Cumulative False-Positives (FP) in the Prostate, Lung, Colorectal, Ovarian (PLCO) Cancer Screening Trial

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 3, 2007

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Presenter: J. H. Miller
Presenter's Affiliation: National Institutes of Health
Type of Session: Scientific

Background

  • Cancer screening tests are recommended to the general public, however, the burden of multiple screening tests is not clear. Prior studies have examined the risk benefit ratios of individual screening tests, but in clinical practice multiple screening tests are commonly used.
  • This study examines the cumulative risk for a false positive (FP) when multiple screening tests are used as well as the risk for a subsequent diagnostic procedure.

Materials and Methods

  • The present study is a randomized clinical trial that randomized patients, in a 1:1 ratio, to an intervention group, which underwent active screening, and a "usual care" group.
  • A total of 78,000 women and 77,000 men were randomized to the two groups.
  • Eligibility Criteria:
    • Patients from 55 to 74 years of age were eligible.
    • Patients could not have a prior history of prostate, lung, ovarian, or colorectal cancer.
    • Patients could not have recent use of finasteride.
    • Patients could not be participating in other cancer or cancer screening trials.
    • Patients could not be on treatment for any type of cancer, except basal cell and squamous cell carcinoma of the skin.
  • Patients were excluded after randomization if:
    • The patient died before completing all screening tests or the patient refused to complete testing.
    • There was less than three years of follow up for the patient.
    • Of the 77,464 patients randomized to the intervention arm, 68,436 were ultimately included in the analysis.
  • Patients in the intervention arm were followed for three years after an intervention.
  • Men and women could each undergo a total of 14 screening tests during the course of the study.
    • Men underwent annual digital rectal exam, prostate specific antigen (PSA), and chest x-ray. A baseline sigmoidoscopy (FSG) was obtained, followed by a 3 and 5 year FSG.
    • Women underwent annual CA-125, transvaginal ultrasound, and chest x-ray. A baseline sigmoidoscopy (FSG) was obtained, followed by a 3 and 5 year FSG.
  • Follow up diagnostic procedures were broken into three categories. Non-invasive diagnostic studies such as x-rays were excluded.
    • Procedures considered "minimally invasive" required conscious sedation, such as endoscopy.
    • An example of a procedure considered "moderately invasive" included laparoscopy.
    • An example of a procedure considered "major" included prostatectomy or laparotomy.
  • False positives were defined as a positive result on screening test with no target cancer diagnosis within three years. Advanced adenomas (villous histology, severe cellular dysplasia, or =1 cm in diameter) were considered true positives in this study.

Results

  • The risk of having at least one false positive test during the course of the study was 50.9% in men and 35.3% in women with an overall risk of 43.1%.
  • The range for the number of FP an individual had was from 0 to 11.
  • Sigmoidoscopy resulted in the most false positive results. The percentage of false positives with colonscopy was not significantly altered even when the definition of a true positive was changed to include all adenomas.
  • The number of men who had to undergo minimal, moderate and major interventions was 3.2, 20.4 and 0.14%, respectively.
  • The number of women who had to undergo minimal, moderate and major interventions was 2.8, 11.3, and 3%, respectively.
  • The estimated risk for at least one false positive after 14 screening tests was 60% for men and 49% for women.
  • The risk of undergoing at least one diagnostic procedure after 14 screening tests was 29% for men and 22% for women. This did not include non-invasive diagnostic procedures such as physical exam and radiological imaging.

Author's Conclusions

  • The study was limited by the following factors.
    • The majority of patients were white (>80%) and well educated.
    • There was potential for healthy volunteer bias in the present study.
    • Some of the screening tests in the present study are not in common use at present. However, all of the screening tests in the present study were advocated at one time for screening, and hence were included in the study.
  • The authors' conclude that there is a significant burden associated with false positives from multiple screening tests.
  • They advise that future studies should examine the risk of false positives in the setting of multiple screening tests which more accurately reflects clinical practice.
  • They advise educating patients about the risks of false positive and the potential for invasive diagnostic tests when discussing cancer screening tests.
  • Difference between the rate of FP in men and women was likely due to a relatively higher rate of FP with PSA screening.

Clinical/Scientific Implications

  • The present study emphasizes the risk of false positives when screening studies are used, which can lead to invasive diagnostic testing. Though some of the screening tests used in the present study are not commonly used at present, several are. For example male participants in this study underwent an annual digital rectal exam, PSA and a sigmoidoscopy at baseline and at five years which is consistent with current guideline. That individual would have undergone twelve screening tests over the course of five years, which is close to the 14 tests that was the cutoff used in the present study. Estimates for invasive testing after 14 screening tests was 22% and 29% in women and men, respectively, which is clearly not an inconsequential number.
  • The authors do point the high proportion of white, educated patients in the present study. This cohort may reflect a healthier portion of the population that is less likely to have health problems. This could decrease the incidence/prevalence of the cancers that are being screened for, affecting the tests' negative and positive predictive values.
  • It would be interesting to see what other risk factors for cancer that these patients had. It would also have been of interest to see how many more non-invasive diagnostic studies were ordered in the invasive group compared with the "normal care" group. Further investigation examining how many cancers were detected with these screening tests in the intervention group compared with the "normal care" group would help evaluate the benefits of the multiple screening tests, in addition to the risks found it the present study.



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