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

Study Overview
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Brief Summary
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The purpose of this study is to test whether the timing of meals can improve treatment adverse events, influence tumor biology and alter a person's mood and behaviors.

Detailed Description
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Combining fasting with chemotherapy is known to cause complete tumor regression and long-term survival in animal models. According to the Differential Stress Sensitization (DSS) theory, acute fasting sensitizes tumor cells to the cytotoxic effects of chemotherapy and radiation, while protecting healthy cells by increasing stress resistance. These effects are believed to be largely mediated via the Insulin-like Growth Factor (IGF-1) pathway. However, extended fasting can be challenging for patients and poses undue health risks. A number of alternative intermittent fasting regimens have been proposed to overcome the challenges of prolonged caloric restriction. One promising approach is time-restricted eating (TRE), which involves eating within a period of 10 hours or less, followed by fasting for at least 14 hours daily. TRE does not involve extended caloric restriction, and because of its simplicity, it may be more sustainable than other fasting regimens. TRE improves several cardiometabolic endpoints independent of calorie restriction in both animals and humans, including insulin sensitivity, blood pressure, fat oxidation, and hunger. Our team's pilot and feasibility trials suggest that TRE may also have anti-cancer effects: it decreases IGF-1 levels, reduces oxidative stress, upregulates antioxidant defenses, and enhances autophagy. Moreover, our data suggest TRE is sustainable, as participants were adherent 6.0 plus or minus 0.8 days/week over a 14-week period. These findings lead to the following provocative question: Can TRE reduce treatment-related toxicity, induce tumor regression, and improve both patient-reported and clinical outcomes? We propose to conduct the largest randomized controlled trial of any form of intermittent fasting in patients undergoing cancer treatment. We focus on patients with localized rectal or breast cancer because it is one of the few treatment paradigms in which tumor characteristics can be measured before and after chemoradiation therapy.

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

Conditions
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Colorectal Cancer, Breast Cancer

Intervention / Treatment
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* Behavioral: Time-Restricted Eating (TRE)
* Behavioral: Control


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any sex/gender of any ethnic/racial background Age greater than or equal to 18 years Histologically confirmed rectal cancer stage II, III, or IV (if curative) per AJCC criteria Histologically confirmed breast cancer stage II, III, or IV (only if definitive intent) per AJCC criteria BMI 18.5 kg/m2 or greater Will receive total neoadjuvant therapy (TNT) Willing and able to adhere to the assessments, visit schedules, prohibitions, and restrictions Exclusion Criteria: History of cytotoxic chemotherapy less than or equal to 12 months prior to rectal or breast cancer diagnosis Allergic reaction to any of the treatment agents Any prior pelvic radiotherapy Currently active second malignancy other than non-melanoma skin cancers or cervical carcinoma in situ History of GI perforation ≤12 months prior to enrollment History of predisposing colonic or small bowel disorders with severe or rapidly worsening symptoms (not related to current cancer symptoms) Receiving any parenteral nutrition or enteral (tube) feeding or using similar nutritional supplement during the study period History of uncontrolled CHF defined as NYHA Class III or greater Pre-existing grade ≥3 neuropathy Currently participating in or has participated in a study of an investigational agent or investigational device ≤4 weeks of the first dose of treatment Pregnant or breastfeeding Currently perform overnight shift work more than one day/week on average Strictly adhering to a <10-hour eating window on most days Known psychiatric or substance abuse disorders that would interfere with adhering to the requirements of the trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Time-Restricted Eating (TRE)<br>8-hour daily eating period, starting 1-3 hours after waking up | Behavioral: Time-Restricted Eating (TRE)<br>* 8-hour daily eating period, starting 1-3 hours after waking up<br>|
| Active Comparator: Control<br>More than equal to a 12-hour daily eating period | Behavioral: Control<br>* More than equal to a 12-hour daily eating period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Related Toxicities | Will test to see if the toxicity index is different between the TRE and control groups as measured by the Common Terminology Criteria for Adverse Events (CTCAE). CTCAE includes all AEs and is graded as of 0 (absence of toxicity) to 5 (deceased), where 3 denotes a dose-limiting toxicity (DLT). This composite score accounts for the frequency and cumulative burden of all toxicities during the treatment period. | at end of 6 month intervention | 
| Patient-reported outcomes (PROs) | average and standard errors of patient-reported outcomes (PROs) as measured by the PRO-CTCAE which includes 78 treatment toxicities that patients can systematically document the frequency, severity (and interference of each toxicity). Descriptive statistics will be presented for both quantitative and qualitative variables, with profile plots showing the average and standard errors of PROs over time. | at end of 6 month intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Signaling | IGF-1 and its binding proteins-IGFBP-1 and IGFBP-3-will be measured in serum collected in the morning after at least 8 hours of fasting. Descriptive statistics will be performed with IGF-1 and the ratios of IGF-1 to its two binding proteins as the response variables. | at end of 6 month intervention | 
| Mood | The NIH Patient-Reported Outcomes Measurement Information System (PROMIS®) was developed to standardize assessment of physical, mental, or social health patient-reported outcomes. Each questionnaire includes Likert-scale type questions ranging from 1-5. Total scores are converted to age-standardized T scores, for which normative mean is 50, and standard deviation is 10. The fatigue, pain, anxiety/depression, and physical function scales are validated in the cancer population. NIH PROMIS short forms will be used to assess symptoms of anxiety, depression. We will compare changes in PROMIS scores across study arms and test whether mood moderate relationships between intervention arms and clinical outcomes. | at end of 6 month intervention | 
| Psychosocial Functioning | Social Adjustment Scale-Self-Report (SAS-SR) assesses both behavioral and emotional social adjustment in the past two weeks across six domains: (1) paid or unpaid work, (2) social and leisure activities, (3) relationships with extended family, (4) role as a marital partner, (5) parental role, and (6) role within the family unit, including perceptions about economic functioning. Each area covers four expressive and instrumental categories: performance at expected tasks; the amount of friction with people; finer aspects of interpersonal relations; and feelings and satisfactions. Each question is rated on a five-point scale from which role area means, and an overall mean can be obtained, with higher scores denoting greater impairment. The instrument has good psychometric properties and is particularly well-tailored to assess whether work, family, and social functioning moderate the relationships between intervention arms and clinical outcomes. | at end of 6 month intervention | 
| Dietary Intake | will be assessed using interviewer-administered, multi-pass 24h-recalls. Participants will complete three in-person dietary recalls (two weekdays and one weekend day) at each assessment time point. The Nutrition Data System for Research software (NDSR; Nutrition Coordinating Center, University of Minnesota) will be used to analyze participants' dietary intake. We will assess changes in total energy (kcals), Healthy Eating Index (HEI 2015) as well as changes in added sugar, fruits, and vegetables, solid fats, alcoholic beverages, sodium, and fat. We will assess changes in dietary intake across study arms and examine whether these changes moderate the relationships between intervention arms and clinical outcomes. | at end of 6 month intervention | 
| Physical Activity | Physical activity will be operationalized as mean metabolic equivalent units (METs) per hour and percent of time spent in sedentary, light, moderate, and vigorous activity as assessed by Friedson (2011) algorithms. | at end of 6 month intervention | 
| Sleep | In accordance with recommendations for measuring sleep, Cole/Kripke scoring algorithms, will be used to determine the number of nighttime awakenings, sleep efficiency, and percent of time awake after sleep onset. The Pittsburgh sleep quality index (PSQI) will be used to assess subjective sleep quality and disturbance. The PSQI is one of the most commonly used self-rated questionnaires to assess sleep quality in clinical and nonclinical populations (5 minutes to complete). We will compare changes in physical activity and sleep (objective and subjective) across study arms and test whether the change in physical activity and sleep moderate the relationships between intervention arms and clinical outcomes. | at end of 6 month intervention |