By Molly A. Brewer, DVM, MD, MS

Professor and Chair, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Connecticut Health Center, Farmington CT

Dr. Brewer reports no financial relationships relevant to this field of study.

SYNOPSIS: This paper is a 15-year median follow-up of extended mortality of the ovarian cancer screening portion of the Prostate, Lung, Colon, Ovary trial.

SOURCE: Pinsky PF, Kelly Yu, Kramer BS, et al. Extended mortality results for ovarian cancer screening in the PLCO trial with median 15 years follow-up. Gynecol Oncol 2016;143:270-275.

The recent publication by Pinsky et al provided an updated review of the Prostate, Lung, Colon, Ovary (PLCO) trial and focused on the ovarian screening portion of the trial. This trial was designed to follow patients over time to determine if CA125 and transvaginal ultrasound (TVUS) affected the mortality rate of ovarian cancer. In this randomized, controlled trial that ran between 1993-2001 at 10 U.S. centers, women between the ages of 55-74 years with no history of ovarian cancer were randomized to either intervention (TVUS + CA125) or usual care (observation). The findings were previously presented in 2011.1 The authors found that there was no decrease in mortality after a median follow-up of 12.4 years in the intervention group when compared to the women in the control group who did not undergo screening. In fact, there were harms associated with screening: 1,080 women with false-positive results from the screening group underwent unnecessary surgery and 15% of these women experienced major complications as a result of this surgery.

The primary endpoint of the 2011 study was ovarian cancer-specific mortality; secondary endpoints of the initial trial included ovarian cancer incidence, cancer stage, survival rates, harms of screening, compliance, and all-cause mortality. The current study only reported ovarian cancer mortality and survival. There were 34,253 (intervention arm) and 34,304 (usual care arm) women randomized, and 187 ovarian cancer deaths (rate 38.2 per 100,000 PY) in the intervention arm vs. 176 (rate 36.0 per 100,000 PY) in the usual care arm (relative risk, 1.06). There was a slight difference in survival at five years in the intervention arm as compared to usual care arm (47.4% vs. 36.0%), but the survival was similar at 10 years (31.3% vs. 27.1%) with no statistically significant difference in survival (P = 0.16).

COMMENTARY

There has been great interest over the years to develop screening technology to improve mortality from ovarian cancer. The disease typically is diagnosed in late stages (III or IV) because of multiple factors. Although recent studies have shown that most women with ovarian cancer have symptoms, the symptoms often are confused with aging or misinterpreted as a gastrointestinal upset, and diagnosis often is delayed.2 Additionally, there is evidence that some of the high-grade cancers metastasize early and grow rapidly.3 The two major screening trials for ovarian cancer are the PLCO trial and the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening). The UKCTOCS trial showed no real benefit in mortality rates after 10 years, but the trial was underpowered to meet the endpoint of ovarian cancer mortality.4 After excluding prevalent cases, the UKCTOCS authors found a slight benefit in survival after 12 years, which is contradictory to the PLCO trial. This group patented its multimodal screening algorithm, also known as Risk of Ovarian Cancer Algorithm (ROCA) and was marketing this test for screening, despite what was considered by many to be a negative trial. A previous report of the PLCO trial applied the ROCA algorithm to the PLCO results to try to mimic the UKCTOCS trial, but there was still no statistically significant mortality benefit of ovarian cancer screening.

Hopefully, the role of screening low-risk women for ovarian cancer finally has been laid to rest. Although a slight survival benefit was detected, attributed to more Stage I cancers found in the screening arms of both the UKCTOCS and the PLCO trials, after 10 years that survival advantage disappeared. In addition, screening has been shown to cause harm. In the PLCO trial, 3,285 (9.6%) women in the intervention arm women had false-positive results and had their ovaries removed, with a 15% serious complication rate as a result of surgery.

How should we interpret these findings? The FDA recently warned that no screening test has been shown to reduce ovarian cancer deaths in average-risk women without symptoms. Subsequently, the ROCA test, marketed by Abcodia and developed by the researchers of the UKCTOCS trial, has been taken off the market. The real problem with screening for ovarian cancer is that it is a rare disease and, thus, any screening test will err on the side of increased false-positive results. Finally, there is cost in unnecessary screening — the cost of the actual test(s) and the cost of the unnecessary surgery. Unfortunately, until we can identify women at increased risk of ovarian cancer or develop an accurate screening test, the cost of screening does not justify the results.

REFERENCES

  1. Buys S, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening randomized controlled trial. JAMA 2011;305:2295-2303.
  2. Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index: Possibilities for earlier detection. Cancer 2007;109:221-227.
  3. Landen CN Jr, Birrer MJ, Sood AK. Early events in the pathogenesis of epithelial ovarian cancer. J Clin Oncol 2008;26:995-1005.
  4. Jacobs I, Menon U, Ryan A, et al. Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): A randomized controlled trial, Lancet 2016;387:945-956.