Ketogenic (or very-low-carbohydrate) diets have been employed since the 1920s as nonpharmacologic therapies for epilepsy and, in some instances, have obviated the need for medication for that disease. Since the 1960s, the ketogenic diet has become better known as a means of managing obesity. This was popularized further in the 1970s by the Atkin’s weight loss diet for the general public. More recently, research provided preliminary evidence for the ketogenic diet’s therapeutic potential against diverse illnesses such as diabetes, heart disease, polycystic ovary disease, and cancer.
Metabolic Effects
The distinguishing feature of the ketogenic diet is its drastic reduction of dietary carbohydrates to 20 grams per day in the initial phase, and to 50 grams per day thereafter, along with a corresponding increase in dietary protein and fat.1 Carbohydrate restriction decreases insulin secretion and reduces fat formation and accumulation—hence, the diet’s effectiveness in weight loss.
The human central nervous system (CNS) uses glucose as a primary fuel source. After approximately 3 to 4 days of pronounced carbohydrate restriction, the CNS must obtain an alternative source of fuel. Ketone bodies, formed in the liver by the process of ketogenesis, become that alternate source. The defining characteristics of physiologic ketosis include the presence of ketone bodies in the urine and blood (ketonuria and ketonemia) and a sweet breath odor resulting from the elimination of acetone, the metabolic byproduct of ketogenesis, from the lungs.1
Cancer Connection
Otto Warburg was the first to observe abnormalities in cancer cell energy metabolism in which cancer cells, unlike their normal counterparts, produce energy by a high rate of glycolysis followed by lactic acid fermentation, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate, even in the presence of oxygen.2,3 This phenomenon is characteristic of many but not all malignancies.
Glycolytic or glucose-dependant malignancies also overexpress glucose transporter-1, which assists the increased glucose uptake that is required to meet the energy needs of these cancer cells.4 Positron-emission tomography technology employs fluoro-2-deoxyglucose because it undergoes a similar transport as glucose and is used in the diagnosis, staging, and treatment of cancers with increased uptake of glucose.5
The role of insulin and insulin-like growth factor (IGF)-1 in cancer is also an area of active research. Most cancer cells express insulin and IGF-1 receptors. Insulin has a demonstrated ability to promote mitogenesis and also may be involved in promoting other cancer-related mechanisms such as antiapoptotic signaling, proliferation, invasion, angiogenesis, and metastasis.
In addition to these direct actions, insulin can act indirectly via IGFs by decreasing hepatic production of IGF-binding proteins 1 and 2. This increases circulating levels of IGF-1, which in turn also promotes mitogenic and antiapoptotic activity. Insulin increases the synthesis of IGF-1 in the liver while simultaneously decreasing IGF binding proteins 1, 2, and 3.
Many studies have implied, without solid proof, that IGF-1 initiates and spreads cancer, as IGF-1 stimulates cell proliferation. Recent evidence also suggests that dairy products increase circulating IGF-1. It is not clear whether this is from absorption of IGFs already present in cow’s milk, or if certain amino acids in the dairy proteins casein and whey upregulate IGF-1 expression or prevent its clearance from the body.6
An emerging relationship is coming to light among carbohydrates, insulin, IGF-1, IGF binding proteins, and cancer initiation, promotion, and proliferation. These findings are the foundation of the hypothesis that a ketogenic diet decreases the insulin response and might delay the progression of certain cancers. The published evidence to date is preliminary.7
Human Studies
Both low-carbohydrate and ketogenic diets have been shown to reduce tumor size in mice.8,9 Recent research provides some evidence that the diet may delay cancer progression in humans.
A 1995 paper published in the Journal of the American College of Nutrition examined two case reports of female pediatric oncology patients with astrocytoma. These children were placed on a ketogenic diet, and their diets were supplemented with medium-chain triglycerides, an easily digested form of oil that was added to shakes.
The study demonstrated that glucose uptake at the tumor sites was significantly decreased. Moreover, one of the children exhibited marked clinical improvement in skill development and mood. She remained on the ketogenic diet for 12 months with no disease progression. The authors of the study stated that they did not believe the diet would be a replacement for standard cancer treatment, but suggested that their results raised interesting clinical possibilities.10
Several case reports suggest that the ketogenic diet may reduce tumor progression, particularly in brain malignancies.12,13 As of this writing, no randomized controlled trials of the very-low-carbohydrate ketogenic diet have been conducted in patients with cancer. Studies to date have been pilot trials that focused on safety and feasibility.14
Recently, a paper by Fine et al demonstrated that inhibition of insulin by way of the ketogenic diet may be a possible adjuvant treatment for patients with cancer. In this pilot study of nine patients with various cancer diagnoses and preexisting rapid disease progression, the five subjects who exhibited threefold or higher ketosis markers had stable disease or partial remission compared to those with continued disease progression.15
Studies are underway to further examine the potential of the ketogenic diet in the treatment of cancer (for numerous examples, see www.clinicaltrials.gov). Research conducted to date clearly indicates the need for well-designed randomized trials to further explore the role that diet might play in cancer prevention, initiation, progression, management, and treatment.
Patient Perceptions
The general public is aware of the ketogenic diet, especially via its popular incarnation as the Atkins weight-loss approach. Over the past few decades, many have experimented with this diet in efforts to achieve weight management goals, as evidenced by the popularity of the Atkins weight loss books.
Today, many cancer patients are familiar with the ketogenic diet and its possible role as an adjuvant cancer treatment. An Internet search leads patients to articles by practitioners who advocate for the diet’s application in cancer treatment. Some Internet sites describe ways to self-monitor blood sugar and ketone bodies.
Savvy patients also visit scientific websites such as clinicaltrials.gov, where they read about ongoing and planned research. A problem faced by oncologists and other clinicians is how to respond to patient inquiries about the diet as a potential anticancer approach.
Patients may decide to pursue the ketogenic diet on their own, assuming that, since it is “only” a diet, it can do little harm. However, patients undergoing chemotherapy may be at risk for malnourishment due to the side effects associated with their treatment.16 Introducing a restrictive diet may be potentially harmful.
Patients who are tolerating cancer treatment well or who are on a break from treatment may also be at risk for harmful effects from a ketogenic diet. The concern here is that the longer-term effects of a high-fat, very-low-carbohydrate diet that maintains a state of ketosis are unknown.
Given the absence of solid data on the merits and potential negative consequences, patients should pursue this diet only via participation in a clinical trial. ■
Disclosure: Drs. Garrity and Cassileth reported no potential conflicts of interest.
References
1. Paoli A, Rubini A, Volek JS, et al: Beyond weight loss: A review of the therapeutic uses of the very-low-carbohydrate (ketogenic) diets. Eur J. Clin Nutr 67:789-796, 2013.
2. Warburg O: On the origin of cancer cells. Science 123:309-314, 1956.
3. Warburg O: On respiratory impairment in cancer cells. Science 124:267-272, 1956.
4. Hanahan D, Weinberg RA: Hallmarks of cancer: The next generation. Cell 144:646-674, 2011.
5. Nutt R: 1999 ICP Distinguished Scientist Award. The history of positron emission tomography. Mol Imaging Biol 4:11-26, 2002
6. Crowe FL, Key TJ, Allen NE, et al: The association between diet and serum concentrations of IGF-1, IGFBP-1, IGF-BP2, IGFBP-3 in the European Prospective Investigation Into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev 18:1333-1340, 2009.
7. Klement RJ, Kammerer U: Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutr Metab (Lond) 8:75, 2011.
8. Ho VW, Leung K, Hsu A, et al: A low carbohydrate, high protein diet slows tumor growth and prevent cancer initiation. Cancer Res 71:4484-4493, 2011.
9. Otto C, Kaemmerer U, Illert B, et al: Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer 8:122, 2008.
10. Nebeling LC, Miraldi F, Shurin SB, et al: Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: Two case reports. J Am Coll Nutr 14:202-208, 1995.
11. Zuccoli G, Marcello N, Pisanello A, et al: Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case report. Nutr Metab (Lond) 7:33, 2010.
12. Seyfried TN, Marsh J, Shelton LM, et al: Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Res 100:310-326, 2012.
13. Zhou W, Mukherjee P, Kiebish MA, et al: The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond) 4:5, 2007.
14. Schmidt M, Pfetzer N, Schwab M, et al: Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer. Nutr Metab (Lond) 8:54, 2011.
15. Fine EJ, Segal-Isaacson CJ, Feinman RD, et al: Targeting insulin inhibition as a metabolic therapy in advanced cancer: A pilot safety and feasibility dietary trial in 10 patients. Nutrition 28:1028-1035, 2012.
16. Huebner J, Marienfeld S, Abbenhardt C, et al: Counseling patients on cancer diets: A review of the literature and recommendations for clinical practice. Anticancer Res 34:39-48, 2014.
Integrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York.
The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and maintains a free website—About Herbs (www.mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 268 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings.
In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http://itunes.apple.com/us/app/about-herbs/id554267162?mt=8.
