symptoms as a possible method for earlier detection of ovarian cancer looked at 149 women with ovarian cancer, 255 women enrolled in an ovarian cancer screening program, and 233 women referred for pelvic/abdominal ultrasound. They were surveyed about types of symptoms they experienced, along with frequency, severity, and duration. The cases and controls were randomly split into an exploratory and confirmatory sample for the purpose of developing a symptom index. In the exploratory sample, the factors most significantly associated with ovarian cancer were pelvic/abdominal pain, increased abdominal size/bloating, and difficulty eating/feeling full when these symptoms were present for less than 1 year and occurred for more than 12 days per month. Evaluation of sensitivity in the confirmatory sample revealed the index could identify 56.7% of women with early-stage disease and 79.5% of those with late-stage disease. The specificity was 86.7% for women under 50 and 90% for women over 50.
The authors then evaluated this symptom index in 1,709 women presenting at a primary-care clinic. Having any one of the six symptoms present for less than a year and occurring more than 12 times a month was considered a positive screen. Evaluation of this group revealed that 45/1,709 (2.6%) tested positive with this index. When stratified by age, 36 out of 1,102 women (3.3%) under age 50 and 8 of 560 (1.4%) aged 50 and older tested positive in this clinic population. Therefore, this symptom index performed at least as well as single modality screening with CA125.
{pagebreak}A consensus on symptom assessment - Ovarian cancer: Recognizing early symptoms can make a difference
Based on these studies, the Gynecologic Cancer Foundation, American Cancer Society, and Society of Gynecologic Oncologists issued a consensus statement regarding symptoms of ovarian cancer in June of 2007. The consensus statement was meant to provide information for both patients and practitioners about the importance of symptom recognition for the early detection of ovarian cancer (Table 3).
Recent studies have shown that these symptoms may not cause women or their physicians to test for ovarian cancer because of their nongynecologic and frequently nonspecific nature. They do, however, appear to cause women to seek medical care, and if the association of specific patterns of symptoms with ovarian cancer could be identified, then the earlier detection of disease may be possible.
When Smith and associates evaluated Medicare claims linked to the California Surveillance, Epidemiology and End Results (SEER) database, they found that ovarian cancer patients were significantly more likely to have provider visits for abdominal swelling and gastrointestinal symptoms in the 6 months prior to diagnosis than the control groups. The study included 1,985 ovarian cancer patients and age-matched breast cancer and non-cancer clinic controls. Their results suggest that there may be a window of opportunity to make an earlier diagnosis of ovarian cancer for women with these symptoms. While we don't know if diagnosing ovarian cancer 3 to 6 months earlier will improve prognosis, we do know that in women for whom an optimal cytoreduction (no gross residual disease following surgery) can be achieved, cure rates are double that of women who do not have an optimal surgery (30%–40% cure vs. 15%–20%). For those who achieve optimal cytoreduction followed by intraperitoneal chemotherapy, we can now achieve median survival of over 60 months. The most significant factor associated with optimal cytoreduction is volume of disease at the time of presentation. Since ovarian cancer can have very rapid doubling times, 3 to 6 months could represent a significant time interval for improved prognosis associated with early diagnosis.
TABLE 3: A closer look at the Ovarian Cancer Consensus Statement Symptoms
We cannot overemphasize the importance of considering ovarian cancer when evaluating a woman who is complaining of bloating, increased abdominal size, and urinary urgency. New symptoms, symptoms that coexist with other symptoms and occur almost daily, and are more severe than expected warrant close attention.
The first step in evaluating these types of symptoms is to perform a pelvic examination, including a rectovaginal examination. If the findings are abnormal, then transvaginal or pelvic ultrasound is usually the next step. Depending on ultrasound results, abdominal and pelvic CT and/or serum CA125 testing may be indicated. If the pelvic examination is normal, then it may be reasonable to wait an additional 2 to 4 weeks to see if symptoms resolve. If they do not, then ultrasonography of the pelvic organs should be performed.
DR. GOFF is Professor in the Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA.
DR. MUNTZ is Clinical Associate Professor of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA.
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Publish date: Mar 1, 2008 By: Barbara A. Goff, MD, Howard G. Muntz, MD