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.