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PLCO: Where Are We Now?
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman is a consultant for GlaxoSmithKline, Eli Lilly Co., Abbott Laboratories, Sanofi-Aventis, and Pfizer; and serves on the speakers bureau for GlaxoSmithKline, Eli Lilly Co., and OrthoBiotech.
Synopsis: The Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial is a large ongoing cohort examining the impact, in this case, of annual ultrasound and CA125 determinations on the identification of ovarian cancer. This report, now through 4 rounds of screening, provides updated information as to the frequency of false-positive screens resulting in surgery and the proportion of cases diagnosed with early-stage distribution. While improving over the time interval, rates of screen-positive surgery are still high, with most cases of ovarian cancer being of advanced stage. Impact on mortality is still unknown.
Source: Partridge E, et al. Results from four rounds of ovarian cancer screening in a randomized trial. Obstet Gynecol 2009:113:775-782.
The primary objective of the PLCO study is to evaluate the impact of annual screening with transvaginal ultrasound (TVUS) and CA125 on ovarian cancer mortality. The study is prospectively following a cohort of more than 34,000 largely postmenopausal women with intact ovaries with an algorithm where either an abnormal CA125 (≥ 35 units/mL) or an abnormality on TVUS is considered a positive screen. Follow-up procedures of a positive screen are not pre-specified but have been tracked, as well as any surgical interventions resulting from these findings. Compliance with the protocol decreased slightly over the 3 years of post-baseline evaluation, but remained above 75%. In contrast to CA125, screen-positive TVUS decreased over the interval from 4.6% at baseline to 3.4% at year 3. Nearly 90 ovarian cancers have been diagnosed so far; 60 were identified by screening abnormalities. Overall, the ratio of screen-positive ovarian cancers relative to benign disease decreased from 30:1 to nearly 20:1. Seventy-two percent of the ovarian cancers identified were of advanced stage. The study continues to mature with relatively good compliance. The impact of screening on the primary endpoint is unknown.
One of the most daunting clinicopathological features of ovarian cancer is the high mortality rate among women diagnosed with advanced stage disease — a rate that has changed little despite a prolific expansion of available therapeutic strategies. Adding to this frustration is the recognition that women with early-stage disease can be routinely cured with surgery and chemotherapy. Unfortunately, the ratio of the former to the latter is 3:1, and has varied little over the last 3 decades. Nevertheless, the dichotomy in prognosis between these two categories of women drives the search for reliable and acceptable screening; in this regard, even a slight adjustment in these stage ratios could have a profound effect on expected outcomes with disease.
There are many different strategies being currently investigated to screen for ovarian cancer in the general population; however, most now incorporate imaging (like TVUS) and biomarkers coupled with a decision algorithm based on their findings. The great challenge of screening a low-risk population is the burden necessarily placed on the performance of the prescribed screening tool or tools. The low prevalence requires the rate of false-positive screening to be a fraction of a percent or else extraordinarily high numbers of women will be taken for surgical evaluation unnecessarily to find very few cancers.
Among the least invasive dual strategy screening programs under way is the one used in the PLCO study. In this cohort of menopausal age women only a single TVUS and CA125 are done annually. There are no guidelines pre-specified for how one is to handle a positive screen but relative to the original report of this study, the ratio of unnecessary surgery has significantly decreased from about 30:1 to 20:1. This report also provides important information on screening compliance, rates of positive screens over time, and modalities of post-positive screen diagnostic and surgical interventions. It is noteworthy that the percentage of positive screens has decreased by about 22% and may reach a steady state with further follow-up. However, the low predictive value positive with this algorithm and the persistent 3:1 ratio of advanced-stage disease relative to early-stage disease is unlikely to have a measurable impact on overall survival.
The largest screening study ever conducted has recently completed its enrollment and results are anxiously awaited. In this 200,000 patient trial, each modality (CA125 and TVUS) is being evaluated relative to controls (no screening). The preliminary data are maturing but the decision algorithm proposed has decreased the ratio of advanced- to early-stage cancers. Like the PLCO, screening sent about 20 women to surgery for each cancer identified, but the impact on mortality may be more favorable given the shift to more early-stage cancers.
Others are evaluating ultrasound and CA125 with different decision algorithms, as well as discovering and testing new biomarkers. It is clear our goals are to vastly expand these technologies to improve our ability to identify this disease in the clinical scenario it is most curable or preventable.