Alternate Day Fasting After Surgery for Patients Undergoing Chemotherapy

Overview

Endometrial cancer is the most common gynecologic cancer and ovarian cancer is the most lethal. The management of both advanced cancers is a combination of chemotherapy and surgery. Standard of care chemotherapeutic treatment for uterine and ovarian cancers is toxic and severely disruptive to the patient's quality of life with the potential for devastating short and long-term side effects. The role of fasting and ketogenic diets has been evaluated in a mixed cancer population and previously shown to be safe. There is no data specifically addressing the impact of a fasting diet regimen on side effects of chemotherapy during treatment for ovarian and endometrial cancers in the front-line setting. The information gathered from this study will inform future trials about the role of time-restricted eating and its impact on side-effects associated with chemotherapy as well as its role in improvement of quality of life for women afflicted with these debilitating diseases.

Uterine cancer is the most common gynecologic cancer diagnosed in women and the fourth most common cancer to be diagnosed in females with an estimated 65,950 cases that will be diagnosed this year in the United States. Although not as common as endometrial cancer, ovarian cancer is the fifth most lethal cancer in females with an estimated 19,880 cases diagnosed this year. Standard of care treatments such as chemotherapy are toxic and severely disruptive to the patient's quality of life with potential short and long-term devastating side effects. The management of advanced gynecologic cancers of the uterus and ovary is often with a combination of surgery and chemotherapy in medically stable patients. The sequence of treatment is dependent on the patient's medical conditions, disease distribution and likelihood of complete resection at the time of surgery. Even when surgery results in complete resection in those with advanced disease, systemic treatment with chemotherapy is frequently prescribed. First line treatment for advanced uterine and ovarian cancer with carboplatin and paclitaxel has been shown to be tolerable and effective. However, these drugs often have a wide range of toxic side effects associated with their administration and may require treatment delays or dosing adjustments for patients to complete the prescribed treatment. In addition to hematologic toxicity and metabolic derangements, systemic chemotherapy often has debilitating side effects associated with treatment such as peripheral neuropathy. Supportive medications for side effects associated with chemotherapy are often given to patients for self-administration at home to combat symptoms in the several days following infusion, but there are limited interventions available to help patients further and with long term toxicities. New strategies are needed to help patients better tolerate these taxing side effects to improve patient outcomes and quality of life. The effect of diet in rodents is well studied and has shown restriction of calories results in improved lifespan, and delayed onset of age associated diseases such as hypertension, diabetes, autoimmune conditions and cancer. With respect to chemotherapy administration in humans, the concept of differential stress resistance has been published and demonstrates protection of normal cells during periods of fasting where, conversely cancer cells become more susceptible to chemotherapy. This has been applied in few human studies where the impact of diet on cancer treatment was evaluated across a variety of cancer diagnoses and was found be safe and without worsening side effects from treatment. In time-restricted eating, participants eat within a specific time (eating window) and fast for the rest of the day (fasting window) every day. There are several definitions and descriptions of intermittent fasting (IF). There are 2 components to the fasting regimen: (1) the duration of the actual time fasting (hours) and (2) the schedule of the periods of fasting (days, weeks, months). Alternate day fasting (ADF) is defined as 24-hour periods of fasting alternating with 24-hour periods of eating/feasting. This can be modified and extend the fasting window up to periods of 72 hours as previously studied in cancer populations and has been feasible and tolerable. The fasting schedule is then either prolonged over periods of weeks or short-term over a period of days. Prolonged fasting has been used for caloric restriction and long-term weight loss, which is not ideal in a cancer population. We chose this short-term, modified alternate day fasting regimen to both limit weight loss and center the prescribed "fasting window" around administration of chemotherapy when we expect to see the largest benefit in terms of reduction of toxic chemotherapy-related side effects. In addition, food intake rapidly initiates a cascade of biochemical responses to process the incoming nutrients. In contrast, during fasting, the body mobilizes stored energy. Specifically, the mechanistic target of rapamycin complexes-1 and -2 (mTORC1 and mTORC2) are regulated by nutrient availability, and loss of mTOR signaling partially mediates the cellular effects of fasting interventions on cancer cells. In muscles, caloric intake activates mTOR signaling within 30 minutes of eating to yield an anabolic state, with peak mTORC1 activity at approximately 60-90 minutes. Subsequently, mTORC1 is gradually deactivated. Approximately 12-16 hours after food absorption, a metabolic switch is activated in which the primary source of energy shifts from glucose to fat and ketones. This metabolic switch, mediated by decreased mTOR signaling, is key for prolonged fasting (\>\~16 hours) to be effective. Using ADF helps in initiating this metabolic switch several times before, during, and after chemotherapy and might increase the benefit of fasting. Another form of intermittent fasting is alternate-day fasting (ADF) which is defined as alternating between fasting day (0-25% of energy needs) and feasting day (eating as desired). Preliminary studies in ovarian cancer patients suggest that restricting energy and/or protein intake at the time of chemotherapy might help reduce chemotherapy-related side effects and improve patients' quality of life. Of particular concern in an ovarian cancer patient population is malnutrition and the contribution of a time restricted eating intervention on weight loss. Intermittent fasting and, more specifically, short-term fasting, has been used in several pilot studies and has shown beneficial effects among the gynecologic and breast cancer populations without weight loss or serious adverse events. There are few published studies which look at multiple cancer types in each study and evaluate patients at variable timepoints in their treatment (ie. Initial vs recurrent disease). The effect of alternate day fasting during front-line chemotherapy on chemotherapy-associated side effects and quality of life has never been tested. Here we propose a dietary strategy in gynecologic cancer patients undergoing their first line of treatment to study the impact of intermittent fasting in patients with uterine and ovarian cancers.