Time-Restricted Eating and Cancer: Clinical Outcomes, Mechanisms, and Moderators

Measures whether participants achieve either a pathologic complete response (no invasive cancer is found in the removed tumor or sampled lymph nodes) or organ preservation at the end of treatment. For rectal cancer, organ preservation is defined as a complete or near-complete clinical response after therapy that allows the patient to safely avoid surgery, based on findings from exam, endoscopy, and MRI. Quantified as a percentage (%).

Adverse events as measured by the PRO-CTCAE (version 5), which includes about three dozen toxicities that patients can systematically document the frequency, severity (and interference of each toxicity).

Clinical response at end of treatment, categorized as: complete (no detectable disease on exam, endoscopy, or MRI); near-complete (minimal residual abnormality); partial (≥30% tumor decrease); stable disease; or progressive disease (≥20% tumor increase). We will also report the objective response rate (complete + near-complete + partial), percent with complete/near-complete responses, and percent with progressive disease. For breast cancer, responses may be estimated by physicians or MRI technicians. Values will also be expressed as percentages.

Different scales by cancer type. Rectal cancer, using MRI Tumor Regression Grade (1-5, with 1 = complete response) at end of treatment and the Neoadjuvant Rectal (NAR) score (0-100) at baseline and post-intervention. Breast cancer measured using the Residual Cancer Burden (RCB) score (0-4), where 0 indicates a pathologic complete response.

Measures treatment-related adverse events (AEs) reported by providers from the start of therapy to the day before surgery. AEs are graded using CTCAE v5, and we will report totals as well as Grade 1-2 and Grade 3-4 events. The Toxicity Index (TI) will also be calculated, which ranges from 0 to 5.83.

Assessed at each testing visit using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (EORTC QLQ-C30) for all participants, the QLQ-breast cancer 23 (QLQ-BR32) for breast cancer, and the QLQ-rectal cancer 29 (QLQ-CR29) for rectal cancer. All scales are scored from 0-100, with higher functional and global health scores indicating better quality of life and higher symptom scores indicating worse symptoms. The QLQ-C30 includes five functional scales, three symptom scales, and a global quality-of-life scale, while the BR23 and CR29 include cancer-specific functional and symptom scales.

Obtained through each site's hospital laboratory; results from within two weeks of a testing visit may be used instead of a new draw. All CBC values collected from consent to surgery will be included in analyses. For rectal cancer patients, Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 19-9 (CA 19-9) results from consent to surgery will also be extracted from the medical record.

Measure molecular markers representing cell growth and death and stress resistance, including Antigen Kiel 67 (Ki-67; cell proliferation), caspase 3 (apoptosis), microtubule-associated protein light chain 3B (LC3-I/LC3-II; autophagy), and phosphorylated histone H2AX (γ-H2AX; DNA damage). Protein expression will be measured in formalin-fixed paraffin-embedded tumor and adjacent normal tissue obtained from both biopsy (baseline) and surgical resection (post-intervention). Values will be expressed as fold changes.

Measured in serum and/or peripheral blood mononuclear cells (PBMCs) collected at each testing visit. PBMCs isolated from whole blood. Values expressed in A.U.

Measured at each in-person visit after ≥8 hours of fasting, using a calibrated metabolic scale. Interim non-fasting weights will be extracted from the medical record when available. Weight will be recorded in kilograms to the nearest 0.1 kg.

Systolic and diastolic blood pressure will be measured using an automated blood pressure monitor following American Heart Association/American College of Cardiology guidelines. After a five-minute seated rest, three readings will be taken 1-2 minutes apart; the average of the two closest values will be used. If blood pressure cannot be collected at a testing visit, values from the nearest clinical encounter will be extracted from the medical record. Blood pressure is reported in mm Hg.

Measured concurrently with blood pressure using the automated monitor. Three readings will be obtained after a five-minute rest, and the average of the two closest measurements will be used. Heart rate is recorded in beats per minute (bpm).

Self-reported in weekly surveys, with participants recording daily eating start/stop times and reasons for non-adherence using surveys. Quantified as the percentage of adherent days (eating window followed within 30 minutes; missing days counted as non-adherent) and the median eating duration.

Measured using the Patient-Reported Outcomes Measurement Information System (PROMIS®) Fatigue subscale. Items are rated on a Likert scale and converted to T-scores (mean = 50, standard deviation (SD) = 10), with higher scores indicating greater fatigue.

Measured using:

• University of California at Los Angeles (UCLA) 3-Item Loneliness Scale: scores range from 3-9, with higher scores indicating greater loneliness.
• PROMIS® Satisfaction with Participation in Discretionary Social Activities (Short Form 7a): Likert-scale items converted to T-scores (mean = 50, SD = 10), with higher scores indicating greater social satisfaction.

Assessed using the PROMIS® Physical Function subscale (Likert-scale items). Scores are converted to T-scores (mean = 50, SD = 10), with higher scores indicating better physical function.

Assessed using the PROMIS® Anxiety subscale. Responses are scored on Likert-scale items and converted to age-standardized T-scores (mean = 50, SD = 10), with higher scores indicating greater anxiety.

Assessed using three-day food records (two weekdays and one weekend day) in conjunction with each testing visit. Measures will include total energy intake, Healthy Eating Index (HEI-2015) scores, and intake of key dietary components such as added sugar, fruits and vegetables, solid fats, alcohol, sodium, and fats.

Assessed using two self-report scales: (1) a retrospective 5-point Likert scale rating the frequency of hunger and fullness over the past week, and (2) a 100-point visual analog scale (0 = "Not at all," 100 = "Extremely") rating typical hunger and fullness levels during eating and fasting windows.

Assessed using the Dutch Eating Behavior Questionnaire (DEBQ), which measures three domains: emotional eating, external eating, and restrained eating. Scores reflect the frequency of behaviors within each domain, with higher scores indicating greater endorsement of that eating pattern.

Assessed using an ActiGraph GT9X accelerometer. Activity outcomes derived using GGIR algorithms, including metabolic equivalents (METs) and the percentage of time spent in sedentary, light, moderate, and vigorous activity (Friedson algorithms). Self-reported physical activity measured using the General Physical Activity Questionnaire (GPAQ), MET-minutes per week for moderate and vigorous activity and estimates daily sedentary time.

Measured using accelerometer-derived estimates from the ActiGraph GT9X (processed with GGIR) for sleep duration, timing, and sleep efficiency. Sleep quality will be assessed using the Pittsburgh Sleep Quality Index (PSQI; global score 0-21, with higher scores indicating poorer sleep), and sleep duration and timing will be self-reported using the Munich Chronotype Questionnaire (MCTQ). Values for the latter will be reported in either minutes or hours.