Ketogenic Diets and Cancer Therapy
Cancer cells demonstrate two distinct and related metabolic alterations: increased anaerobic glycolysis (Warburg effect) and defective mitochondrial function leading to increased levels of reactive oxygen species, such as H2O2. Therefore, reducing the glucose supply and increasing fat-derived fuel by feeding a ketogenic diet forces cancer cells to use mitochondrial oxidative metabolism; and this enhanced metabolic oxidative stress sensitizes cancer cells to chemotherapies. The ketogenic diet is a high-fat, low-carbohydrate diet that is used to manage epilepsy. Recently, the ketogenic diet has gained popularity among cancer patients.
1. What is a Ketogenic Diet?
In 1921, R.M. Wilder, M.D., from the Mayo Clinic proposed the concept of a “ketogenic diet” that mimicked starvation by limiting dietary carbohydrate and providing high amounts of dietary fat. The ketogenic diet significantly improved seizures in more than 50% of patients; thus, the ketogenic diet was widely used to manage epilepsy throughout the 1920s and 1930s. After introducing a new class of antiepileptic drugs in the late 1930s, the ketogenic diet began to fall out of favor. In the past 10 years, there has been renewed interest in ketogenic diets, and there is a significant amount of evidence showing benefits in cancer patients.
The ketogenic diet essentially is a high-fat, low-carbohydrate, and normal-protein diet. It was designed to mimic the metabolic state of fasting, where the body burns body fat for fuel in the absence of carbohydrate. The ketogenic diet includes 80% fat, 15% protein, and 5% carbohydrate; the ratio of fat to carbohydrate plus protein is around 4:1. Most of the fat is provided as long-chain triglycerides. A variant of the classic ketogenic diet is the medium-chain triglyceride (MCT) diet, which is more ketogenic. However, MCT often causes gastrointestinal side effects.
2. Effect of a Ketogenic Diet on Cancer Cells
Cancer cells are unable to produce energy via cellular respiration in the mitochondria, but instead use glucose fermentation. Ketogenic diets reduce blood glucose that feeds cancer cells. In addition, cancer cells have dysfunctional mitochondria and lack efficient energy production from mitochondrial aerobic respiration. In other words, cancer cells cannot metabolize the fatty acids from a ketogenic diet for energy. Perhaps most important is that ketones directly poison cancer cells. Acetoacetate and ß-hydroxybutyrate are the two most abundant and physiologically relevant of the three ketone bodies that result in decreased viability and increased apoptosis of human colon cancer cells, breast cancer cells, lymphoma cells, and melanoma cells, but have no harmful effects on normal human cells.
3. Animal Studies
Several animal studies have shown that a ketogenic diet can reduce tumor growth and improve survival rates. For example, in a mouse model of brain cancer, 60% of mice fed a ketogenic diet survived, whereas none of the mice in the control group fed a regular diet survived.
4. Human Trials
Several clinical trials with ketogenic diets are ongoing. At present, preliminary clinical data seem to show that a ketogenic diet may reduce tumor size and prevent tumor progression in certain cancers. In one study, three out of five patients on a ketogenic diet combined with radiation or chemotherapy experienced complete remission. Interestingly, the disease progressed in the other two participants after they stopped the ketogenic diet. It was noted that the high response rate of more than 60% to bevacizumab in patients on the ketogenic diet may not have been achieved with bevacizumab alone. In clinical trials, the ketogenic diet was safe and well tolerated. No severe toxicity was observed, as indicated by the absence of serious diet-related adverse events and unchanged routine laboratory parameters. Furthermore, weight loss, although statistically significant, was only minimal.
One quality-of-life study investigated the effects of a ketogenic diet in 16 patients with advanced cancer. Out of the 16, five remained on the ketogenic diet for the entire 3-month study period. The patients reported improved emotional well-being and reduced insomnia, without any negative side effects caused by the diet.
6. How the Ketogenic Diet is Practiced
Meal plans are flexible and include high-fat and low-carbohydrate products such as heavy cream, bacon, eggs, tuna, shrimp, vegetables, mayonnaise, and sausages. Patients are not allowed any starchy products such as starchy fruits or vegetables, breads, pasta, or grains; no simple sugars are allowed.
Commercially available ketogenic formulas include KetoCal (Nutricia, Gaithersburg, MD) and KetoVie (Cambrooke Therapeutics, Ayer, MA). These diets are available in 3:1 and 4:1 formulations and are fortified with vitamins and minerals.
The content of regular, non-ketogenic total parenteral nutrition (TPN) solutions is 60% carbohydrate, 20% amino acids, and 20% fat. Conversely, ketogenic TPN solutions have a high-fat, low-carbohydrate profile. To prevent parenteral nutrition-associated liver disease and cholestasis, the content of lipids is limited. Therefore, while ketogenic ratios of 4:1 are not possible in TPN, ratios in the 2:1 range are achievable. Glycerol in parenteral lipid emulsions is a type of carbohydrate. TPN should be initiated with 3 g/kg glycerol for a few days and then increased to 4 g/kg. In addition, prolonged administration of lipids over 24 hours has been utilized to minimize complications. Carnitine facilitates the transport of long-chain fatty acids into the mitochondria. The administration of carnitine should be considered when the major source of calories is derived from fat. Medium-chain fats do not use carnitine, which is an additional benefit of including this fat source in TPN solutions. Enteral feedings should be initiated as soon as possible.
7. Side Effects and Concerns
The ketogenic diet is very safe. Occasionally, it predisposes patients to nutritional deficits in calories, proteins, minerals, and vitamins and excess lipids, saturated fat, and cholesterol. Most of the side effects from the ketogenic diet are due to nutrient deficiencies, such as lack of protein, low calcium, and low fiber. Acidosis is also commonly observed. Less common are kidney stones and hyperlipidemia. Laboratory tests for electrolytes, liver function, plasma lipid profile, proteins, and complete blood count should periodically be performed.
8. Take Home Message
The ketogenic diet can be considered as an option for patients with cancer undergoing chemotherapy or radiation.