The FastingMimicking Diet
This article will offer background on fasting, based on research, supported by both preclinical studies and clinical patient data relevant to supportive patient care of cancer.
In a healthy population, fasting has shown benefits for weight loss, regulation of blood sugar and lowering insulin, reduction of inflammation, and in prevention, a reduced risk of developing chronic disease and improved longevity.
Table of Contents:
Fasting or Fasting Mimicking Diets in Cancer
Treatment of cancer utilizing fasting, especially fasting mimicking diets, is being established in preclinical or laboratory studies, and patient clinical studies as a potential complementary treatment to standard oncologic therapies in supportive cancer care.
The experiments of Dr Otto Warburg, in the 1930s, contributed to our understanding that cancer cells utilize carbohydrates, glucose, to create energy differently than normal cells for continued growth and proliferation.
His conceptualization provided insights into cancer metabolism that showed cancer energy production relied on glucose, requiring a pathway called glycolysis to convert glucose into energy, and importantly, that cancer cells are limited in their ability to shift to other available fuels when glucose is unavailable.
Dr Warburg surmised that if glucose was reduced or removed from cancer cells’ accessibility, and being highly dependent on it for growth, it would reduce their ability to grow and proliferate at a rapid rate. This concept has led to multiple studies that show glucose is the primary driver of energy production for cancer growth, and has been a foundational contribution to cancer research and treatments.
The glycolysis energy pathway used by cancer cells, located in the cell’s cytoplasm, uses glucose to quickly produce energy in the form of ATP and to also produce amino acids and lipids needed for growth, making it the preferred pathway for cancer proliferation.
In normal cells, oxidative phosphorylation is the energy pathway located within the cellular mitochondria that uses the transport of electrons to produce an energy gradient to create significant amounts of energy, ATP.
If, however, carbohydrates are diminished either by choice or due to adverse conditions, the body can shift from glucose as a substrate to using fat, converting it to fatty acids and then ketones, which can then be used as an alternative cellular energy source. The concept is that normal and cancer cells both use glucose for energy, but in its absence, normal cells can adapt, while cancer cells are thought to be unable to. However, current research now shows that cancer cells can also use ketones from fats as well as the amino acid glutamine as alternative fuels when necessary for energy production. When in starvation mode, the liver produces beta-hydroxybutyrate (BHB) from fatty acids during fasting when there are low carbohydrates, and these can be used by cancer cells for limited energy production.
This is a newly discovered perspective and challenges the long-held absolute of the Warburg effect by demonstrating the creativity and ingenuity of the cancer cells and their flexibility in shifting from one fuel to another, similar to the new hybrid cars.
Since glucose is the preferred source of energy production in cancer cells, it suggests that both during treatment and after, lifestyle modifications that reduce carbohydrate intake can be beneficial as a supportive treatment. Low carbohydrate intake also offers preventive effects since excessive sugar intake contributes to obesity and chronic inflammation, which are associated with increased cancer risk.
In addition, when glucose levels in the body are elevated, a secondary effect is an increase in insulin levels to help transport more sugar into the cell. This stimulates growth hormone production in response to increased insulin, the effect of which is the production of insulin-like growth factor 1, IGF-1, to promote tissue growth, cell reproduction, and repair, which stimulates cancer cell growth while reducing cancer cell death. By lowering glucose, insulin levels, and growth hormone are decreased, impacting cancer growth.
Fasting in cancer patients is, however, subject to a distinct and unique set of circumstances, which include:
Weight Loss and Malnutrition
The importance of nutrients as necessary resources for the maintenance of strength, support of immune function, and tissue repair associated with cancer therapies cannot be overemphasized. Regardless of your pretreatment constitution, chemotherapy will directly impact multiple systems, and specifically the digestive system, at some time during cancer treatment. Decreased appetite, changes in smell and taste, nausea, abdominal distention, or diarrhea are often experienced intermittently or persistently during and after treatment, affecting the intake or absorption of nutrients. They are important contributors to cancer-related fatigue, weight loss, and loss of muscle mass, called cachexia.
With the existence of these effects from treatment, cancer patients are often malnourished with significant nutritional deficiencies. In these situations, there is impaired healing and repair, risks to reduced organ function, immune weakness, and a diminished quality of life. These are people who will need time and guidance to heal and recover before rebuilding can begin.
Limiting caloric intake further, with fasting protocols, increases the risk of even greater impairment and problems, such as cachexia and weight loss, which actually impair a person’s ability to tolerate continued chemotherapies, impacting long-term survival.
In these situations, it is prudent to consider postponing fasting during treatment, but knowing that it can remain a viable option upon its completion.
(Please refer to the website article for other causes of fatigue and Sleep disruption and impaired immune function.)
Fasting’s Benefits in Cancer Support
Preclinical research and clinical patient fasting studies suggest its ability.
Slow tumor growth and decreased recurrence
Enhances autophagy, in which the body removes, recycles, and reuses damaged or old parts of a cell.
Reduces insulin and insulin-like growth factor, IGF1, which impairs its production of energy, inhibiting cancer cell growth
Supportive of standard chemotherapy, radiation, and immunotherapy by reducing side effects. By reducing GI side effects and fatigue without decreasing the effectiveness of treatment.
This article will review the scientific benefits of fasting and again emphasize the adverse effects of calorie restriction in cancer patients, especially during treatment.
It will also present contemporary cutting-edge research and clinical studies on the application of the fasting mimicking diet developed by Dr Victor Longo and his associates, demonstrating specific dietary protocols that mimic fasting, provide nutrition, are safe to use, and can synergize with standard cancer treatment with this supportive approach.
The Ketogenic Diet
While offering needed calories, the information available from clinical studies is limited due to compliance with the large amount of fat consumed in the diet and its associated side effects, and difficulty with study consistency, due to dietary variations in the ratios of fat to carbohydrates used.
There are, however, individual cases of extended survival, offering potential for supportive care in specific situations and under experienced guidance.
Ketogenic diets have been used as a therapeutic modality in the treatment of pediatric epilepsy for decades, and it is also currently utilized for the treatment of several neurodegenerative diseases, including Alzheimer’s, Parkinson’s, ALS, traumatic brain injury, headaches, and, in some cases, cancer. It has also been embraced as a treatment for obesity.
The diet’s design stresses a low ratio of carbohydrates compared to a significantly higher ratio of natural, non-processed, saturated fats and Omega-3 fatty acids with low to moderate protein intake.
Achieving a higher ratio of fat from the diet is supported by using the following foods; seeds- almonds, walnuts, flax, chia seeds, and pecans, grass fed, and limited amounts oft clean animal fats- pork, duck, bison and lamb along with wild caught fatty seafood especially wild Alaskan salmon, sardines and herring which are lowest in heavy metals. Oils used are avocado, olive, coconut, and butter. Non-starchy veggies like organic broccoli, cauliflower, and zucchini, and organic greens like kale and spinach, along with avocado. Full-fat organic dairy includes yogurt and cottage cheese in limited amounts, and limited strawberries and raspberries, which are nutritious and low in sugar.
An important response to fasting is to cause an alteration of cellular energy production. If dietary intake of carbohydrates, glucose, drops below 50 grams a day, this amount becomes inadequate for energy production, requiring a metabolic shift. First, glucose stored as glycogen in the liver and muscles is utilized until those stores are exhausted. Then cellular energy production shifts using fat as an alternative energy source.
Fats can be metabolized to fatty acids, and then modified to create ketone bodies, which can then be metabolized into the molecule acetyl-CoA, which can enter the Krebs cycle in the mitochondria to create energy, substituting for sugar.
There are a number of preclinical studies, involving mouse models, that distinctly show that the ketogenic diet has the potential to inhibit tumor growth. In these laboratory studies, ketogenic diets have positive effects in pancreatic, lung, colon, and brain cancer, but their effect on breast, stomach, and liver cancer is limited, and the diet is contraindicated in kidney cancer as it is pro-tumor growth.
However, clinical patient studies on its use as a supportive treatment in cancer are extremely few, and often limited to individual cases. The Ketogenic diet appears not to have therapeutic efficacy when it is used as a single therapy, and its potential in cancer treatment requires integration with other therapeutic modalities such as chemotherapy and radiation.
In the field of brain tumors with glioblastoma and neuroblastoma, there have been individual cases of stabilization of tumor growth and longer survival.
It was also important to remember that many cancer patients going through chemotherapy and radiation have digestive problems that are often prominent. The ketogenic diet can be difficult to tolerate, as it needs to be followed for long periods. Some people get nausea, lethargy, and vomiting from the increase in fat, along with issues of higher cholesterol, dizziness, fatigue, low blood sugar, and muscle cramps. There can also be associated mineral deficiencies.
Also, there is no current data that supports the ketogenic diet as having the ability to shift normal cells into a protective, diminished growth mode, like FMD, fasting mimicking diets, which protect normal cells from chemotherapy toxicity.
Brain Cancer Treatment and the Effects of the Ketogenic Diet
Ketogenic Diets in Glioblastomas
An early case report of a patient with a glioblastoma, in 2010, utilized the protocol from cases of ketogenic diets being used to treat refractory epilepsy in children and tested its ability to target energy metabolism in brain tumors. It was adopted to be used with standard therapy in this case. After 2 months on the diet, body weight decreased by 20% and no tumor was detected on follow-up scan. When the diet was suspended, after 10 weeks, there was a recurrence of the tumor.
Other Forms of Fasting
Calorie Restriction, CR
This is the reduction of caloric intake by 20-40%. It has been studied for over a century and has been shown in preclinical animal models to have preventive effects on cancer and increase longevity, but interestingly, this is not seen in all mice. It appears to be dependent on the mouse’s genetics, and in some, it is not effective or may even be detrimental.
And while there is evidence of cancer prevention using CR, its potential for support in cancer is limited, first due to the difficulty in maintaining the caloric reduction, and importantly, by the expected effect of weight and muscle loss.
However, in prevention, utilizing CR in conjunction with exercise has been shown in people to be a proactive approach to reducing cancer risk, which can be a proactive approach for those with family histories of cancer.
Intermittent or Periodic Fasting Includes:
Cycles of fasting, which involve specific periods of time during which there is caloric intake, and specific periods of not eating. During cancer treatments, restricting caloric intake can potentially exacerbate existing and developing symptoms of malnutrition and weight loss, creating increased risks for already fragile patients. Its applications are limited during active cancer treatment and should be avoided until completion of therapy and recovery from adverse symptoms before its consideration.
Time Restricted Fasting
As the name indicates, it is a pattern in which there are specific hours during the day, a window of time, when you consume calories, alternated between the other hours when you fast.
In the healthy population, Overnight Fasting is probably the commonest form of time-restricted fasting and is designed so that food intake is for 12-13 hours, finishing the last food intake at dinner, and then taking in no calories for the next 12-13 hrs. This time frame maximizes the benefits of improved energy and sleep, reduced cardiovascular risk, and potentially a reduced risk of recurrence of the cancer.
However, a study of longer periods of fasting and shorter periods of eating appears problematic based on data from an article in The Journal of Diabetes and Metabolic Syndrome, which shows that food and calorie intake in a window of 8 hrs or less, in the long term, doubles the risk of death from cardiovascular disease and increases the risk of gallstones.
Alternate Day Fasting consists of a day of normal eating followed by a day of fasting in which very few calories or water only are taken.
Periodic Prolonged Fasting has shown validation and support both in preclinical, laboratory research, and in limited clinical patient applications.
Cancer treatment and fasting walk a fine line together between seeking improved benefits from fasting, balanced against the adverse effects that can occur with calorie deprivation.
Fasting Before and Immediately After Chemotherapy
Fasting utilized prior to and after chemotherapy infusions has been shown to reduce both gastrointestinal side effects, fatigue, and quality of life, by acting as a protective shield for normal cells while sustaining the beneficial effects of destroying cancer cells.
A small pilot study of 34 women in 2018 with gynecologic cancers, breast and ovarian, was individually randomized to evaluate the effects of short-term fasting (STF during 4-6 cycles of chemotherapy. There were diverse populations of the participants; both pre- and post menopausal, those with different hormone statuses, primary and advanced breast cancer, and women with primary and advanced ovarian cancer. Participants were receiving several different chemotherapy drugs.
The duration of STF was 36 hours before and 24 hrs after chemotherapy, using unrestricted water intake, herbal teas, and limited vegetable juice and vegetable broth, but only up to 350 calories a day. Mild side effects included hunger, headache, and nausea, usually in the initial cycle.
The results, with these small numbers of patients, showed that STF significantly benefited quality of life and fatigue, resulting in a recommendation for much larger trials to be developed.
A study with 20 women receiving platinum plus a second chemotherapy regimen was fasted, with less than 2000 calories/ 24 hours. Americans, on average, consume 3600 calories/day. The fasting was 48 hours prior to and 24 hours after chemotherapy. This calorie amount was considered safe and practical in this study, and the results indicated less decrease in white blood cell counts and symptomatically less fatigue, headache, and dizziness.
An early study, 2009, described 10 cases of patients with several different cancers who fasted 48-140 hours prior to their chemotherapy combinations, and for 5-56 hours post-treatment. And fasting did not change chemotherapy effects, but did improve fatigue, weakness, and GI side effects while fasting.
Ketones and The Immune System
Fasting does increase fatty acids and ketones that can be utilized for energy production, and research has shown from a 2023 article by Dr. Victor Longo and his associates that ketone bodies are the preferred energy source for specific immune cells.
Effector T cells or TEFF cells areT lymphocytes and participate in adaptive immunity and respond to pathogens and cancer by attacking and removing abnormal or foreign cells.
They can be divided into subtypes, each with specific functions targeting cancer cells. They support immunity by releasing cytokines that are chemical messengers that regulate immune actions.
CD4 T helper cells direct and activate the needed immune cells to destroy cancer cells
CD8 cytotoxic T cells function to kill cancer cells, and ketone bodies are an essential fuel for these cells.
Fasting Mimicking Diet, FMD
This article represents an overview of the research and clinical applications of the Fasting Mimicking Diet, a specifically designed nutritional program that was initially designed as a supportive therapeutic modality for cancer patients. Using nutritechnology, an approach that integrates nutritional science with technological tools, the focus in FMD is to evaluate and improve health outcomes that can be supported by scientific research and clinical studies.
Conceptually, it was developed by Dr Victor Longo and his colleagues, both in the United States and Italy, and has focused on nutritional interventions that are designed to protect normal cells from the damage of chemotherapy while allowing cancer treatments to remain effective in killing cancer cells.
Research on the fasting mimicking diet has generated information demonstrating both in preclinical, in the laboratory, and in patient clinical testing its potential in supportive care for cancer patients. Importantly, its use as a dietary intervention is safe, feasible, and allows the maintenance of a normal diet when not fasting and the consumption of nutritious food while fasting. The dietary plan developed utilizes real food, specifically designed to be plant-based, low in sugar, protein, and carbs, but high in fat.
It has been adapted for application in situations prior to and after chemotherapy, in between cycles of treatment, and after the completion of therapy.
Cancer chemotherapies are indiscriminate in their effects. They are designed to target and kill cells that are rapidly growing and dividing, which, while specifically directed at the cancer cells, also creates collateral damage to our own body’s cells. These include the epithelial lining cells in the gut, genitourinary and respiratory systems, the bone marrow, and hair follicles, but the intensity of the effect depends upon the type of drugs and an individual’s unique response.
These resulting consequences to normal cells, the side effects of treatment, have many patients seeking measures that could reduce or mitigate the associated damage and support the repair of their injured systems.
Supportive cancer care is available through experienced integrative physicians practicing in the paradigms of Chinese, Naturopathic, Homeopathic, and Ayurvedic medicine and offering practical recommendations, nutritional advice, and experience-driven, successful approaches focused on symptomatic care during treatment and system rejuvenation following its conclusion.
Healing pathways have used fasting techniques for centuries, and recently, based on controlled preclinical and clinical data, fasting mimicking diets in cancer have demonstrated the ability to protect our vulnerable cells from damage during treatment while continuing to effectively kill cancer cells.
The following healing pathways will be explained in greater detail
The Mechanisms of FMD (and other forms of fasting) on Cancer Growth
Energy Production
The application of FMD has exposed a cancer vulnerability by altering its ability to create the necessary energy required for continued growth and spread. Cancer cell survival is based on its ability to adapt to environmental changes by countering the body’s attempts to control and destroy it. Fasting affects cancer’s ability to create energy by shifting the body into starvation mode, reducing the use of glucose, and requiring the substitution of fatty acids as the source of energy. As a result, cancer cells are able to produce a minute fraction of the energy potentially generated from glucose.
The mechanisms involved in primary energy production in normal and cancer cells
Energy Production by Cancer Cells
The Warburg effect, discovered over 100 years ago, made the observation that in cancer, the rapidity of cell division requires and consumes large amounts of glucose to produce energy, ATP, preferably in low levels of tissue oxygen. This is called glycolysis. Glucose is the essential raw material, and the process generates small amounts of ATP energy molecules.
Another pathway to glycolysis, for cancer cells, is to circumvent control of the P53 tumor suppressive gene, which, besides regulating cancer growth, can also upregulate glycolysis, providing another advantage for cancer cells for energy production.
Energy Production in Normal Cells
Energy production, in mammals, comes from the production of adenine triphosphate (ATP via
Oxidative phosphorylation, which occurs in the mitochondria using oxygen and glucose molecules to produce large amounts of ATP via electron transport, creates chemical energy.
In normal cells, glycolysis is a backup system that is used in oxygen-deprived environments. Energy can be created from sugar via this process, but the yield is much lower. Normal cells prefer oxidative phosphorylation, which creates significantly more energy.
Differential Resistance Between Normal Versus Cancer Cells During Treatment With FMD
Chemotherapy, as discussed, is indiscriminate in destroying rapidly dividing cells, whether normal or cancerous. Cancer cell destruction is paramount, but it comes with the price of damage to normal cells. One area of current research is focusing on preferential cancer cell destruction while reducing damage to normal cells.
The fasting mimicking diet, FMD, can be used for supportive care during cancer treatment but differs from other protocols. It creates the effects seen in fasting but adds specific nutritional foods that maintain the fasting state, which can reduce the associated muscle and weight loss while enhancing the effectiveness of standard treatments.
FMD has been shown to be a “Protective Shield” for normal cells, triggering “Differential Stress Resistance”, two terms proposed by Dr Victor Longo. His studies reveal that under the adversity of fasting, both in the laboratory and in clinical studies, the body’s cells shift to a protective mode of stopping growth and shifting into survival mode.
Cancer cells, on the other hand, have preprogrammed genetic oncogenes that continually stimulate and demand continuous growth, regardless of the situation, allowing them to remain susceptible to cancer therapies.
FMD triggers a sense of starvation in normal cells, causing:
A reduction in growth and proliferation occurs as cells shift into a protective mode of survival.
A reduction in metabolism to conserve energy.
A reorganization of energy-producing structures to optimize output
Effects on The Immune System
Allows DNA repair in only normal tissues, not cancer cells
Increasing tumor responses to programmed cell death, called apoptosis, but preventing apoptosis-mediated damage to normal cells
Removing cancer cells’ ability to avoid immune surveillance
Decreasing immune regulatory T cells while increasing cytotoxic T cells
Research Associated With FMD, Fasting Mimicking Diet
Fasting and Cancer Response
In a clinical trial of 101 cancer patients, 5 5-day FMD was used with 2-3 weeks of refeeding during standard chemotherapy cycles.
There were multiple data points evaluated, but one set of data showed.
Decreased immunosuppressive monocytes
Decreased inflammatory white blood cells
Reduced immunosuppressive T cells
Increased effector T cell activation
The authors believe and support continued clinical trials in combination with standard chemotherapies to gain the needed information to support greater integration into oncologic treatment.
Prostate Cancer and Its Association with Glucose Intake (Carbohydrates)
Carbohydrate Intake Is Associated With
Increased weight and increased carbohydrate intake in patients with prostate cancer can increase their risk of recurrence.
In situations, using the fasting mimicking diet showed improved weight parameters, and maintaining weight can also reduce the risk of recurrence.
A restricted carbohydrate diet prolonged the PSA doubling time, a marker that, when increasing, suggests progressive disease.
In 2 individual cases, these patients with metastatic prostate disease, fasting mainly before but during and after chemotherapy, for up to a total of three days, allowed these patients to tolerate chemotherapy that in the past they were unable to, offering them a greater opportunity to control their disease.
Obesity
A prostate study from 2020 looked at obesity and weight gain for a period of 10 years and its impact on mortality for localized prostate cancer without metastasis. The BMI post-diagnosis was followed one to six years and included several thousand men.
In the group with the highest weight gain, which was considered greater than 5% of body weight or greater than 10 pounds after their diagnosis, these men were more likely to die of prostate cancer than those who maintained their normal weight.
It was also noted that weight gain before the diagnosis of prostate cancer and up to one year after increased the risk of recurrence.
FMD in Men With Prostate Cancer and Pre Diabetes
In a study in 2023, men who had prostate cancer and associated metabolic syndrome, pre-diabetes, from being overweight, or as a result of testosterone hormone blocking treatment for their cancer, were followed. Participants did three cycles of the four-day mimicking diet as an intervention consisting of low carbohydrates, sugar, and protein but high amounts of unsaturated fats. In the group with metabolic syndrome, the diet was well tolerated and safe, and 80% of the participants completed the cycles, which showed decreases in weight, abdominal circumference, and blood pressure.
FMD, Weight Control, and Recurrence
The information from these and other studies, on localized prostate cancer, shows that by reducing weight and abdominal circumference by doing the fasting mimicking diet cycles and/or by maintaining weight and keeping BMI and total weight in the normal range offers an approach that can be used to reduce generalized health problems and also decrease the likelihood of dying from or having recurrent prostate cancer.
In 2007, utilizing toxins or testosterone as a positive stimulus for prostate cancer development, rats were given normal diets or had 15% or 30% calorie restriction. The data showed that calorie restriction did not prevent prostate cancer.
Case Studies
In Dr. Longo’s book, Fasting Cancer, he presents two cases of men with metastatic prostate cancer who became unable to tolerate the chemotherapies that were needed for cancer control. It was found that fasting and fasting mimicking diets started 60 hours prior to chemotherapy and continuing for 8 to 24 hours post chemotherapy, allowed the patients to tolerate the chemotherapy with minimal side effects.
Low Carbs and PSA Doubling Time
Studies on weight loss and carbohydrate-reduced diets, even without weight reduction, in animals, have shown prolonged survival in prostate cancer.
This was a six-month multi-site randomized trial in patients with prostate cancer and biochemical recurrence. The diet of two different groups was a regular diet with carbohydrates, and a group with a limited carbohydrate intake by design. The lower carbohydrate diet decreased triglycerides and hemoglobin A1c, but importantly, the time to doubling of the PSA was 28 months in the low carbohydrate group and 13 months in the ad libitum group. Carbohydrate group.
Colorectal Cancer, CRC
FMD and CRC Growth
A lab study was designed to look at the effect of fasting on CRC proliferation and growth. The Farnesyl-Diphosphate Farnesyltransferase 1 (FDFT1) gene is recognized as a specific enzyme that encodes for the cholesterol synthesis of cellular membranes, but in cancer, when upregulated or increased, it suppresses tumor growth. Its action influences the AKT/mTOR pathway, whose signals regulate cancer cell growth, proliferation, and survival, so increasing FDFT1 decreases tumor stimulation.
Fasting unregulates FDFT1 and decreases cancer stimulation via the AKT/mTOR pathway, and also decreases aerobic glycolysis, which is the preferential source of cancer’s energy production.
CRC and KRAS Mutations
KRAS is a signaling system that works within our bodies to control cell growth and proliferation. Forty to forty-five percent of patients with metastatic colorectal cancer cells have mutations in this pathway that allow continued cancer growth and reduced survival.
It has been shown in animal studies that vitamin C has strong anti-cancer activity and is effective against KRAS mutant cancer cells by causing prooxidant reactions, creating ROS, the reactive oxygen species, hydrogen peroxide, and hydroxy radicals that damage these cells and result in their destruction.
Cancer cells need iron to synthesize DNA. KRAS mutations are able to manipulate iron enzyme systems to neutralize the effects of Vitamin C, increasing survival. Fasting mimicking diets are able to selectively reverse this capability by allowing Vitamin C to be effective in causing KRAS mutation cancer cell death.
This creation of ROS by Vitamin C also supports the effects of some forms of chemotherapy in cancer cell destruction, making the potential addition of FMD and Vitamin C treatment together with chemotherapy a safe additional component for colorectal cancer treatment.
FMD and Immune Activation
The study was designed to gain a better understanding of the fasting mimicking diet and its ability to activate the immune system against colorectal cancer. There is a balance between B cells that produce IgA antibodies that protect the mucosal surfaces and T cells, which kill and damage cancer cells. It appears that there is a balance between B and T cells, but the FMD suppressed B cells, thereby allowing improved antitumor immunity by reducing the suppression of CD8 T cells that are cytotoxic to cancer cells.
FMD and Irinotecan Side Effects
Irinotecan is a chemotherapeutic agent often used in combination with other drugs for colorectal cancer. However, its side effects of diarrhea and low white blood cell counts often limit its use.
A study in mice having colorectal cancer divided them into two groups, one that was fasted and the other fed normally, with both then treated with Irinotecan. Fasting prevented the mice from having diarrhea or low blood counts, while the animals fed had lower white blood cell counts.
Intermittent Fasting, Akkermansia, and FOLFOX Chemotherapy in Colorectal Cancer
FOLFOX is a combination chemotherapy protocol consisting of Folinic acid or Leucovorin, fluorouracil or 5-FU, and Oxaliplatin that is used to treat metastatic colon cancer. Studies have shown that the human intestinal microbe Akermansia, a commensal, friendly, intestinal bacterium, has been shown to be very beneficial in gut health, also improving the antitumor effects of FOLFOX. Its action is to ferment dietary fiber into the short-chain fatty acid, propionate, which is anti-inflammatory and improves insulin sensitivity to regulate blood glucose.
In mouse models, propionate is associated with the prevention of colorectal cancer in colitis by decreasing cellular DNA damage, increasing programmed cell death and apoptosis in aging or damaged colonic cells, and decreasing colon cancer cell growth.
It is, however, diminished in CRC and pre-cancerous adenomatous colon polyps. In volunteers that followed guidelines for intermittent fasting,16 hours/ day without food, Akkermansia volume increased 85% in young people and 74% in older people, whereas it increased only 20% in unfasted people.
The authors recommend that, with increased Akkermansia benefiting CRC prevention, improving the effects of FOLFOX treatments, and its increase in intermittent fasting, those in treatment or at risk of colon cancer should follow a guided protocol from an experienced health professional and do intermittent fasting, if their health allows it.
Breast Cancer
FMD and Hormone Receptor Positive Disease
Three-quarters of breast cancers express estrogen hormone receptors. Estrogen receptor blockers are used when the receptor is present to inhibit cancer growth. However, in time, these blockers lose their effectiveness.
Using a mouse model with estrogen receptor + cancer, a fasting mimicking diet (FMD) enhanced the effects of estrogen hormone blockers, tamoxifen and fulvestrant, Fasodex, by lowering insulin, IGF-1, and leptin, as well as inhibiting the AKT/mTOR pathway, which signals growth and replication in cancer. In more advanced disease, when Fasodex is combined with a cyclin-dependent kinase 4/6, adding FMD promotes tumor regression by reverting previously acquired drug resistance.
FMD also prevented excessive uterine cellular growth while on tamoxifen, which is associated with uterine cancer.
Triple Negative Breast Cancer, TNBC, and Immunotherapy
Immunotherapy has become an important therapeutic modality, extending cancer survival in several different cancer types. In breast cancer, immunotherapy with PD-1 inhibitors is used in treatment as they unblock the immune response regulation to allow it to recognize and attack the cancer more aggressively. However, limitations can occur due to the development of resistance, and/or issues with severe side effects from overactive immune reactions.
Triple-negative breast cancer is difficult to treat because of a poor immune response to the cancer. In this mouse model, utilizing periodic FMD, it was shown to alter the tumor microenvironment in a way that allowed increased effectiveness of anti-PD-1 against TNBC by:
Improving the function of exhausted Immune T cells needed to kill cancer cells
Impeding the cancer’s energy production
Decreasing the adverse side effects of an overactive immune response
The conclusion of the researchers was to suggest that combining FMD and anti-PD-1 drugs may improve their anti-cancer effects and decrease side effects.
Triple negative Breast Cancer, TNBC
In a 2024 study, 14 patients with advanced TNBC on a carboplatin and gemcitabine combination had FMD added to their protocol. This group, compared to chemotherapy alone, had better overall survival from 17 to 30 months.
Triple negative breast cancer (TNBC is associated with progression due to either resistance to chemotherapy or repopulation of the tumor with cancer stem cells capable of growth and proliferation.
The data from mouse studies have revealed that FMD affects each category of tumor metastasis by affecting different pathways.
In stem cell cancer growth, FMD decreases glucose-dependent protein kinase A, which reduces the stem cell numbers, while in non-stem cells, metastasis inhibits multiple pathways, PIK-3-AKT, mTOR, and CD4/6, all of which stimulate primary cancer cell growth.
FMD offers different but wide efficacy for reducing multiple cell types associated with TNBC.
Intermittent Fasting, IF in HER2 Negative Breast Cancer
IF was introduced in this study in a group of 48 newly diagnosed HER2-negative women who were divided into two groups prior to adjuvant chemotherapy, or treatment prior to surgery. One group ate regularly while the second group intermittently fasted for three days around chemotherapy, from 12 am to 6 pm, and then could eat from 6 pm to 12 am. This was repeated for four cycles of chemotherapy.
The results showed, in the fasting group only, reduced GI issues, a significant reduction in insulin levels, and no diminished tolerance to the chemotherapy.
Using the Fasting Mimicking Diet (FMD) in Neoadjuvant Chemotherapy for Breast Cancer
One hundred and thirty-one HER2-negative, stage 2/3breast cancer patients received either the FMD or a normal diet 3 days prior to and during neoadjuvant chemotherapy. A steroid, dexamethasone, was given to the normal diet group to reduce potential adverse chemotherapy reactions, but not to the FMD group. It was shown that the toxicity of the chemotherapy was no different, even when omitted, in the FMD group, and the FMD group had a greater tumor cell loss than the normal group.
Night Fasting and Breast Cancer
Data was collected for over a decade in breast cancer patients enrolled in the Women’s Healthy Eating Study, based on nightly duration of fasting compiled in dietary journals. They looked at a baseline level, at 1 year, and 4 years to see outcomes in breast cancer recurrence, new primary tumors, or death from breast cancer or any cause, over a 7-year period.
The information gathered from over 2400 women revealed that fasting <13 hrs, with a mean of 12.5 hrs, was associated with an increased risk of breast cancer recurrence compared to > 13 hrs. It was not, however, associated with increased risk of death in either category mentioned.
Head and Neck Cancer
Cisplatin and Head and Neck Cancer
Squamous cells are the major cell type associated with head and neck cancer, originating from the mucosa of the mouth, throat, and larynx. Cisplatin, which is used in combination with other drugs, is the primary chemotherapy used in treatment.
This recent lab study used a specific squamous cell cancer cell line divided and tested in 3 different situations: a group of cells with no treatment, a group with standard cisplatin therapy, and a group receiving cisplatin therapy along with fasting by restricting glucose for 48 hrs prior to treatment. The cancer cell growth was then measured 48 to 72 hrs after chemotherapy.
The results revealed that short-term fasting before chemotherapy increased cancer cell death as well as programmed cell death.
FMD and The Effect on Immune Macrophages in Oral Cancer
Macrophages, a type of white blood cell, can be altered in the microenvironment of solid cancers to support tumor growth and survival and increase new blood vessel growth to allow spread. A lab-altered macrophage, called TAM, tumor-associated macrophage, was designed to express this type of functionality in oral cancer. Treatment of oral cancers often utilizes the chemotherapy Gefitinib, when the cancer has a positive epidermal growth factor receptor, because it inhibits cancer growth. However, its effect can be reduced by these tumor-associated macrophages. FMD was shown to enhance both oral cancer sensitivity to the effects of Gefitinib as well as reduce the effects of TAMs.
Lung Cancer
Non-small cell lung cancer, NSCLC, comprises over 75% of all lung cancers, with over one-third in an advanced stage at the time of diagnosis. Its origin is often from overexpressed genetic driver mutations such as EGFR, epidermal growth factor receptor, that are stimulated by the signaling pathway tyrosine kinase, which promotes abnormal cancer growth and progression. It is present in over 50% of NSCLC, and while amenable to treatment with tyrosine kinase inhibitor drugs, their effectiveness is generally short-lived.
Preclinical studies have shown that fasting can slow tumor growth, as can EGFR inhibitor drugs, but in combination, they are slightly more effective than either alone. Researchers are recommending that specifically designed FMDs be studied for clinical application.
A study in mice using multiple lung cancer cell lines compared mice that were fed normally and mice that were on a 6-hour time-restricted feeding, TRF. It was shown that TRF inhibited lung cancer progression, but the reasons were unique and a first in research. TRF in this mouse model reprogrammed the rhythms of the circadian clock and the rhythms of metabolism in genes associated with cancer, glycolytic energy production, and increased programmed cell death.
Brain Cancer
There are many different cancers, both solid and blood cancers, that can secondarily spread or metastasize to the brain. There are primary tumors that originate in the brain, with approximately 50% being glioblastomas, which are extremely aggressive and difficult to treat.
Glioblastoma multiforme is a commonly diagnosed brain cancer and is very invasive, with shortened survival for most people, even with a combination of chemotherapy, radiation, and surgery. In a mouse model, the effect of starvation, for 48 hrs prior to chemo or radio therapy, on both human and mouse glioma cancer cells was studied and showed that fasting lowered blood glucose and insulin-like growth factor 1 (IGF-1 ), which sensitized these brain cancer cells to chemo and radiation and extended survival.
Gynecologic Cancers
The most aggressive and deadly ovarian cancers are composed of epithelial cells. This study used mice with epithelial ovarian cancer and intermittently fasted them for 16 hours.
The research showed an improved T cell immune response of both CD4 helper cells and CD8 cytotoxic cells, and both reduced tumor growth and inflammatory molecules due to the creation of a hostile tumor microenvironment.
A randomized control study of women with stage 3 and 4 cancers, 11 ovarian, eight breast cancers, and one cervical cancer, utilized 24 hr fasting before their combination chemotherapies and 24 hrs after, compared to women who were not fasting, for a total of 4 cycles of combination therapies.
The fasting group had fewer reductions, delays, or modifications of their treatment protocols and showed an improved quality of life over the course of treatment.
A study in 51 women with gynecologic cancers, in a randomized controlled study, was followed for four cycles of chemotherapy, during which half of the patients fasted for 96 hours, eating 25% of each patient’s daily caloric intake. The other half of the cycle, women ate normally.
Results, in the fasting cycles, revealed fewer headaches, weakness, stomatitis, and fewer GI toxicities and postponements of chemotherapy.
Pancreatic Cancer
A study of pancreatic cancer in a mouse population was designed to study the effects of the chemotherapy gemcitabine, in terms of outcomes associated with 24-hour starvation before treatment.
In the fasted mice, the cancer cells showed increased transport across their cell membranes, enhancing their effectiveness by decreasing tumor growth by 40% compared to controls.
The authors suggested that dietary interventions could enhance cancer treatments in pancreatic cancer.