Cancer remains a significant global health challenge, necessitating the exploration of complementary approaches to enhance the efficacy of standard anticancer therapies. A healthy diet program is an essential strategy during cancer treatment. Recently, the ketogenic diet (KD) has emerged as a metabolic therapy in cancer treatment, targeting cancer cell metabolism rather than a conventional dietary approach. This article delves into the potential role of the ketogenic diet (KD) as an adjuvant therapy in cancer treatment, exploring its history, mechanisms of action, clinical evidence, and practical considerations for implementation, including a sample meal plan.
Introduction: Cancer and the Need for Complementary Therapies
Cancer, often termed "the sickness of the century," is a leading cause of mortality worldwide. The increasing number of cancer cases and the disease's ability to resist existing therapeutic and pharmacological approaches make it a significant threat. In 2020 alone, the American Cancer Society reported 1,806,590 new cancer cases and 606,520 cancer deaths in the United States. Conventional interventions like surgery, chemotherapy, hormonal therapy, radiation therapy, monoclonal antibodies, and tyrosine kinase inhibitors have shown success in eliminating some cancers, inducing regression, and inhibiting growth in others. However, these interventions have limitations, such as ineffectiveness in advanced stages of cancer and metastasis.
The metabolic differences between normal and cancerous cells have been recognized since Otto Warburg's discovery of the Warburg effect in the 1920s. Warburg hypothesized that cancer cells have irreversible damage in cell respiration and mitochondrial dysfunction, making them dependent on fermentation for ATP production. This understanding has led researchers to explore diet-based strategies as complementary therapies that target cancer cells' metabolic pathways. A ketogenic diet (KD) causes a metabolic shift from glycolysis into mitochondrial metabolism, the differential stress resistance phenomenon with high tumor control ability and lower normal-tissue complications, which makes the ketogenic diet an interesting dietary approach for cancer patients under supervision and follow up of a healthcare provider.
Historical Perspective of the Ketogenic Diet
The ketogenic diet's roots trace back to ancient times. Based on the Hippocratic collection, the only therapeutic measure against epilepsy was fasting. In the 5th century BC, complete fasting was prescribed and known to be effective. The ketogenic diet was established early in the 20th century as an approach to mimic the effects of fasting. Marie and Guelpa published a study on the effect of fasting in epileptic patients, which reported less severe seizures observed during such a treatment, without further detail.
Contemporary reports regarding fasting were also recorded early in the 20th century in the USA, with a report on a patient of Dr. Hugh W. Macfadden was a physical fitness cultist who established his first magazine, Physical Culture, in 1899, in which he directed the readers to maintain their health and to deal with sickness through diet and exercise; the magazine was widespread by the end of World War I. Macfadden emphasized fasting and his rationale was that much of the body’s energy is used in food digestion; as a result, if there is no food to digest, more energy could be used to recover health. Macfadden’s assistant, Dr. Conklin, adopted his method of using fasting to treat epilepsy in his practice, with results that drew other pioneers into epilepsy studies, such as H. Rawle Geyelin, who was an endocrinologist at the New York Presbyterian Hospital. Geyelin first reported his exposure to fasting as a treatment for epilepsy at the American Medical Association (AMA) conference in 1921. His report was based on an observation of a young cousin who had epilepsy for four years and in spite of multiple recommended treatments, the patient failed to respond and his seizures were not controlled. Consequently, Dr. Conklin subjected the child to four periods of fasting over several months and observed the cessation of seizures after the second day of fasting; no seizures were observed over two years of follow-up. Dr. Geyelin began using the same fasting strategy after observing two other patients who had apparently been cured of epilepsy by Dr. Conklin, but initially used different fasting periods and finally decided to use a 20-day fasting period. Geyelin suggested that fasting can almost always be used as a method to clear a clouded mentality. This observation has received strength in recent years, after reports of an association between developmental and behavioral improvements and the ketogenic diet.
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Initially, Dr. News of Conklin’s successful therapy had spread to others in conventional neurology practices even before he published his results. Moreover, Conklin’s fasting therapy was mentioned by Dr. Penfield and his colleague Dr. Erickson in their textbook on epilepsy published in 1941. Earlier in 1919, Dr. John Howland, professor of pediatrics at Johns Hopkins, used a grant from Charles Howland to determine the first laboratory to establish whether there was a scientific basis for the positive results of starvation treatment in epilepsy, and by 1937, it was used to support research on the KD.
Moreover, the first two physicians who confirmed and explained the effects of fasting on epilepsy were reported by Lennox. The first was Dr. James Gamble, who was recruited by Howland; in 1915, he reported a study on the acid-base balance of two children on a fasting program. Furthermore, Gamble’s report established a model for clinical research and produced the fundamentals for pediatric electrolyte physiology and nephrology fields. In addition, he also reported an increase of calcium elimination in patients on the ketogenic diet, which necessitated calcium supplements. H. Rawle Geyelin was the other doctor who was also recruited by Howland and presented his findings on fasting as a treatment of epilepsy at the 1921 AMA conference. Unfortunately, his data were never published, but he informed Lennox that in the long term, no seizures occurred in 19% of the treated children, while this was observed only in 0.5% for the treated adults.
Dr. Stanley Cobb, an associate professor of neuropathology at Harvard Medical School with the assistance from a colleague, W. G. Lennox, studied a selected group of five patients during a fasting period of two weeks, and throughout the study, chemical assays were performed on the blood and urine of both the subjects and controls. All the analyses showed an increase in blood acidosis and serum uric acid that was usually evident after two or three days of fasting and was accompanied by a decrease in seizures.
These reports on the efficacy of fasting triggered a surge of clinical and research activity with a rise in theories that tried to offer an explanation for the therapeutic efficacy of starvation. Dehydration, ketosis, and acidosis were all put forward as mechanisms that may explain the efficacy of fasting. Similarly, in 1921, at the same time of the Cobb and Lennox study, in a review article about diet adjustments and diabetes, Woodyatt reported that starvation in normal subjects leads to the production of acetone, acetic acid, and beta hydroxybutyric acid, as well as being on a diet consisting of low carbohydrate content with a high fat content and that ketoacidosis appeared to be the immediate result of the oxidation of certain fatty acids in the absence of a sufficient proportion of ‘oxidizing’ glucose.
Simultaneously and possibly grounded on the work summarized by Woodyatt, Dr. Wilder at the Mayo Clinic suggested that to obtain the benefits of fasting, ketone bodies and thus ketonemia can be produced from fat and protein when there is variance between the amount of fatty acids and the amount of sugar burning in the tissues. The possibility to stimulate ketogenesis by consuming diets rich in fat and low in carbohydrate was well known. Therefore, it was proposed to test the effects of such ketogenic diets on epilepsy. Moreover, Wilder also suggested that a ketogenic diet could be maintained for a much longer period than fasting with same effectiveness and eventually he was the first to formulate the ketogenic diet term. Later, Peterman with pediatricians eagerly acted on Wilder’s suggestion, and in 1924, Peterman reported the calculations and effectiveness of the KD from the Mayo Clinic. The ketogenic diet being used today is identical to Peterman’s KD, which is composed of 1.0 g of protein per kilogram of body weight for children, 10 to 15 g of carbohydrate per day, and fat as the remainder of the calories.
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The first prospective study, “the effects of the KD on development and behavior was completed by M. B. Pulsifer and colleagues” in 2001, revealed statistically significant behavioral improvements in social functioning and attention in children with intractable seizures, thus confirming the earlier observations of Peterman. Later reports from Talbot et al. in 1926 and from McQuarrie and Keith in 1927 followed those preliminary reports. Talbot reported the following: “In 1921, the Massachusetts General Hospital children’s medical service began a study on the treatment of idiopathic epilepsy. The first method used was the fasting recommended by Conklin”. Consequently, the ketogenic diet that was carried out by the Mayo Clinic, which was described by Dr. Peterman, was adopted in 1924 by MGH. Moreover, Talbot, by the year 1928, had already used different compositions of ketogenic diets in his practice and reported that in order the achieve the best therapeutic outcomes in epilepsy, the ratio of 4:1 must be approached, which is acknowledged as the most common composition for the ketogenic diet in modern time.
The ketogenic diet was extensively utilized in the 1920s and throughout the 1930s, up until the discovery of the drug diphenylhydantoin by Merritt and Putnam in 1938, which lead to the withdrawal of researchers’ interest from the ketogenic diet mechanism of action and effectiveness to that of new antiepileptic drugs (AEDs). This marked the beginning of a new age of medical therapy for epilepsy, and the ketogenic diet was given up since medications were easier to administer and new chemicals were always at hand. Furthermore, in a pediatric neurology manuscript in 1937, Ford reported that the ketogenic diet was difficult to use, inflexible, and expensive, and as more AEDs became available, use of the ketogenic diet was phased out. In addition, sodium valproate was introduced and this branched-chain fatty acid was believed to be effective in the treatment of children with seizures of Lennox-Gas taut syndrome who were previously placed on the diet; thus, the diet could no longer be defended. These findings resulted in a decline in the number of dieticians training for the initiation and maintenance of the diet.
Although the ketogenic diet use greatly declined over the years, an NBC-TV Dateline program aired on October 1994 reinvigorated attention to the treatment and was based on the true story of a two-year-old, Charlie, who suffered from generalized tonic, myoclonic, and tonic-clonic seizures. Charlie’s father, while researching treatments for epilepsy on his own, found a reference that linked the ketogenic diet to Johns Hopkins, to which Charlie was transported and was initiated on the diet, after which he became seizure-free and also displayed developmental progress.
In the 1920s and 1930s, all preliminary reports that verified the effectiveness of the ketogenic diet were retrospective reports. Unfortunately, some of these included a small number of patients and few clinical details and it was often not clear what should be regarded as a “good” or “partial” response to the ketogenic diet. Despite these limitations, the literature supports that seizure control can be improved by adopting the ketogenic diet in some children. In later years, specifically in 1999, Sirven et al. carried out a modern, prospective study to assess the ketogenic diet efficacy and safety in treating adult patients with intractable, symptomatic partial, or generalized epilepsy.
Understanding Cancer Metabolism and the Warburg Effect
The Warburg effect, a key concept in cancer metabolism, describes the phenomenon where cancer cells preferentially utilize glycolysis (anaerobic glucose metabolism) for energy production, even in the presence of oxygen. This is in contrast to normal cells, which primarily use oxidative phosphorylation (aerobic metabolism) in the mitochondria.
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This metabolic shift provides cancer cells with several advantages:
- Rapid ATP Production: Glycolysis, though less efficient in ATP production per glucose molecule, is faster, allowing cancer cells to meet their high energy demands for rapid proliferation.
- Production of Building Blocks: Glycolysis intermediates are diverted into biosynthetic pathways, providing the necessary building blocks for cell growth and division.
- Acidic Microenvironment: Glycolysis produces lactic acid, which creates an acidic microenvironment that promotes tumor invasion and metastasis.
Mechanism of Action of the Ketogenic Diet as a Cancer Therapy
The ketogenic diet (KD) is a high-fat, very-low-carbohydrate diet with adequate amounts of protein. The macronutrient distribution of KD is about 90% fat, 2% carbohydrate, and 8% protein. This is achieved by following the standard fat to carbohydrate and protein ratio of 4:1 and 3:1, respectively. Another recent study has suggested that the clinical use of KD is composed of at least 80% fat with a KD ratio of 2:1 to 3:1.
The ketogenic diet exerts its potential antitumor effects through several mechanisms:
- Reduced Glucose Availability: By drastically reducing carbohydrate intake, the KD lowers blood glucose levels, depriving cancer cells of their preferred fuel source.
- Ketone Body Production: The liver converts fats into ketone bodies (beta-hydroxybutyrate, acetoacetate, and acetone), which become an alternative energy source for normal cells. Some cancer cells cannot efficiently utilize ketone bodies for energy, leading to energy stress and impaired growth.
- Metabolic Stress: The shift from glucose to ketone body metabolism creates a metabolic stress environment that is unfavorable for cancer cell survival and proliferation.
- Reduced IGF-1 Levels: The low intake of glucose accompanied by high fat and adequate protein content causes a reduction in IGF1 and an increase in ketosis or ketone body production in human clinical studies.
- Carbohydrate Restriction: Moreover, multiple studies have also supported that carbohydrate restriction has a protective effect against cancer in animal models.
The use of a ketogenic diet was reported to show improvement in a patient condition in one of two girls with advanced astrocytoma, and this observation may be explained on the basis that brain tumors are incapable of using ketones as an energy source in comparison with healthy brain tissue.
Clinical and Experimental Studies on KD as an Anticancer Therapy
The application of ketogenic diets in cancer therapy has been explored in various clinical and experimental studies.
- Animal Studies: Numerous animal studies have demonstrated the potential of KD to slow tumor growth and improve survival rates in various cancer types, including brain, prostate, colon, and lung cancers.
- Human Studies: While human studies are limited, some clinical trials have shown promising results, particularly in patients with brain tumors (gliomas). These studies suggest that KD may be safe and feasible, with some evidence of improved tumor control and quality of life.
- Combination Therapy: KD has also been investigated as an adjuvant therapy in combination with conventional cancer treatments like chemotherapy and radiation therapy. Some studies suggest that KD may enhance the efficacy of these treatments and reduce side effects.
- eFT508 Drug Interaction: Ruggero’s team first uncovered how a protein known as eukaryotic translation initiation factor (eIF4E) changes the body’s metabolism to switch to fat consumption during fasting. They found that a new cancer drug called eFT508, currently in clinical trials, blocks eIF4E and the ketogenic pathway, preventing the body from metabolizing fat.
Potential Benefits and Risks of Ketogenic Diet in Cancer Patients
While the ketogenic diet shows promise as a potential anticancer therapy, it is essential to consider both its benefits and risks.
Potential Benefits:
- Tumor Growth Inhibition: KD may slow tumor growth by reducing glucose availability and creating a metabolically unfavorable environment for cancer cells.
- Enhanced Treatment Efficacy: KD may enhance the efficacy of conventional cancer treatments like chemotherapy and radiation therapy.
- Improved Quality of Life: Some studies suggest that KD may improve quality of life, reduce fatigue, and improve mood in cancer patients.
- Weight Loss: A Ketogenic Diet CAN be useful for weight loss and particularly loss of central adiposity and visceral fat.
Potential Risks:
- Nutrient Deficiencies: The ketogenic diet lacks fibre, fruit and vegetables. It can also lead to low levels of calcium, vitamin D and other salts (electrolytes).
- Kidney Stones: This diet can cause kidney stones in people with a family history of the condition.
- Gastrointestinal Issues: There are potential side effects though, including gastrointestinal upset, nausea, constipation, excess strain on the kidneys, hypoglycaemia, micronutrient deficiencies and unwanted weight loss.
- Muscle Loss: In some individuals, KD may lead to muscle loss if protein intake is not adequate.
- Cachexia acceleration: In mice with pancreatic and colorectal cancer, keto accelerates a lethal wasting disease called cachexia. Patients and mice with cachexia experience loss of appetite, extreme weight loss, fatigue, and immune suppression.
Practical Considerations for Implementing a Ketogenic Diet
Implementing a ketogenic diet requires careful planning and monitoring to ensure safety and efficacy.
- Consultation with Healthcare Professionals: It is crucial to consult with a doctor and a registered dietitian before starting a KD, especially for cancer patients.
- Individualized Approach: The KD should be tailored to the individual's specific needs, cancer type, treatment plan, and overall health status.
- Macronutrient Ratios: Adhere to the recommended macronutrient ratios (high fat, very low carbohydrate, moderate protein) to achieve and maintain ketosis.
- Nutrient-Dense Foods: Choose nutrient-dense, whole foods to meet nutritional needs and minimize the risk of deficiencies.
- Monitoring Ketone Levels: Regularly monitor ketone levels using urine strips, blood ketone meters, or breath analyzers to ensure adequate ketosis.
- Hydration and Electrolyte Balance: Maintain adequate hydration and electrolyte balance by consuming plenty of water and supplementing with electrolytes as needed.
- Gradual Transition: Gradually transition into the KD to minimize side effects like the "keto flu."
Sample Ketogenic Meal Plan for Cancer Patients
This sample meal plan is designed to support overall health with nutrient-rich, low-carb, high-fat foods, focusing on meals that are easy to digest and nourishing for individuals undergoing cancer treatment.
Foods to Eat:
- Non-Starchy Vegetables: Leafy greens, broccoli, cauliflower, asparagus
- Healthy Fats: Avocado, olive oil, coconut oil, fatty fish (omega-3s)
- Lean Proteins: Chicken, turkey, fish, tofu
- Low-Sugar Berries: Strawberries, blueberries, raspberries (in moderation)
- Fermented Foods: Yogurt, sauerkraut, kimchi (for gut health)
- Bone Broth: Nutrient-rich broth for hydration and minerals
- Nuts and Seeds: Almonds, walnuts, flaxseeds
Foods to Avoid:
- High-Sugar Foods: Minimize intake of sugary items to control blood sugar levels.
- Processed Meats: Limit processed and cured meats with additives.
- Processed Foods: Avoid highly processed and refined foods.
- Excessive Dairy: Limit dairy intake and choose low-sugar options.
- High-Carb Foods: Minimize consumption of high-carb items for ketosis.
- Alcohol: Consume alcohol in moderation, if at all.
- Artificial Additives: Avoid artificial colors, flavors, and preservatives.
- Vegetable Oils: Opt for healthy fats like olive oil over vegetable oils.
Meal Plan Overview:
This keto meal plan emphasizes low-carb, high-fat foods that may help manage energy levels and reduce inflammation during treatment. This guide is a valuable resource for integrating ketogenic eating into a cancer care regimen, focusing on meals that nurture and strengthen. It also includes easy keto meals for cancer patients, designed to be both simple to prepare and gentle on the digestive system.
- Breakfast: Scrambled eggs with spinach and avocado
- Lunch: Salad with grilled chicken or fish, olive oil and vinegar dressing, and a side of mixed greens.
- Dinner: Baked salmon with roasted broccoli and cauliflower.
- Snacks: A handful of almonds or walnuts, a small serving of low-sugar berries, or a cup of bone broth.
Grocery List:
- Dairy & Eggs: Eggs, full-fat Greek yogurt
- Fresh Groceries: Spinach, mushrooms, avocado, lemon, mixed greens, broccoli, cauliflower
- Meats: Chicken breast, turkey
- Fish & Seafood: Salmon
- Plant-Based: Tofu
- Dry Goods: Nuts, seeds
- Spices & Sauces: Olive oil
Budgeting Tips:
- Eggs, spinach, and mushrooms can be bought in bulk.
- Olive oil, salmon, and mixed greens are often cheaper when purchased in larger quantities.
- Avocado, lemon, and chicken breast can be more economical in bulk.
- Broccoli, cauliflower, and full-fat Greek yogurt are also more affordable in larger sizes.
The Importance of a Balanced Approach
It's crucial to approach the ketogenic diet as part of a holistic cancer care plan. Complementary therapies are meant to be used alongside conventional medical treatments to help patients feel more in control. While some individual diets claim to cure cancer or have certain benefits, it is important to maintain a balanced diet and consult with a dietitian about any specific dietary needs or problems with eating.