Time-Restricted Eating and Cancer: Clinical Outcomes, Mechanisms, and Moderators - ABSTRACT Combining fasting with chemotherapy can cause complete tumor regression in animal models. Acute fasting is thought to sensitize tumor cells to the cytotoxic effects of chemotherapy and radiation, while protecting healthy cells by increasing stress resistance—a phenomenon known as the Differential Stress Sensitization theory. However, the potential risks of extended caloric restriction hamper clinical implementation. Time-restricted eating (TRE) is a promising alternative, which involves eating within a period of 10 hours or less, followed by fasting for at least 14 hours daily. Because of its simplicity, TRE may be more sustainable. Moreover, our pilot data suggest that TRE has several anti-cancer effects: it decreases IGF-1 levels, reduces oxidative stress, upregulates antioxidant defenses, and enhances autophagy. We propose to conduct the first clinical trial of TRE in cancer patients undergoing active treatment, as well as the largest randomized controlled trial of any form of intermittent fasting in cancer patients. We will focus on rectal cancer because it is one of only a couple cancers where tumor size and characteristics can be measured before and after treatment. We will enroll 300 newly diagnosed localized rectal cancer patients (stage II-III) aged ≥18 (BMI ≥ 18.5 kg/m2). All participants will receive the standard of care during oncological treatment at Cedars-Sinai Medical Cancer (Los Angeles, CA) or the University of Alabama O’Neal Comprehensive Cancer Center (Birmingham, AL) and be randomized to one of two eating schedules: (1) control schedule: 12-hour or longer daily eating period; (2) TRE: 8-hour daily eating period (16 hours of daily fasting). Participants will be counseled to maintain their weight. All endpoints will be measured at least three times: at diagnosis prior to the onset of chemoradiation (baseline), after chemoradiation treatment, and at tumor resection (post-intervention). Our primary aim is to determine how TRE affects clinical outcomes, including treatment-related adverse effects (toxicity index based on CTCAE v.5), patient-reported outcomes (PRO-CTCAE) and quality of life (EORTC QLQ-C30), and clinical (cCR) and pathological (pCR) complete response rates. Aim 2 tests the Differential Stress Sensitization Theory—the first complete test of this theory in humans. We test whether TRE acts through the IGF-1 pathway to increase stress resistance in healthy cells (DNA damage and antioxidant defenses as measured by gamma-H2AX and total antioxidant capacity, respectively) and enhance tumor cell death (apoptosis and autophagy as measured by activated caspase-3 and LC3-I/LC3-II, respectively). Aim 3 compares longitudinal changes in mood, social functioning, sleep, diet, and daily physical activity across intervention arms (control vs. TRE) and explore how these changes interact with intervention arms to predict clinical outcomes. We expect this innovative trial will help improve cancer treatment outcomes and reshape the standard of care for cancer patients.
