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New ovarian cancer test shows promise, but some call it risky

This article first appeared in the St. Louis Beacon: September 23, 2008 - Finding a single test to screen for early detection of ovarian cancer has been cancer researchers' equivalent of the search for the Holy Grail.

Doctors use mammography to screen for breast cancer, the Pap smear for cervical cancer and PSA blood tests for prostate cancer. Ovarian cancer has had no equivalent screening test.

This summer, it appeared Yale University and Laboratory Corporation of America had hit the mark. On June 23, LabCorp announced it was releasing a blood test marketed as OvaSure for women at high risk of ovarian cancer. LabCorp said the Phase II clinical trials conducted by Yale showed OvaSure correctly identified women who have ovarian cancer in 95.3 percent of cases. False positives occurred less than 1 percent of the time.

But medical experts are wary.

"We all believe it has to go through some more rigorous testing," said Dr. Diane Yamada, section chief for gynecologic oncology at the University of Chicago Medical Center and vice chair of marketing and communications for the Society of Gynecological Oncologists.

Last month, the Federal Drug Administration demanded a meeting with LabCorp.

"We believe you are offering a high-risk test that has not received adequate clinical validation and may harm the public health," the FDA said in an Aug. 7 letter.

LabCorp said it agrees patients should be protected but without "unnecessary regulatory burdens." The test remains on the market.

Why So Deadly?

Ovarian cancer is the most deadly of gynecologic cancers. More than 21,000 women will be diagnosed with the disease and 15,000 women will die of it this year. Breast cancer is eight times more prevalent, but has a much higher survival rate.

The reason for ovarian cancer's high mortality rate is that it typically is detected late. Four out of five women who are diagnosed with the disease are in an advanced stage, when the cancer has spread outside the ovaries. A woman with advanced-stage ovarian cancer has a 30 percent chance of surviving five years. If the cancer is caught before it has spread, that survival rate soars, to 90 percent.

"Screening is all about identifying patients when they're asymptomatic," says Dr. Nick Chobanian, director of the gynecologic oncology division at St. John's Mercy Medical Center. "Right now we don't have anything."

Diagnosis is difficult, not only because there's no approved screening test but because symptoms are vague and can be mistaken for other conditions.

Take Susan Bober, for example. It took more than a year for Bober, 56, a retired teacher from Fenton, to be diagnosed with advanced-stage ovarian cancer, Stage IIIC on a scale where IV is the most advanced. (click here for more on ovarian cancer stages)

She had suffered from incontinence, diarrhea, severe abdominal pain, bloating and fatigue. She had seen her OB/GYN and an urologist, and made one visit to an emergency room.

Bober finally went to her internist, who eventually sent her back to the ER and doctors ordered exploratory surgery. The cancer, found at last, had spread beyond the ovaries. Bober had a complete hysterectomy and underwent chemotherapy. Five to six months after completing treatment, the cancer was back. She's been undergoing chemotherapy since May 2007.

Know the Symptoms

In the absence of a screening test, education seems to be the best tool in a physician's arsenal.

The oncology community has coalesced around four symptoms. Doctors hope publicizing the symptoms will result in women being diagnosed before their cancer has spread. They are:

  • Bloating
  • Pelvic or abdominal pain
  • Difficulty eating or feeling full quickly
  • Urinary symptoms (urgency or frequency)

The oncologists' group, the SGO, advises that if any of these symptoms persist for two weeks, a woman should see her primary care physician or OB/GYN. Experts say an OB/GYN should conduct a recto-vaginal exam, and if anything suspicious is found, he or she should order a trans-vaginal ultrasound to look for fluid around the ovaries.

Getting It Right

Sandy Bauer's diagnosis of ovarian cancer is a textbook example of how diagnosis should occur.

Bauer, 64, of Ballwin, was a librarian at a St. Louis County Library branch in 2005 when she picked up a bookmark on the counter that listed the symptoms of ovarian cancer.

"It said ovarian cancer whispers, so listen. I had had constipation, gas and fatigue and tiny flutters in the lower pelvic area," she said.

Constipation, gas, fatigue - all were listed as symptoms on the bookmark. Another symptom is abdominal pain. Bauer described the feelings in her pelvic area more as "baby scratches" rather than pain.

She saw her gynecologist the next day. He ordered a trans-vaginal ultrasound and a blood test known as the CA-125, which detects a protein found in greater concentrations in cancerous cells. The blood test registered 356 - well above the recommended ceiling of 35. Within two weeks, she'd had a hysterectomy. She had Stage IIIC ovarian cancer. Her doctor ordered chemotherapy.

Why Not Use the Ca-125?

The CA-125 often is one element in diagnosing ovarian cancer. But it's not used as a screening test because it produces a high rate of false positives. Doctors say that fibroids, endometriosis and other cancers can produce an elevated CA-125. The blood test also is unreliable for producing a true negative result.

Dr. David Mutch used a hypothetical group of 100,000 50-year-old women to illustrate why the CA-125 is not used to screen for ovarian cancer. Mutch is director of the division of gynecological oncology at Washington University School of Medicine and president-elect of the SGO.

Doctors would expect 40 women in 100,000 to have ovarian cancer, statistically speaking. If the CA-125 was tested on all 100,000, 4,000 might have elevated levels. Yet only 40 would actually have ovarian cancer.

A false positive can lead to unnecessary surgery. That's because ovarian cancer can only be verified through surgery. In the hypothetical group of 100,000 women, 3,960 of those with elevated CA-125 levels might have been subjected to surgery unnecessarily if doctors relied on the CA-125 as a screening test.

Doctors do consider the CA-125 to be a reliable tool to test ovarian cancer patients for a recurrence. After a patient finishes chemotherapy, her doctor generally will run a CA-125 every three months to watch for a change in that biomarker.

"Now it's different because it's not screening and we're looking for something in particular," said Dr. Chobanian, at St. John's Mercy.

 Ovarian cancer Breast cancer Cervical cancer
Lifetime risk 1 in 72 women will be diagnosed1 in 8 women will be diagnosed1 in 145 women will be diagnosed
Overall 5-year survival rate 46% of women with this cancer are alive 5 years after they are diagnosed89% of women with this cancer are alive 5 years after they are diagnosed71% of women with this cancer are alive 5 years after they are diagnosed
Screening or early detection tools NoneMammograms have reduced deaths from breast cancer in the United States by approximately 46% over the past 25 yearsPap smears have reduced deaths from cancer of the cervix in the United States by approximately 70% over the past 50 years
Prevention Methods None -- methods exist to reduce risk but nothing will prevent the diseaseTamoximfen citrate is FDA-approved to reduce the incidence in high-risk women. A number of large prevention studies have been completed which propose new prevention methodsVaccine for human papillomavirus was approved in 2006 and prevents close to 70% of all cervical cancers

Source: Ovarian Cancer National Alliance

Saving Lives or Doing Harm?

The CA-125 is one of six biomarkers tested by LabCorp's OvaSure blood test. All specimens are sent to LabCorp for analysis. The test costs $220 to $240.

Eric Lindblom, LabCorp's senior vice president for investor and media relations, said in response to e-mailed questions that Yale has completed Phase III clinical trials on OvaSure and is expected to publish the results later this year.

"Our expectation is that this test can help physicians detect ovarian cancer sooner so that it can be treated at an earlier stage -- saving lives," he said.

But none of the three gynecologic oncologists in the St. Louis area who were interviewed for this story said they would order the test.

Mutch said that's because OvaSure isn't reliable enough.

"The problem is the incidence of ovarian cancer is so low that tests have to be extremely specific," he said.

"What OvaSure wants to do we need," he said. "But until it's reliably predictive of the general population, it can do more harm than good."

Jean McKibben, 66, of Centennial, Colo., would agree, based on her personal experience with OvaSure. McKibben was first diagnosed with ovarian cancer, Stage IC in 2003. She had a hysterectomy and chemotherapy and was cancer-free for three years.

When her CA-125 count jumped from single-digits to double-digits in 2006, she suspected the cancer had returned. A CT scan verified her suspicion, and she underwent more surgery and more chemo.

Last spring [2008], her CA-125 count nudged upward slightly. McKibben had read about the forerunner of OvaSure, which was in Phase II clinical trials at Yale. She sent her blood work to the researchers, and they said it was negative.

In June, she returned for another CA-125. This time the count had doubled, to 25, but remained within the normal range. Still, she knew that any change was significant for her.

"I was freaking out," she said. "I knew what had happened, again." The cancer was back.

On June 24, the day after OvaSure was put on the market, McKibben sent LabCorp a sample of her blood. The result? "It said I had zero chance of having ovarian cancer," McKibben recalled. "I knew that they were wrong."

Her doctor ordered a PET scan, which showed a small mass on her liver. He recommended another course of chemo. Instead, McKibben traveled to Houston to seek a second opinion from M.D. Anderson Hospital. In August, she began a clinical trial for a second generation of the drug Avastin.

Waiting for Validation

The Ovarian Cancer National Alliance, a Washington-based advocacy and awareness group, is taking a wait-and-see approach.

"We're excited about anything that comes out that works," said Cara Tenenbaum, OCNA's senior policy director. "We're excited to hear about the data, but it's still in Phase III trials. We're waiting for that validation data."

McKibben is waiting, too. For now, she says it's just not there.

"Women will have a false sense of security and that could mean their life," McKibben said. "[LabCorp] should have waited till all the trials are over before marketing it."

LabCorp's Lindblom says that technical review data that is supplied to doctors states that OvaSure tests for new cases of ovarian cancer and does not monitor for recurrence.

Despite the absence of a screening test, doctors see reason for optimism.

Dr. Yamada, of the University of Chicago, says advances in treatment of ovarian cancer in the last three decades have produced better survival rates for patients.

"We are improving the ability for people to live longer,'' she said. More aggressive surgery and intraperitoneal chemotherapy, which is delivered directly into the abdominal cavity, are extending the lives of women diagnosed with advanced-stage disease.

In the mid-1970s, the average survival time for such patients was 12 months. Now, the median survival for women with optimal surgery and intraperitoneal chemo is about five and a half years.

"You have to hit it from all fronts," she said.

Who's high risk?

Generally speaking, these categories of women are characterized as being at high risk for ovarian cancer:

  • A woman who has had ovarian cancer or who has a family history of ovarian cancer (a first- or second-degree relative with the disease).
  • A woman who has had breast cancer, has a family history of breast cancer diagnosed before age 50 (first- or second-degree relative) or has a family history of any male breast cancer.
  • A woman with a mutation in the BRCA1 or BRCA2 genes.
  • A woman who has had hereditary non-polyposis colon cancer or who has a family history of mutations in the genes associated with colorectal cancer.

Jan Paul, a former reporter and editor for the St. Louis Post-Dispatch, is a two-year survivor of ovarian cancer. Her cancer was diagnosed at Stage IIIB. 

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