Cancer Outcomes in the Watch the Spot Trial: A Pragmatic Clinical Trial of Less Compared to More Intensive Strategies for Active Surveillance of Patients With Small Pulmonary Nodules

Abstract Rationale: Most small pulmonary nodules are managed by using surveillance imaging to discriminate between lung cancer and benign causes. In the absence of direct evidence from controlled trials of specific surveillance strategies, current guidelines rely on expert judgment and indirect evidence from studies of lung cancer risk. To fill this evidentiary gap, we conducted a multicenter, cluster-randomized, pragmatic clinical trial that compared less versus more intensive strategies for surveillance of patients with nodules measuring ≤15 mm in size, detected incidentally or by screening. Study design including participants: Participants with small lung nodules were enrolled at one of 14 U.S. healthcare systems between March 2017 and July 2019. Cluster randomization to the assigned surveillance arm was performed at the health system or hospital level (n=24). Surveillance protocols were modeled after published guidelines, and recommendations for surveillance were delivered by practicing radiologists at the point of care. The primary outcome was progression in tumor size >20 mm at the time of lung cancer diagnosis. We hypothesized that less intensive surveillance would be non-inferior to more intensive surveillance, with a non-inferiority margin of 5 percentage points. Additional outcomes included AJCC 8th edition tumor stage >T1bN0M0, timeliness of diagnosis and treatment, and overall survival. Analyses, performed in both the intention to treat (ITT) and adherent populations, employed generalized linear mixed-effects models to adjust for clustering and possible confounding. Key existing data and/or data trends: N/AMain outcomes: The study enrolled a socio-demographically diverse sample of 34,686 men and women, with a mean (SD) age of 64.5 (11.7) years and a median (IQR) nodule size of 5 (4-7) mm. Non-adherence with study protocols for follow-up was observed in 27.5% and 45.8% of those in the less and more intensive study arms, respectively. In the intent to treat population, 504 participants (1.5%) were diagnosed with lung cancer within 27 months of nodule identification, including 261 cases of adenocarcinoma (54.7%) and 91 cases of squamous cell carcinoma (19.1%). In the ITT population, progression in tumor size and stage was observed in 159 of 491 (32.4%) and 253 of 475 (53.3%) participants with non-missing outcome data, respectively, whereas size and stage progression in the adherent population were seen in 23.5% and 46.6% of participants, respectively. The less intensive arm was not non-inferior to the more intensive arm for either tumor size progression (adjusted difference 7.0 percentage points, 95% CI -2.0 to 15.9) or stage distribution (adjusted difference -0.2 percentage points, 95% CI -9.9 to 8.6) in the ITT population. Tumor size progression (adjusted OR 0.38 (95% CI 0.19-0.75) and stage >T1bN0M0 0.39 (adjusted OR 0.39, 95% CI 0.23-0.68) were significantly less frequent among those who adhered to protocol recommendations compared to the non-adherent. The odds of diagnosis, treatment or death within 6 months or 1 year did not differ between study arms in the ITT population, but the odds of receiving a diagnosis within 1 year were 66% higher in the more intensive arm among the adherent. Significance of study: In this large, pragmatic clinical trial of patients with pulmonary nodules measuring ≤15 mm in size, non-adherence was common and cancerous nodules frequently progressed in size and stage during surveillance, even among the adherent. Less intensive surveillance was not non-inferior to more intensive surveillance for these key outcomes, but size and stage progression occurred less frequently in participants who adhered to study protocols for follow-up. These results highlight some of the limitations of current strategies for the evaluation of patients with small pulmonary nodules and suggest that better approaches are needed. Results from high-profile Phase II and Phase III clinical trials: N/A