Tuesday, August 26, 2008
The New York Times reports that the FDA is concerned about a new blood test aimed at detecting ovarian cancer at its earliest stage, saying that the data appears insufficient to back the company's claims about the test. Andrew Pollack writes,
A new blood test aimed at detecting ovarian cancer at an early, still treatable stage is stirring hopes among women and their physicians. But the Food and Drug Administration and some experts say the test has not been proved to work.
The test, called OvaSure, was developed at Yale and has been offered since late June by LabCorp, one of the nation’s largest clinical laboratory companies.
The need for such a test is immense. When ovarian cancer is detected at its earliest stage, when it is still confined to the ovaries, more than 90 percent of women will live at least five years, according to the American Cancer Society. But only about 20 percent of cases are detected that early. If the cancer is detected in its latest stages, after it has spread, only about 30 percent of women survive five years.
But far from greeting the new test with elation, many experts are saying it might do more harm than good, leading women to unnecessary surgeries. The Society of Gynecologic Oncologists almost immediately issued a statement saying it did not believe the test had been validated enough for routine use.
“You’ve got industry trying to capitalize on fear,” said Dr. Andrew Berchuck, director of gynecologic oncology at Duke University and the immediate past president of the society. “We’d all love to see a screening test for ovarian cancer,” he added, “but OvaSure is very premature.”
OvaSure’s debut also raises questions about whether greater regulation is needed to assure the validity of a trove of sophisticated new diagnostic tests that are entering the market and are being used as the basis for important treatment decisions. OvaSure did not go through review by the Food and Drug Administration because the agency generally has not regulated tests developed and performed by a single laboratory, as opposed to test kits that are sold to laboratories, hospitals and doctors. (All OvaSure blood samples are sent to LabCorp for analysis.)
But the F.D.A. has now summoned LabCorp to discuss OvaSure, saying the data appear insufficient to back the company’s claims about the test. “We believe you are offering a high-risk test that has not received adequate clinical validation and may harm the public health,” the agency said in an Aug. 7 letter sent to LabCorp that was posted on the F.D.A. Web site. A spokesman for LabCorp, which is short for Laboratory Corporation of America Holdings, said the company looked forward to reviewing the data with the agency but would continue offering the test in the meantime.
Dr. Myla Lai-Goldman, chief medical officer of LabCorp, said that OvaSure had been validated in several studies and that additional data were expected by the end of this year. Diagnostic tests typically are studied further after they have reached the market, she said. Dr. Goldman said there was “tremendous interest” from physicians in learning more about OvaSure.
Patients and advocacy groups seem divided on OvaSure, which costs about $220 to $240.
“We are hearing from people that they are very excited about it,” said Cara Tenenbaum, policy director for the Ovarian Cancer National Alliance. But the alliance urges women to wait for more data before relying on the test.
More than 21,000 new cases of ovarian cancer will be diagnosed in the United States this year and more than 15,000 people are expected to die from the disease, according to the American Cancer Society.
OvaSure measures the level of six proteins in a sample of blood, some produced by a tumor and some produced by the body in reaction to a tumor. It then calculates a probability that the woman has ovarian cancer. One of the six proteins is CA-125, which is used by itself as a test to monitor disease progression in women who already have ovarian cancer but is not good at picking up early disease.
In a study published in the journal Clinical Cancer Research in February, the test correctly classified 221 of 224 blood samples taken from women with ovarian cancer or from controls. It identified 95 percent of the cancers, and its false positive rate — detecting a cancer that was not there — was 0.6 percent.
But Dr. Beth Y. Karlan, director of the Women’s Cancer Research Institute at Cedars-Sinai Medical Center in Los Angeles, said the samples tested were not representative of what might be encountered in routine screening. There were very few blood samples from women with early stages of the most deadly type of ovarian cancer. “That’s really what we want to find,” she said.
The biggest concern is not that the test will miss cancers but that it will say a cancer is there when it is not. That would then subject women to needless surgery to have their ovaries removed.
Dr. Berchuck of Duke said only 1 of 3,000 women has ovarian cancer. So even if a screening test had a 1 percent rate of false positives, it would mean that 30 out of 3,000 women tested might be subject to unnecessary surgery for every one real case of cancer.
Teresa Hills, who had a visible mass on her left ovary, got a positive result from OvaSure. But when the ovary was removed, the mass turned out to be benign.
The false positive did not prompt unnecessary surgery because Ms. Hills was going to have the mass removed in any case. But it did cause needless anxiety.
“You can’t sleep, you can’t eat, you’re paralyzed with fear,” said Ms. Hills, a 44-year-old mother of three from Rockford, Ill. She said she lost 10 pounds in two weeks after the false diagnosis.
Dr. Lai-Goldman at LabCorp said that OvaSure should be restricted to women at high risk of ovarian cancer and that the test should be repeated if the result is positive. Those measures would limit the number of false positives.
LabCorp estimates that there are 10 million women at high risk. These include carriers of mutations in genes called BRCA1 or BRCA2, as well as women with histories of ovarian or breast cancer.
Dr. Gil Mor, the lead developer of the test at Yale, said the use of OvaSure might reduce ovarian surgeries, not increase them. That is because women with BRCA mutations often have their ovaries removed to prevent cancer. A negative result on the OvaSure test might allow such women to put off the surgery.
“They are removing the ovaries without the test,” said Dr. Mor, an associate professor of obstetrics and gynecology. “So what are we talking about here? We are trying to do the opposite and say don’t remove the ovaries.”
That logic appeals to some. Dr. Elizabeth Poyner, a gynecologic oncologist in Manhattan with a lot of high-risk patients, said she was thinking about how to incorporate OvaSure into her practice. One of her patients, a Manhattan woman with a BRCA2 mutation, said she was planning to take the test in hopes of postponing ovary removal.
“I’d really like a couple of more years to have the heart health and the bone health and all the benefits that come from having estrogen naturally,” said the woman, who is in her early 40s and spoke on the condition she not be identified because she had not told some relatives that she has the mutation.
But Dr. Julian C. Schink, director of gynecologic oncology at Northwestern University, said it would be “playing Russian roulette” to put off ovary surgery unless OvaSure detected cancer. “We just don’t have any data to show this test will turn positive before the disease turns metastatic,” he said.
The test is also not intended to detect the recurrence of cancer. Jean McKibben, a retired schoolteacher from Centennial, Colo., said her test result suggested zero probability that her cancer had returned. But scans then found a tumor. Only later did Ms. McKibben learn that the test does not work for women whose ovaries have been removed.
The ovarian cancer detection field has had disappointments before. Four years ago, the F.D.A. intervened to effectively stop the marketing of another complex ovarian cancer screening test developed by a company called Correlogic Systems. The test, called OvaCheck, had also spurred great hope, but never made it to market as experts questioned its validity.
With the number of genetic and other tests proliferating, the agency has been under pressure to assure that the tests are accurate. Two years ago, the agency said it intended to regulate complex tests, like OvaSure, that measure multiple proteins or genes and use a mathematical formula to compute a result. But it has not finalized the policy.
Peter J. Levine, president of Correlogic, said the company was developing a new ovarian screening test and would apply by the end of the year for F.D.A. approval. He said it would be unfair if LabCorp did not need approval.
Another company, Vermillion, applied to the F.D.A. in June for approval of a test, called OVA1, aimed at determining whether ovarian masses are cancerous.
Dr. Daniel Schultz, who oversees diagnostic tests for the F.D.A., said the agency was trying to balance demands for greater oversight of tests against concerns that regulation could impede development of needed diagnostics.
“We understand that concerns have been raised regarding the impact that F.D.A. regulation would have on this whole field,” he said.
Even if OvaSure is validated, or a better test is developed, questions will remain on whether screening is useful, similar to controversies that have arisen about prostate cancer screening.
Dr. Berchuck of Duke said it had not been proved that a test that detects cancer early would cut deaths from the disease. It could be that cancers detected early were the less aggressive ones that would not have killed the woman anyway.
Some experts say women should pay more attention to symptoms, like pain and bloating. But these symptoms can also be caused by other conditions.
The Canary Foundation, which finances research on early cancer detection, is focusing on developing better imaging techniques. Transvaginal ultrasound, which is sometimes used now, is not that good at detecting early disease.
“Too much of the dialogue has been on how good is the blood test,” said Don Listwin, a Silicon Valley executive who started the foundation after his mother died from ovarian cancer that was diagnosed late. “They thought it was a bladder infection.”
Mr. Listwin said mammograms and the P.S.A. test were fairly unreliable in detecting breast and prostate cancer, respectively. Yet they can be used for screening because a positive test result can be followed by a needle biopsy to confirm whether cancer is present.
But it is difficult to do a biopsy of the ovary because of its location, so a positive blood test result might lead directly to surgery. If imaging could be used for confirmation, he said, then even a somewhat inaccurate blood test might suffice for screening.