Not So Fast: Mailman Public Health Biostatisticians Raise Concerns Over Ovarian Cancer Screening Study
Late last year, The Lancet published the long-anticipated results of the largest ovarian cancer screening trial to date. The study of more than 200,000 women over a 14-year period examined a new screening protocol for a disease called the 'silent killer' because its symptoms often don't manifest until the cancer has spread. While results were inconclusive, the investigators presented enticing evidence in the paper that the screening was effective. Shortly after, Abcodia, the company behind the screening test, made it available commercially.
But earlier last month, the Food and Drug Administration issued a 'safety communication' statement recommending against the screening test, and a week later, Abcodia voluntarily pulled their product, the $295 ROCA (Risk of Ovarian Cancer Algorithm) test, from the market. The FDA action came on the heels of a June editorial in American Family Physician authored by a group of experts —including two Mailman School biostatisticians — that pointed to uncertainties in the Lancet study and expressed reservations about the marketing of the screening test.
The proprietary algorithm developed by Harvard biostatistician Steven J. Skates works by assessing changes in levels of a protein biomarker called CA-125 over time. In the 2012 study known as the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), postmenopausal women were randomized to one of three groups: multimodal screening (MMS) using ROCA, transvaginal ultrasound (USS), or no screening. On the surface, the results of UKCTOCS published in The Lancet several years ahead of the study's conclusion, were very promising.
For women enrolled in the MMS arm, who were followed up by ultrasound screening when increasing CA-125 was found, ovarian cancer was diagnosed earlier than for those not screened. Even more exciting, the researchers reported a significant reduction in risk of death for women in the subset screened annually for at least seven years. Yet at a February meeting called by the Ovarian Cancer Research Fund that gave rise to the June editorial, Mailman's Bruce Levin and Cody Chiuzan and others voiced serious concerns about the research and underlined the significant downside of imprecise screening.
A test that is insufficiently specific would generate many false positives — which at the least would give women a bad scare, and at the most, lead to unnecessary surgery, chemotherapy, and radiation. On the other hand, a test that is insufficiently sensitive would miss cancers, potentially delaying necessary treatment.
While there was nothing fraudulent about the UKCTOCS study, the Mailman biostatisticians say its most promising results are the result of several misleading statistical contortions.
For starters, they question why it would take seven years to show a survival benefit for the screening test. In the typical screening trial, Levin, a professor of Biostatistics, explains, it may take several years until enrolled patients develop a disease, but in the UKCTOCS trial, the survival curves in both the ROCA and no screening arms overlap perfectly for about ten years, a period during which many women had died. Experts at the June meeting said there was no plausible explanation for the delay in mortality reduction, except perhaps as an artifact of shifting demographics as older study participants dropped out — a possibility the study hadn't explored but is currently. "Older women might be less likely to go through all the repeated screenings," posits Chiuzan, an assistant professor of Biostatistics.
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