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.