The Ketogenic Diet has been quite the buzzword in recent years, and for good reason! There are many purported health benefits of utilizing the low-carb, high-fat diet ranging from weight loss, to lowering inflammation, even improved energy and cognition. Currently, despite the limitations presented by COVID-19, there are almost 70 clinical trials that are open or about to start recruitment to see if the beneficial effects of the diet can be validated. But what about cancer research around the ketogenic diet for types of cancer, such as carcinoma, melanoma, prostate cancer, colon cancer, and others? Can it help support or replace standard treatment? Read on to find out what we know right now.
History of the Ketogenic Diet as a Treatment
The classic ketogenic diet is a high fat, moderate protein, and low carbohydrate diet. It restricts carbohydrates such as those found in bread, pasta, rice, crackers, sugar, root vegetables like potatoes, most fruits, and even some dairy so that your body uses fat from your diet and stored in the body as its primary energy source. The diet is a well-established medical treatment for refractory pediatric epilepsy or for children who have seizures and do not respond to their anti-seizure medications. Its first documented use in the United States dates back to the 1920s. Despite it being around for 100 years, we currently have very few human studies with evidence supporting its use in different diseases, such as cancer. This, in addition to the diet getting great attention in the media has led to a lot of confusion as to what the keto diet is and is not, and who would benefit from it. So, what is the diet, exactly?
Basic Principles of the Ketogenic Diet
First, let’s go over normal nutrient metabolism. We have three main macronutrients: protein, carbohydrates, and fats. These are our dietary building blocks for fuel and energy needs of the body. In order for us to use these sources for energy and stored for later use, they need to be broken down into smaller components that our body can use. To put it simply, carbohydrates get broken down into a sugar called glucose. Protein gets broken down into amino acids. Then there are fats, which get broken down into free fatty acids.
In normal nutrient metabolism (aka the Standard American Diet or SAD), people use glucose as their primary fuel source to produce energy, and their blood-glucose levels tend to be higher. When people go long periods of time without eating (i.e., fasting) or eat a ketogenic diet, they use the byproduct of fat metabolism, called ketone bodies, instead of glucose as their primary fuel source. When you use fat as fuel and produce enough ketone bodies (usually ≥ 0.5mmol/M), you enter a metabolic state called ketosis.
Types of Ketogenic Diets
There are many different types of ketogenic diets that are currently being followed and popularized for their potential health benefits and the promise of a better quality of life (especially for people with obesity or diabetes). Most call for a maximum of 20 grams of carbs per day. But there are other nuances. Some keto diets, especially those used for therapeutic reasons such as to inhibit tumor growth or cancer growth, recommend specific macronutrients ratios as a means to dictate how much fat to consume compared to protein and carbohydrate intake. A “4:1” ketogenic diet is a good example; it calls for eating four times as much daily grams of fat as grams of protein and carbs combined. Meanwhile, the “MCT diet” allows for more carbohydrates to be eaten than most other keto diets because it is supplemented with plenty of Medium Chain Triglyceride oil (MCT oil), which helps ensure ketosis is achieved despite the extra carbohydrates consumed. This can work because MCT oil requires no breakdown for absorption, goes straight to the liver to create ketone bodies, and blunts the usual glucose spike that occurs after consuming carbs. Another type of ketogenic diet uses the glycemic index of foods, which measures how a food will affect our blood glucose, as a way to eat and maintain ketosis.
The Metabolism of Cancer
Nobel Laureate, Otto Warburg, identified through his research in the early 20th century that 80 percent of human cancer cells have an increased use of glucose, using no oxygen, in order to produce very little energy (this is known among oncologists as the Warburg effect). This is incredibly unusual in comparison to normal cellular energy metabolism, where a small amount of glucose yields a large amount of energy with the presence of oxygen. This simply means the metabolism of most cancer cells is altered. The ketogenic diet can potentially change the tumor’s metabolism and growth by reducing the amount of glucose and other nutrients, like insulin and insulin-like-growth factor (IGF-1), going to the tumor that promote uncontrolled growth. This can reduce or create inhibition of the vasculature (blood flow) going to the tumor that carries the nutrients tumor cells need. In turn, blood carries oxygen, so this can help get more oxygen to the tissues around the tumor. All of these factors make it much less favorable for cancer cells to grow.
Research on the Keto Diet & Cancer
Interest in conducting research to study the effects of the ketogenic diet on cancer have been growing, although there is much more that needs to be done. Recently, there has been a promising study looking at the ketogenic diet for reducing fat mass, insulin, and IGF-1 in obese endometrial and ovarian cancer patients, thus potentially decreasing their tumor burden. There are also current studies looking at how one of the ketone bodies that is measured in the blood, beta-hydroxybutyrate, can actually function as an antioxidant to help minimize damage to other healthy cells. There has been well documented evidence, especially in preclinical animal studies, that the ketogenic diet can be supportive with brain tumor treatment.
There is an ever-increasing amount of evidence growing in support of the keto diet’s use, specifically for brain tumor patients. In our brain tumor clinic, we generally recommend and use “classic” ketogenic diets for our patients, or about a 3:1 ketogenic diet. This translates to about 80 percent of total calories coming from fat; or 1,600 calories coming from fat alone for someone eating 2,000 calories a day. This specific ratio is being investigated to see if it can be considered therapeutic within neuro-oncology, and in my opinion, it is optimal for a few different reasons.
We are currently using the diet in our phase I clinical trial within the first three months of diagnosis of glioblastoma multiforme (the most aggressive kind of brain cancer), either before, during or after their standard of care, consisting of oral chemotherapy and radiation. During this time, many patients are on steroids. A very well-known side effect of these steroids is hyperglycemia (high blood sugar level). Having this 3:1 ratio of fat in the diet ensures that patients can achieve ketosis, despite this side effect. Another reason for this high ratio of fat is that most patients with brain tumors have seizures. Fat provides nine calories per gram, whereas carbohydrates and protein have four calories per gram. Thus, fat provides a steadier stream of energy, leading to changes in neurotransmitter concentrations within the brain as well as gut microbiota variations, and creates a less favorable environment in the brain to have a seizure. Lastly, if planned correctly, having most of the fat coming from mono- and polyunsaturated fatty acids, also known as omega-3s and omega-6s, can help reduce the inflammation, including cerebral edema or brain swelling these patients can experience.
Thus far, the studies that have the most support for the ketogenic diet as a cancer therapy are mainly for brain tumors. There has been a plethora of compelling evidence from cancer biologist and brain cancer researcher Dr. Adrienne Scheck, and her lab is looking at if and how the ketogenic diet sensitizes malignant glioma cells to be killed and saves normal cells during chemotherapy and radiation.
Additionally, Dr. Thomas Seyfried has been studying the ketogenic diet and its effects on epilepsy and brain tumors for over 20 years. He has published over 20 articles on the subject, with the most recent case series published looking at a 38-year-old male with glioblastoma using the diet along with other metabolic therapies, who has stabilized his disease for 3 years. The diet is now currently being investigated in endometrial cancer, breast cancer, and other advanced cancers. There is no evidence to date that supports using the ketogenic diet alone as a way to treat cancer.
As promising as the progress above sounds, there are several considerations to think of before starting this diet if you have a cancer diagnosis and are on active treatment. For instance, if you have a diagnosis of non-small cell lung cancer, esophageal, pancreatic, gastric cancer and/or are undergoing a stem cell transplant, your metabolism tends to be altered and you burn calories much faster than other cancer diagnoses. This can lead to rapid weight loss, which is dangerous when you have already lost weight or have trouble maintaining weight during cancer treatment. Weight loss is very common on the ketogenic diet. Also, pancreatic cancer and cancers of the bile duct and gallbladder tend to have fat malabsorption and consequently may not benefit from a ketogenic diet. There are also considerations if you are on treatment and have nutrition-impact side effects that may be hard to manage on the diet, such as diarrhea and nausea. Poor appetite and intake are common during cancer-treating therapies. Some people who do not eat regularly are prone to hypoglycemia, have a certain pancreatic neuroendocrine tumor, or are taking glucose lowering medications such as metformin, can experience very low blood sugars. This effect is enhanced on the diet and can be very dangerous.
So, what’s the skinny on this keto diet and cancer? In my opinion, you really have to take many different factors into consideration. Do you have a cancer diagnosis that is currently being researched for the ketogenic diet or is there any research to support it? Have you recently lost or gained weight unintentionally? Are you having side effects from your treatment that has impacted your eating? Are you in survivorship? I encourage anyone with cancer or who has had cancer and are thinking about utilizing the ketogenic diet as an adjunct to their treatment plan to speak with their healthcare provider, oncologist, and registered dietitian about it, and to avoid doing the diet without proper supervision.
L.J. Amaral, M.S., R.D., CSO, is board certified in oncology nutrition. Amaral attended the University of Connecticut where she obtained a Bachelor of Science in nutritional science and went on to get her Master of Science in clinical nutrition and dietetics from NYU while subsequently completing her internship to become a registered dietitian at Memorial Sloan Kettering Cancer Center in Manhattan. She is currently located in the outpatient cancer center at Cedars-Sinai in Los Angeles, CA as a clinical and research Dietitian, and is researching the efficacy of the Ketogenic Diet as a therapy for CNS malignancies. Amaral specializes in cancer nutrition during treatment, for survivorship, for cancer prevention, and specifically, in therapeutic Ketogenic diets.