Although only about 1.5 percent of women in the United States will be affected by ovarian cancer during their lifetime, it ranks as the fifth most common cause of cancer death among women. The five-year survival rate is about 45 percent because most women present with advanced-stage disease.
In February, the Ovarian Cancer Research Fund Alliance brought together 25 clinicians, scientists and advocates in a meeting at the Banbury Center at Cold Spring Harbor Laboratory in Huntington, N.Y., to discuss results from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS),(www.thelancet.com) which were published online in December in The Lancet. Specifically, the group sought to determine what implications the trial findings might have for clinical care and public health.
The group's comments have now been summarized in an editorial published in the June 1 issue of American Family Physician (AFP). The editorial accompanies a review article on diagnosis and management of ovarian cancer, as well as a patient information handout written by the review's authors.
At the time of the Banbury conference, no organizations had issued guidelines recommending screening for ovarian cancer in women not at increased risk. The AFP editorial's authors said this is because there is a paucity of evidence to support screening for asymptomatic women to reduce death from ovarian cancer.
- American Family Physician (AFP) has published an open-access set of articles and editorials that examine findings from a recent international trial of ovarian cancer screening.
- One of the editorials -- penned by 25 clinicians, scientists and advocates convened to discuss the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) -- agreed with that study's authors that "further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening."
- AFP Editor Jay Siwek, M.D., described specific shortcomings of the UKCTOCS study, including that the reduction in ovarian cancer mortality it cited was not statistically significant.
Current recommendations, including the AAFP's recommendation against screening for ovarian cancer, are based on the large U.S. prospective randomized Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.(prevention.cancer.gov) The PLCO trial demonstrated(jama.jamanetwork.com) that an annual cancer antigen (CA) 125 measurement (using a fixed cutoff value for a positive test result) and transvaginal ultrasonography were not associated with a reduction in mortality from ovarian cancer.
Furthermore, the authors said screening was associated with significant harms resulting from surgeries that were triggered by false-positive findings.
Analysis of UKCTOCS Results
In the AFP editorial, the authors called UKCTOCS a "landmark study" that included about 200,000 healthy postmenopausal women, with one-half randomized to no screening, one-fourth randomized to receive annual pelvic ultrasonography and one-fourth randomized to multimodal screening (MMS).
In contrast to the PLCO approach, MMS uses a risk of ovarian cancer algorithm (ROCA) that assigns a level of risk based on a woman's individual CA 125 levels and changes over time combined with her age and known risk factors for ovarian cancer. "Based on these findings, further CA 125 testing and ultrasonography may be required," the authors said.
In the editorial, researchers said the UKCTOCS' primary analysis suggested that during years 0-14 of screening, there was a nonsignificant mortality reduction of 15 percent (95 percent confidence interval, -3 to 30; P = .10) in the MMS group versus the usual-care (i.e., nonscreened) group. "However, the reduction in mortality was not constant over time, appearing only after seven to 10 years of screening," they noted.
Compared with the screening protocol studied in the PLCO trial, which involved annual, fixed-cutoff CA 125 levels and ultrasonography, the MMS algorithm was more sensitive and led to fewer unnecessary surgeries, they said.
Although the UKCTOCS trial demonstrated a stage shift in which more cases were diagnosed at an early stage with the MMS approach (40 percent) compared with usual care (26 percent), there was no stage shift observed for the ultrasound-only group.
"Additional exploratory analysis suggested even more encouraging, though as yet inconclusive, evidence of the potential for a greater mortality reduction in the MMS group," the group said.
The Banbury group agreed with The Lancet's UKCTOCS analysis and conclusion that "further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening."
The group also concluded that it is premature to recommend MMS for the early detection of ovarian cancer at this time. "Although women and health care professionals may look to these findings as finally providing a strategy for successful screening for ovarian cancer, the study investigators and participants at this meeting believe that screening policy requires a sound scientific foundation, which we currently do not have," they said.
If additional data are produced in the next three years, the study's results will be reanalyzed. "This analysis will be eagerly awaited, because there will not be a similarly powered ovarian cancer screening study in the foreseeable future," said the group.
The editorial's authors pointed out that some women may approach family physicians asking about periodic ovarian cancer screening with CA 125 testing. "Therefore, health care professionals must advise women regarding the potential benefits and risks as we understand them now," they said. "Given the gaps in the evidence, the majority of Banbury participants were uncomfortable with direct-to-consumer advertising of an ovarian cancer screening test at this time."
Family Physician's Take
Family physician and AFP Editor Jay Siwek, M.D., of Washington, D.C., wrote an additional AFP editorial on the UKCTOCS study.
Siwek acknowledged that the UKCTOCS trial generated a lot of publicity because it appeared to support effective screening for ovarian cancer, but he compared screening for ovarian cancer to that for prostate cancer in that although there are tests that should work to reduce mortality (such as CA 125, ultrasonography and prostate-specific antigen testing), the evidence does not fully support them yet.
He pointed to the fact that the protocol consisted of the rigorous application of a ROCA rather than just relying on the results of CA 125 testing with a single cutoff value for an abnormal result.
"From the PLCO trial, we already know that using a single cutoff value does not reduce mortality," Siwek said. "Although some findings seemed promising in the current study, they ultimately did not show convincing effectiveness."
He described specific shortcomings of the UKCTOCS study, including
- the reduction in ovarian cancer mortality was not statistically significant,
- the reduction was not constant over time,
- only one-fourth of the patients were followed long enough to begin to see a possible benefit,
- the effect of screening on all-cause mortality was not reported and
- the ROCA is a proprietary algorithm patented by the investigators.
"The final point is potentially problematic because physicians and patients, inspired by this trial's publicity, might embark on a screening program but not employ the precise protocol used in the study," Siwek said. "However, this protocol has been commercialized (at $295 per use) and promoted to the public in an unqualified way."
He concluded by recommending family physicians adhere to the principles of the Choosing Wisely campaign, which seeks to avoid overscreening, and instead await more evidence-supported recommendations on ovarian cancer screening.
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