Jennifer M. Croswell

Screening has long been portrayed as an inherently beneficial activity that saves lives, rather than as a complex mixture of potential benefits and harms that must be carefully weighed for each modality. The early success of the Pap smear in reducing deaths from cervical cancer may have inadvertently fostered simplistic messaging about unqualified benefits of screening. Over time, large-scale randomized controlled trials (RCTs) of prostate and other cancers have highlighted the potential harms caused by mass screening programs (especially those related to overdiagnosis and unnecessary treatment) and have revealed the counterintuitive elements involved in evaluating such programs. The criteria for evaluation now extend beyond the performance criteria of the test itself to include the net balance of benefits, risks, and costs. PSA screening, widely used in the United States since the late 1980s, has now been removed from the list of routinely recommended procedures, based on evidence from RCTs.

Background: Direct-to-consumer promotion of lung cancer screening has increased, especially low-dose computed tomography (CT). However, screening exposes healthy persons to potential harms, and cumulative false-positive rates for low-dose CT have never been formally reported. Objective: To quantify the cumulative risk that a person who participated in a 1- or 2-year lung cancer screening examination would receive at least 1 false-positive result, as well as rates of unnecessary diagnostic procedures. Design: Randomized, controlled trial of low-dose CT versus chest radiography. (ClinicalTrials.gov registration number: NCT00006382) Setting: Feasibility study for the ongoing National Lung Screening Trial. Patients: Current or former smokers, aged 55 to 74 years, with a smoking history of 30 pack-years or more and no history of lung cancer (n = 3190). Intervention: Random assignment to low-dose CT or chest radiography with baseline and 1 repeated annual screening; 1-year follow-up after the final screening. Randomization was centralized and stratified by age, sex, and study center. Measurements: False-positive screenings, defined as a positive screening with a completed negative work-up or 12 months or more of follow-up with no lung cancer diagnosis. Results: By using a Kaplan–Meier analysis, a person's cumulative probability of 1 or more false-positive low-dose CT examinations was 21% (95% CI, 19% to 23%) after 1 screening and 33% (CI, 31% to 35%) after 2. The rates for chest radiography were 9% (CI, 8% to 11%) and 15% (CI, 13% to 16%), respectively. A total of 7% of participants with a false-positive low-dose CT examination and 4% with a false-positive chest radiography had a resulting invasive procedure. Limitations: Screening was limited to 2 rounds. Follow-up after the second screening was limited to 12 months. The false-negative rate is probably an underestimate. Conclusion: Risks for false-positive results on lung cancer screening tests are substantial after only 2 annual examinations, particularly for low-dose CT. Further study of resulting economic, psychosocial, and physical burdens of these methods is warranted. Primary Funding Source: National Cancer Institute.

Multiple cancer screening tests have been advocated for the general population; however, clinicians and patients are not always well-informed of screening burdens. We sought to determine the cumulative risk of a false-positive screening result and the resulting risk of a diagnostic procedure for an individual participating in a multimodal cancer screening program. Data were analyzed from the intervention arm of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomized controlled trial to determine the effects of prostate, lung, colorectal, and ovarian cancer screening on disease-specific mortality. The 68,436 participants, aged 55 to 74 years, were randomized to screening or usual care. Women received serial serum tests to detect cancer antigen 125 (CA-125), transvaginal sonograms, posteroanterior-view chest radiographs, and flexible sigmoidoscopies. Men received serial chest radiographs, flexible sigmoidoscopies, digital rectal examinations, and serum prostate-specific antigen tests. Fourteen screening examinations for each sex were possible during the 3-year screening period. After 14 tests, the cumulative risk of having at least 1 false-positive screening test is 60.4% (95% CI, 59.8%-61.0%) for men, and 48.8% (95% CI, 48.1%-49.4%) for women. The cumulative risk after 14 tests of undergoing an invasive diagnostic procedure prompted by a false-positive test is 28.5% (CI, 27.8%-29.3%) for men and 22.1% (95% CI, 21.4%-22.7%) for women. For an individual in a multimodal cancer screening trial, the risk of a false-positive finding is about 50% or greater by the 14th test. Physicians should educate patients about the likelihood of false positives and resulting diagnostic interventions when counseling about cancer screening.