Volunteer effect and compromised randomization in the Mayo Project of screening for lung cancer

Abstract

It has been confirmed recently that the volunteer effect in lung cancer screening is characterized by higher lung cancer mortality risk in self-selected screening participants. The Mayo Lung Project, the most influential trial of screening for lung cancer ever completed, was conducted in nonvolunteer Mayo Clinic outpatients, with a peculiar study design that rendered the randomization vulnerable to the volunteer effect. Of all nonvolunteers randomized in the Mayo Lung Project, only those allocated in the screened group were asked consent to participate in the trial. The final Mayo Lung Project report stated that 655 randomized nonvolunteers refused screening and were excluded from the study, thus documenting violation of the rule that no selection should occur after randomization. The long-term follow-up of the Mayo Lung Project showed an enigmatic result which has never been explained: the lung cancer mortality was 13% higher in the screening intervention group than in the control group [4.4 (95% CI 3.9–4.9) vs. 3.9 (95% CI 3.5–4.4) per 1,000 person-years; P = 0.09]. Such overrepresented mortality is consistent with the volunteer effect and supports the concept that the Mayo Lung Project randomization was compromised by the post-randomization self-selection of participant nonvolunteers.

Assessment of lung cancer mortality reduction after chest X-ray screening in smokers: A population-based cohort study in Varese, Italy

“…Moreover, in the PLCO about 80% of the total of intervention group LCs were nonscreen-detected and could be diluting any screening effect [5]. While in theory a population-based randomized trial is the ideal method to assess the efficacy of an LC screening intervention [27], in practice the historical randomized CXR screening trials have subsequently been associated with important methodological weaknesses [1,4,7,8]. In addition, the recently reported findings of the PLCO randomized radiographic screening are difficult to generalize to smokers, as about half of participants were never smokers [5].…”

“…No public policy organization recommends chest X-ray (CXR) screening, as randomized studies showed no LC mortality benefit [2][3][4][5][6]. However, the published randomized CXR screening trials present relevant methodological weaknesses [1,4,7,8]; moreover, these studies were performed in highly selected volunteers [2,3,5], and the external value of their results remains uncertain. Notably, the U.S. Preventive Service Task Force concluded that the evidence is insufficient to recommend for or against screening with CXR [9].…”

Exploring the uncertainties of early detection results: model-based interpretation of mayo lung project

“…Rather, this difference might have reflected a "volunteer effect" [18] since in MLP only those randomized to the screening intervention group were asked about their consent to participate in the trial. Ideally, the trial's randomization process should have occurred after rather than before the baseline prevalence screening, since the prevalence screening could have created behavioral differences between the two trial arms.…”

Small median tumor diameter at cure threshold (<20 mm) among aggressive non‐small cell lung cancers in male smokers predicts both chest X‐ray and CT screening outcomes in a novel simulation framework

“…However, the PLCO and MLP results likewise demonstrated an increased rate of early‐stage lung cancer detection attributable to chest X‐ray screening, relative to usual care 2, 4. Debate over the interpretation of chest X‐ray screening results persists 5–8. Estimates of the median size at which lung cancers transition to advanced‐stage of 40 mm suggest that a mortality benefit to chest X‐ray screening should exist 9…”