The CHRONO trial: Protocol for a randomized controlled trial of early time-restricted eating in patients with breast or rectal cancer

Fasting combined with anti-cancer therapies improves tumor regression and survival in animals. Fasting sensitizes cancer cells to cytotoxic therapies while promoting stress resistance in healthy cells, a phenomenon known as differential stress resistance. Since prolonged water-only fasting is challenging, intermittent fasting has emerged as an attractive alternative. Here, we describe the protocol of a single-blind, randomized controlled trial testing whether time-restricted eating (TRE) can improve clinical, molecular, and behavioral outcomes in cancer patients. We will enroll 175 adults with newly diagnosed stage I-III human epidermal growth factor receptor 2-positive or triple-negative breast cancer or stage II-IV rectal cancer who are receiving neoadjuvant therapy. Patients will be randomized to early TRE (eTRE; ≤8-hour eating window early in the day) or to eat over a ≥12-hour window (control group) from around the start of treatment until surgery (typically 4-8 months). The primary outcomes are the pathologic complete response, the organ preservation rate, and patient-reported adverse events. Secondary outcomes include clinical response, tumor response, quality of life, and provider-reported adverse events. To test the differential stress resistance theory, we will measure the expression of proteins involved in cell growth, cell death, and stress resistance in tumor and adjacent normal tissue. Finally, we will determine the effects of eTRE on emotional, psychosocial, and lifestyle factors and how these factors influence adherence and clinical responsiveness. This trial will provide critical insight into whether intermittent fasting can potentially improve cancer outcomes, reduce toxicities from anti-cancer therapies, and enhance quality of life in cancer patients. The study is registered on ClinicalTrials.gov (NCT04722341).