Journal of the National Cancer Institute Advance Access originally published online on September 11, 2007
JNCI Journal of the National Cancer Institute 2007 99(18):1359-1361; doi:10.1093/jnci/djm163
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© Oxford University Press 2007.
NEWS |
Cancer Killer May Be "Silent" No More
Long dubbed the "silent killer," ovarian cancer may be a disease that whispers, producing symptoms that the vigilant can recognize, according to a consensus statement released in June by three cancer organizations.
However, the statement has stirred up controversy because the symptoms are so vague that they are usually caused by other less serious conditions. They include bloating, pelvic or abdominal pain, difficulty eating or feeling full quickly, or a frequent or urgent need to urinate, according to the patient education group Gynecologic Cancer Foundation (GCF), the Society of Gynecologic Oncologists (SGO), and the American Cancer Society (ACS). They say that women should be tested for ovarian cancer if the symptoms appear suddenly and continue persistently for several weeks (read the statement at http://www.sgo.org/publications/OvarianCancerSymptoms.pdf).
These groups hope that recognition of these symptoms will lead to earlier diagnosis of the cancer, which is the second most common gynecologic malignancy in the United States and the most deadly. More than 70% of women are diagnosed at an advanced stage. This year, 21,000 women are expected to be diagnosed with the cancer, and 15,000 women will die.
The groups recognize that these symptoms are also associated with common disorders, such as bladder infections and irritable bowel syndrome, and that there is no evidence that early detection substantially affects mortality.
In fact, the American Cancer Society wrestled with the decision to cosign the consensus statement. "This really wasn't easy for us," said Debbie Saslow, M.D., director of breast and gynecologic cancer at the society. "It's not because we don't believe that there are symptoms but because of concerns that there is no standardized diagnostic workup for women who go to their gynecologist or primary care physician because of these symptoms."
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While there is no evidence that early detection will save patients, Saslow said that "in the end we felt there was more benefit to signing than to not sign because this might push doctors into taking women who complain of these symptoms more seriously."
Gynecologic oncologists all know of patients who have been "bounced around and have seen a lot of doctors and had a lot of tests before anyone thinks of looking for ovarian cancer," said Andrew Berchuk, M.D., director of the division of gynecologic oncology at Duke University Medical Center and president of the SGO. "That has been one of our big problems. Ovarian cancer is often not thought about until a [computed tomography] scan is performed and a mass is seen. By then it is usually advanced."
But not everyone believes this symptom index will lead to efficient diagnosis of ovarian cancer. "Everyone has these symptoms, and the worst choice we can make as doctors is to immediately order tests for ovarian cancer," said Judy Chamberlain, M.D., a family practitioner in Brunswick, Maine. Family physicians are the first point of contact for millions of older women, and Chamberlain has already had patients come to her waving newspaper articles about the "new" signs of ovarian cancer. Their complaints are much more likely to be something other than ovarian cancer, so it is more important to get a thorough history to figure out what else is going on. She said you should first do testing that rules out common conditions.
Some gynecologists are concerned that the consensus statement will force an increased use of ultrasound and its associated expenses, said Katie Wakeley, M.D., chief of the division of gynecology–oncology at Tufts–New England Medical Center in Boston. "They tell me it means that everyone will have to get an ultrasound, even though the symptoms are likely to be something else," Wakeley said.
More troublesome to some is that the groups didn't launch a prospective study to validate what is being dubbed the "ovarian cancer symptom index" in the general population, and no such investigation is planned. Without a trial, it will be impossible to determine if the index, which was culled from the experiences of ovarian cancer patients, has any effect on the number of women who are diagnosed early, acknowledges Sherry Salway Black, executive director of the Ovarian Cancer National Alliance, the umbrella advocacy group that pushed for recognition of symptoms. "It is vital to have such a follow-up study," she said. "But we don’t have the resources for that, and I am not sure anyone is setting up such a study."
Advocates Push For Studies
By all accounts, the growing influence of ovarian cancer survivors—now estimated at 172,000 women—first fueled a movement 10 years ago challenging physicians to recognize symptoms of early ovarian cancer.
Physicians have long been trained that symptoms of ovarian cancer occur primarily in advanced, less treatable stages. In fact, textbooks in internal medicine, family practice, and gynecology say that symptoms do not occur until the disease is advanced. But survivors of early-stage ovarian cancer argue that originally they sought medical attention because of such symptoms. That disconnect between physicians and survivors became public in 1998, when representatives of the year-old Alliance attended a GCF-sponsored meeting of advocates and representatives of organizations interested in women's health. Black recalled that when a prominent gynecologic oncologist mentioned that there were no symptoms of early-stage ovarian cancer, survivors stood up in protest to recount how signs of trouble had prompted them to see parades of physicians before their cancer was diagnosed.
Attending the meeting was Barbara Goff, M.D., a professor and director of gynecologic oncology at the University of Washington in Seattle, who decided to research the issue. She said several retrospective studies had indeed indicated that most patients do have some symptoms, but the studies were criticized because of the method of collecting data and because few patients participated.
Working with the late Cindy Melancon, an ovarian cancer survivor and founder of the alliance, Goff put together a survey of symptoms that was answered by 1,725 survivors. The analysis, published in Cancer in 2000, reported that 95% of patients experienced one or more symptoms, and 89% of women with stage I/II reported symptoms in the disease's early stages. A 2001 case–control study of 419 patients by researchers at Memorial Sloan-Kettering Cancer Center also found that 89% of patients with early-stage disease complained of symptoms prior to diagnosis.
Both her study and the Memorial Sloan-Kettering study, however, suffered from weaknesses, Goff said, such as the fact that most women were surveyed months or years after their diagnosis, making recall bias an issue. And primary care physicians pointed out that women without ovarian cancer often have the same symptoms.
"There has been a body of literature that shows ovarian cancer is not asymptomatic, but when you looked at the list of symptoms you knew that we all have these symptoms from time to time," Goff said. "The question is how can you distinguish ovarian cancer from what we all just have as part of normal life?"
A second survey by Melancon and Goff, published in the Journal of the American Medical Association in 2004, found that women with ovarian cancer had symptoms of greater frequency and severity and more recent onset than did women without cancer. Researchers compared questionnaires of survey symptoms from 1,709 women who visited two primary care clinics with survey results from 128 women diagnosed with a pelvic mass. While 72% of women in the clinic population reported a median of four recurring symptoms two to three times a month, ovarian cancer patients experienced about eight symptoms much more frequently—20–30 times per month—and the symptoms were much more severe and more recent.
Goff was able to narrow the original list of 23 symptoms down to a few whose frequency and duration were associated with ovarian cancer. In the Jan.15 issue of Cancer, Goff detailed the results from a study of 488 women who were enrolled in ovarian cancer early-detection programs, as well as women who were referred for an abdominal ultrasound. The group included 149 women with ovarian cancer, including 55 women with early-stage disease. The patients were divided randomly into an exploratory group and a confirmatory group. In the exploratory group, Goff found six symptoms that were independently associated with ovarian cancer if they occurred more than 12 times per month but were present for less than a year. These were the symptoms that formed the "symptom index" in the consensus guidelines.
In the confirmatory sample, this symptom index picked up the disease correctly 56.7% of the time for early-stage disease and 79.5% for advanced-stage disease. It also correctly identified women who did not have ovarian cancer 90% of the time in those older than 50 years and 86.7% of the time in younger women. "The cost of the symptom index is minimal (compared with CA125 testing), which may be useful in selecting women who should have additional diagnostic testing," she said. The key, she added, is how the symptoms present: suddenly, persisting for more than 12 times per month but for less than 1 year, and as a new experience for the woman. Women who understand that will be much less likely to run to their gynecologist when they have just occasional symptoms, Goff said. "They will be empowered to understand when it might be problematic."
Beyond the Symptom Index
Like physicians, most cancer-free women are not aware that symptoms of early ovarian cancer exist. A 2005 poll of 800 women commissioned by the GCF found that respondents had an outsized fear of developing gynecologic cancer and felt powerless to prevent these cancers.
Goff's research, combined with findings from the poll, persuaded the GCF, the SGO, and the ACS to release the consensus statement to news media in June, which resulted in a front-page New York Times story on June 13. But while that article discussed ovarian cancer symptoms, it told only half the story, Berchuk said. Women also need to be educated about other risk factors, such as the fact that women who have never had children are twice as likely to develop the disease and to stress family history and inheritance of the susceptibility genes BRCA1 and BRCA2, he said. "It is estimated that 10%–15% of ovarian cancer occur in women with a strong predisposition," Berchuk said. A 1998 meta-analysis of 15 studies, published in the British Journal of Obstetrics, found that the relative risk of developing ovarian cancer increases by 300% if a first-degree relative also developed the disease. "We can do genetic screening and prophylactic oophorectomy. We can save lives," he said. "We can prevent ovarian cancer."
That education may soon come. The advocacy community successfully lobbied Congress to pass "Johanna's Law," which President Bush signed in January. The law was proposed in 2002 to honor teacher Johanna Silver Gordon, who had experienced symptoms of ovarian cancer but did not recognize them for what they were. She died of ovarian cancer in 2000 at age 58. Formally known as the Gynecologic Cancers Education and Awareness Act of 2005, the law authorizes the Centers for Disease Control and Prevention to spend $16.5 million on a national gynecologic cancer early detection and awareness campaign.
Will Early Detection Save Lives?
Advocates and experts agree that too little is known about ovarian cancer. While many hope that early detection will save lives, no one yet knows that it does. "There is a lack of evidence that early detection impacts survival," ACS's Saslow said.
Ovarian tumors are believed to be as varied as other tumor types: Some will be benign, some may be slow growing and treatable, but others will be so aggressive that little can be done to control them. What is understood is that ovarian tumors rapidly double in size and that a surgery that leaves clean margins is the best hope for a cure, Goff said. "Although it remains unknown whether diagnosing ovarian cancer from 3 months to 6 months earlier will improve diagnosis, we do know that one factor that determines a successful surgery is the volume of the tumor," she said. "For some ovarian cancers, 3 months may make a big difference, and for other cancers, it may be more like 6 months. We just don’t know."
Goff adds that the symptom index will become truly useful only if it is validated in primary care women who have not yet been diagnosed with the disease. "I’m the first one to say that needs to happen," she said, but added that, so far, no one has plans to do that study. This lack of information about the value of early detection and the relevance of symptoms to survival is what led ACS's Saslow and her advisory board to wrangle with endorsement of the consensus statement.
Advocates and scientists agree that a woman experiencing persistent and prolonged symptoms like the ones Goff found should be seen by a physician. Odds are that they will not have ovarian cancer, but they may have another disorder that should be diagnosed, Chamberlain said. "If a woman comes in mentioning the ovarian cancer symptom index, I see that as an opportunity to educate a woman about her other risks factors as well, such as that heart disease is the number-one killer of women, and [tell her] that ovarian cancer only affects 1 of 70 women in their lifetimes," she said. "Any entry into the primary care system gives us a chance to do a comprehensive patient history."
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