Randomized evaluation of the routine use of circulating tumor DNA in patients with advanced malignancies using routinely collected patient outcome data

Background: Cancer remains the leading cause of mortality and morbidity in Switzerland. Advanced solid cancers pose a major challenge for treatment optimization, as they often exhibit high genomic heterogeneity and resistance. Circulating tumor DNA (ctDNA) from liquid biopsies is a promising avenue to support treatment decision making, better tailor treatment strategies and thus improve quality of life and survival in cancer patients. However, randomized evidence is lacking.Objective: We aim to investigate the effects of offering routine ctDNA measurements and subsequent clinical management in addition to usual care versus usual care only on global quality of life and survival in patients with advanced solid tumors receiving first line systemic therapy.Design: Pragmatic randomized controlled trial using routinely collected health care data.Intervention: Embedded in routine clinical care, patients in the intervention group will be offered repeated ctDNA measurements in addition to usual care. Results from these measurements will serve the already established molecular tumor board to optimize treatment decisions. The intervention will be compared to usual care (disease assessment and treatment) in the control group.Endpoints: The primary endpoint will be between-group differences in global quality of life as measured by EORTC-QLQ standardized questionnaires up to 6 months following randomization. Secondary endpoints will include overall and progression free survival at 6 and 12 months among others. Sample size and statistical analysis: Based on routinely collected quality of life data at the department of Medical Oncology, University Hospital Basel, we calculated a target sample size of 166 patients (83 per arm) to be able to detect a minimally clinically important difference of 10 points between groups measured by EORTC-QLQ. The primary endpoint will be assessed using a linear mixed model with a random intercept at the patient level and following the intention-to-treat principle.Impact: Results from this pragmatic trial have the potential to change clinical practice for patients with advanced solid cancers. To the best of our knowledge, this project will be the first randomized trial using routinely collected quality of life data at a Swiss department of oncology and may serve as a model for future pragmatic trials.