Ovarian cancer screening does not reduce mortality [Classics Series]

This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials

1. Randomization of patients to either yearly ovarian cancer screening with transvaginal ultrasound (TVUS) and serum CA-125 levels or usual care did not significantly reduce cancer-related mortality.

2. False-positive results among the screening cohort were associated with significant surgical morbidity, with at least one serious complication suffered by roughly one-sixth of those who underwent surgical workup.

Original Date of Publication: June 2011

Study Rundown: Ovarian cancer remains both a diagnostic and therapeutic dilemma: it is often diagnosed late in its course due to vague and nonspecific presenting symptoms, and has poor long-term survival rates once it has spread beyond a single ovary. However, surgically managed ovarian cancers that remain confined to the ovary display 5-year survival rates greater than 90%, suggesting that early recognition and treatment could lead to a substantial mortality benefit. The referenced trial, part of a series of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), randomized women to either yearly screening for ovarian cancer with TVUS for 3 years and measurement of serum CA-125 levels for 5 years, or standard care with yearly bimanual examination in an effort to determine if ovarian cancer screening would yield earlier diagnoses and resultant prognostic improvements. Screening did not significantly increase the number of cases of ovarian cancer diagnosed, though the results did trend toward significance. More poignantly however, the distributions of cancer stage at diagnosis were similar between groups, with a majority diagnosed at stage III-IV, and therefore ovarian cancer-related survival remained similarly low between groups. Screening was itself not a benign intervention, with positive findings frequently requiring surgical management. Nearly 10% of women in the screening cohort had false-positive results, requiring the performance of ultimately unnecessary surgeries in which 15% of patients suffered at least one serious post-surgical complication. This trial demonstrated that annual screening with simultaneous TVUS and CA-125 does not reduce cancer-specific mortality among average risk women, but does increase the risk of harm related to the performance of invasive procedures, particularly when due to false-positive findings or overdiagnosis.

Click to read the study in JAMA

In-Depth [randomized controlled trial]: A total of 68 557 women (roughly 88.5% of non-Hispanic white ethnicity, primarily aged 55-64 years) of average risk for ovarian cancer were enrolled at 10 screening centers across the United States. Subjects were excluded from analysis if they had a pretrial history of ovarian cancer or bilateral oophorectomy. Women were randomized to either the screening arm of the trial, in which they underwent yearly TVUS for 3 years, and yearly serum CA-125 measurements for 4-6 years, or the control arm of the trial, in which they underwent only yearly bimanual examination. Due to the invasive nature of the screening tests, no blinding could be performed. The positivity threshold for TVUS included ovarian volume greater than 10 cm³, cyst volume greater than 10 cm³, complex ovarian cysts with solid or papillary projections into the cavity, or any mixed (solid or cystic) components within a cystic ovarian tumor. Of note, this size threshold may have been too high to effectively detect low stage ovarian tumors, which are thought to be less than 10 cm³, but would have introduced further false-negative results. A positivity threshold of 35 U/mL was used for serum CA-125 levels. A total of 212 cases of ovarian cancer were detected in the screening arm (5.7 per 10 000 person-years) while 176 cases were detected in the control group (4.7 per 10 000 person-years; RR 1.21; 95%CI 0.99-1.48) during the mean 12.6 year follow-up period. Of the cancers detected, the majority were high grade serous cystadenocarcinomas in both groups with a similar distribution of histological subtypes and grades. No stage shift, or difference in the cancer stage at time of diagnosis, was observed between groups. The majority of tumors were diagnosed at stage III-IV, with 69% of those detected during screening being advanced stage, as compared to 78% in the control group. As a stage shift is believed to be necessary for a mortality benefit, no significant difference in cancer-related mortality was noted between the two groups (RR, 1.18; 95%CI 0.82-1.71). A total of 3285 (9.6%) women suffered false-positive screening results, 1080 of whom underwent surgical management as part of their diagnostic workup. Of these women, 163 (15%) suffered at least one major surgical complication. This trial demonstrated that screening for ovarian cancer with TVUS and serum CA-125 levels does not reduce cancer stage at the time of diagnosis or cancer-related mortality, and may in fact introduce potential harm related to the workup of false-positive results.

Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. Effect of screening on ovarian cancer mortality: The prostate, lung, colorectal and ovarian (PLCO) cancer screening randomized controlled trial. Journal of the American Medical Association. 2011 Jun 8;305(22):2295–303.

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