Ketogenic Diet
Also known by these names
- Classical Ketogenic Diet 4:1
- Low glycemic index diet
- Medium chain triglyceride (MCT) diet
- Modified Atkins Diet
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Key Points
- This therapeutic diet was designed to induce ketosis and deprive cancer and cancer-associated stromal cells of glucose for energy production.
- BCCT’s interest in this therapy derives from preclinical animal studies and published case studies showing that a ketogenic diet may reduce tumor growth and improve survival.
- Limited human studies are available, most of which were not designed to measure effectiveness.
- Risk of nutrient deficiencies, unwanted weight loss and other potential side effects suggest using KD only under qualified medical supervision.
- Dietitian or qualified clinical nutritionist monitoring and support are suggested to improve adherence and outcomes.
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The ketogenic diet (KD) is becoming attractive to oncology clinicians and patients as a potential anticancer therapy. The goal is to alter the metabolism of cancer cells and their associated stromal cells by decreasing glucose and increasing ketones as available energy sources. KD can be implemented either with calorie restriction or as an isocaloric diet, with no change in total calories from the patient's previous diet.
While isocaloric KD may be somewhat beneficial, caloric restriction is considered an important component of an anticancer KD. Caloric restriction supports the body’s retention of ketones and also lowers caloric drivers of cancer growth pathways.
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Both a reasonable rationale and some encouraging evidence support its use in cancer, originating with malignant glioblastoma. However, researchers vary in their conclusions about KD’s safety and effectiveness for any single cancer diagnosis or as an adjunct therapy.
Increasing anecdotes of clinicians recommending and/or patients deciding to try KD without adequate assessment, individualization, education, monitoring and ongoing support raise concerns.
Ketogenic diets are medically regimented, high in fat, moderate in protein and low in carbohydrates. The goal of using KD in cancer is to reduce the energy production of cancer cells as well as tumor-associated stromal cells, thereby decreasing cancer growth and spread.
KD has been studied primarily in malignant glioblastoma. To date, few clinical trials using an isocaloric ketogenic diet as a therapy for cancer patients have been conducted. No clinical trials have been published to date on calorie-restricted KD.
While some reviewers conclude that insufficient clinical evidence supports recommending KD for any single cancer diagnosis or as an adjunct therapy, others suggest that even with limited human studies, animal studies “show that KD presents a viable option as an adjunct therapy for cancer” and can be a good option to complement other therapies, "depending on the situation and the extent of the disease.”
Treating the Cancer
Working against cancer growth or spread, improving survival, or working with other treatments or therapies to improve their anticancer action
Anticancer Action
Clinical Evidence
Case and pilot studies of the KD in cancer in humans:
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- Two pediatric patients with advanced glioma successfully achieved ketosis and had a reduction of glucose uptake on PET scans, with a significant clinical improvement in one patient.
- A 65-year-old with glioblastoma multiforme received KD both before and along with radiation and chemotherapy. Imaging studies suggested tumor regression, although MRI evidence of tumor recurrence was found 10 weeks after suspension of strict KD therapy.
- Case studies of patients with breast cancer showed improvement or complete responses to ketogenic diets in combination with other therapies.
- Ten subjects completed 26 to 28 days of the study diet. The extent of ketosis was associated with stable disease or partial remission.
- In 16 patients with advanced metastatic tumors, KD was associated with positive results in tumor regression and improved blood parameters.
- According to a 2016 review, the "available completed clinical trials focused mostly on safety and feasibility of the KD in cancer patients, with for the most part favorable and encouraging results.”
In a 2017 review of human studies using the KD in cancer, the reviewers cite some important limitations of clinical trials to date:
- Most didn’t or couldn’t evaluate anti-tumor effects of the KD.
- Non-rigorous study designs, small sample sizes and marked variations in patient and disease characteristics make comparisons and conclusions difficult.
- 37 percent of those on the KD were able to follow the diet for the duration of the study.
- No two studies used the same dietary protocol.
- In some studies, registered dietitians didn’t supervise the patient’s diet.
In that same review, of the studies reporting anti-tumor observations:
- No correlations were found between clinical response and ketosis or glycemia.
- KD delivered through intravenous infusions showed no significant difference in tumor growth among three groups.
- Six (of 53) patients’ high-grade glioma treated with KD along with chemoradiotherapy and/or adjuvant chemotherapy produced no major complications, but too few patients were involved to make conclusions about survival or tumor growth.
Look Deeper
Inducing Ketosis: Countering the Warburg Effect; “Starving the Cancer”
Some cancer cells within tumors, as well as tumor-associated cells (such as fibroblasts and macrophages) undergo metabolic changes in response to hypoxia (low oxygen and oxidative stress) of the tumor microenvironment.
Read more A key alteration of these cells is to convert to a complete dependence on glucose for energy generation. These catabolic cells do not have intact mitochondria, and so normal energy production via citric acid cycling and oxidative phosphorylation is not available.
Cells with intact mitochondria can use various metabolic substrates including glucose, fatty acids, glutamine and even ketones to fuel energy production. Catabolic cancer cells and tumor associated stromal cells, on the other hand, lose the ability to make ATP in the mitochondria and instead rely solely upon metabolizing glucose via glycolysis in the cytoplasm to generate ATP. This is called the Warburg effect and is a known attribute of the tumor microenvironment. Thus a ketogenic diet, which severely limits the supply of glucose in favor of ketones ,can selectively starve these tumor cells.
Evidence suggests that some cancer cells appear less able to metabolize ketones compared with healthy cells, while other experiments show that some tumor cells are able to use ketones for energy. More recent preclinical research indicates that the impact of ketosis on cancer cells does not rely solely on the Warburg effect. The effects of ketosis may induce oxidative stress specific to cancer cells, which may potentiate the effect of chemotherapy and radiation.
Typical Western diets high in refined carbohydrates provide this glucose substrate as well as promote the insulin pathway, releasing growth factors that are associated with promoting cancer development and progression. KD is one potential means of minimizing dietary sources of carbohydrates and instead supply fats as the primary energy substrate.
Reverse Warburg Effect: Cancer Cells Adapt
More recently, researchers have proposed the reverse Warburg effect.
As tumor-associated cells such as fibroblasts and immune cells struggle under the highly oxidative tumor environment, these cells lose the ability to retain oxidative phosphorylation and, instead, revert to glycolysis for energy production and start to undergo autophagy, a process of self-digestion. The glycolysis and autophagy generate many energy-rich substrates such as fatty acids, lactate, and ketones which these tumor-associated cells release. These substrates are then taken up by growing (anabolic) cancer cells as fuel. In this way, tumor associated cells essentially feed growing cancer cells, the reverse Warburg effect.
In lab studies researchers have found that human breast cancer cells with an enzyme capable of re-using ketone bodies used nearby ketogenic fibroblasts to fuel their growth. The authors conclude that ketone production and re-utilization drive tumor progression and metastasis.
Huebner et al. note: “In vitro data showed that cancer cells not only adapt to the situation but develop mutations and characteristics of stem cells. One hypothesis is that the [ketogenic] diet puts the tumor under stress and thus selects for resistance and malignancy. In an experiment on mice, the tumors in the diet-treated group initially grew less but later tumor growth accelerated and exceeded that of the control group.”
Researchers propose that the Warburg and reverse Warburg effects are not totally competitive, but rather reflect the ability of cancer cells to use different metabolic substrates depending upon what is available and what mutations are present.
Yaojie et al. suggest that the glycolytic pattern is not the only way cancer metabolizes glucose, and therapeutics including the ketogenic diet targeting glycolysis in cancer patients have not always had positive responses.
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Lab and Animal Evidence
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Preclinical animal studies indicate a ketogenic diet may reduce tumor growth and improve survival in these cancers:
- Malignant glioma
- Prostate cancer .
- Colon cancer
- Gastrointestinal cancer
- Slowed mammary tumor growth and increased tumor latency in mice, and this effect was increased when mice were also treated with metformin.
- Human breast cancer cells with an enzyme capable of re-using ketone bodies used nearby ketogenic fibroblast cells to fuel their growth—ketosis was not successful in treating the cancer.
Enhancing Treatment
Lab and Animal Evidence
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- In animal model studies, KD acted synergistically with radiation, chemotherapy, or both.
- In mice with metastatic cancer, KD combined with hyperbaric oxygen prolonged survival compared to using either therapy alone.
- Ketogenic diets decrease the initiation, progression and metastasis of cancer.
Managing Side Effects and Promoting Wellness
Managing or relieving side effects or symptoms, reducing treatment toxicity, supporting quality of life or promoting general well-being
Clinical Evidence
Ketogenic diets may have a protein-sparing effect that preserves lean body mass, reducing the risk or severity of cancer cachexia (muscle wasting).
A small pilot study of patients with advanced cancer suggests KD is suitable even for advanced cancer patients. The authors didn’t observe any severe side effects during the three-month study period and concluded that KD might improve aspects of quality of life, such as improved emotional function and less insomnia.
Some studies point to the low rate of acceptance of the KD dietary restrictions by patients, which may indicate negative impacts on quality of life.
Access
A naturopathic oncologist, integrative oncologist or integrative medicine physician may be able to determine which patients might benefit from following a KD. A dietitian or clinical nutritionist with experience with the KD is important to help patients properly implement a KD. Participating in a clinical trial of a ketogenic diet for your type of cancer may be another source for a program (see the side bar on this page).
Although people can follow a ketogenic diet on their own, the complexity of following the diet and the possibility of side effects (see the Cautions section below). Web resources and books are available regarding this diet, although they are not specifically tailored to people with cancer. These web resources and books do not include diet counseling or monitoring.
Cautions
KD is a complex diet to follow and may cause side effects, some serious (weight loss, nutrient deficiencies, and others listed at right). Many patients in studies discontinue the KD because of difficulty complying. Individualized close monitoring of the diet and ongoing education and support is recommended to improve safety and enhance patient’s completion of the KD.
Moreover, many of the ketogenic diets, as developed, focus on coconut oil, heavy cream, fatty red meats from conventionally-raised animals--including cured red meats such as bacon and sausage--to achieve high levels of fat. These are not recommended elements of a cancer-protective diet.
Adverse Events/Side Effects
Most studies don’t report serious side effects in cancer patients following a KD. However, Erikson, et al. advise, “As cancer patients are particularly susceptible to clinically significant malnutrition in the form of weight loss from both fat and muscle mass, this side effect should be most carefully evaluated before applying the diet in clinical settings.”
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Short-term effects in early implementation of this diet, usually transient and easily managed:
- Constipation
- Nausea and vomiting (most common)
- Gastro-esophageal reflux (heartburn)
- Acidosis (a condition resulting from blood being too acidic, especially due to dehydration)
- Hypoglycemia (low blood sugar)
- Dehydration
- Lethargy
- Weight loss: However, Fearon, et al. report that non-calorie-restricted ketogenic diets can slightly increase lean body mass
Other short-term effects observed in human studies:
- Anemia
- Decreased amino acid levels
- Functional changes in basal ganglia, granulocytes (neutrophils) and thrombocytes (platelets)
- Flu-like symptoms/fatigue
- Halitosis (bad breath)
- Hyperuricemia (high uric acid levels in blood)
- Hypocalcemia (low calcium in blood)
- Hypo- and hyperkalemia (low and high potassium levels in blood)
- Hypomagnesemia (low magnesium in the blood)
- Optic neuropathy (eye nerve damage)
- Pancreatitis
- Pedal (foot) edema
- Pruritis (itching)
Common long-term effects:
- Hyperlipidemia (high blood lipids): most common (although with conflicting reports of improvement in lipid profile)
- Hypercholesterolemia (high cholesterol) (although with conflicting reports of improvement in cholesterol)
- Nephrolithiasis (kidney stones)
- Cardiomyopathy (disease of heart muscle)
Other long-term side effects observed in human studies:
- Arteriosclerosis
- Carnitine deficiency (a metabolic state in which carnitine concentrations in plasma and tissues are less than the levels required for normal function of the organism)
- Irregular menses (menstrual periods)
- Osteopenia, osteoporosis and bone fractures
- Decreased growth in children and adolescents
- Vitamin, mineral and enzyme deficiencies
Integrative Programs, Protocols and Medical Systems
- Programs and protocols
- McKinney protocol for brain/nerve cancer
BCCT staff, November 13, 2017: BCCT advises that those considering a ketogenic diet consult with a clinician who has expertise in prescribing and monitoring ketogenic diets specifically for cancer patients. Additionally, work with a ketogenic-savvy dietitian or qualified clinical nutritionist for instructions and ongoing support. Look for “KD-savvy” professionals:
- Consider participating in a clinical trial, favoring those that provide a registered dietitian or qualified clinical nutritionist to provide education, monitoring and ongoing support.
- If considering trying the KD outside of the research setting,
- Find a doctor with expertise in ketogenic diets (such as an oncology naturopath or integrative oncologist) to determine if this is an appropriate therapy for you, set the plan and monitor your response. Favor clinicians who include a registered dietitian or qualified clinical nutritionist to counsel you.
- Work with a registered dietitian or clinical nutritionist experienced in KD counseling for the course of the KD therapy.
September 18, 2017: The potential that ketogenic fibroblasts may fuel cancer growth raises concern for some clinicians, such as naturopathic oncologist Lise Alschuler, ND, FABNO. Dr. Alschuler thinks a KD may benefit some cancer patients, but is concerned about using it long-term in someone with active cancer. She thinks there is a role for the KD, but that its usefulness may be limited in duration and may be dependent upon the type and nature of the patient’s tumor. Since not enough research is available yet to determine susceptible cancers, nor to guide dosing and duration of a ketogenic diet, Dr. Alschuler follows tumor markers and imaging to monitor the continued effectiveness of the KD. If tumor growth is detected, she takes the patient off of the KD and transitions them to a different, plant-based diet.
Non-cancer Uses of a Ketogenic Diet
Originally established as a non-drug treatment for intractable childhood epilepsy, the KD is being studied in other diseases including these:
- Diabetes mellitus
- Cardiovascular diseases
- Neurological diseases like Alzheimer’s and multiple sclerosis.
BCCT has not reviewed the effectiveness of this therapy for non-cancer uses.
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Written by Laura Pole, RN, MSN, OCNS; Lise Alschuler, ND, FABNO; and Nancy Hepp, MS; most recent update April 5, 2019. BCCT is grateful for the review of this document by our advisor Rebecca Katz, MS, director of the Healing Kitchens Institute.
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View All References
More Information
- Oncology Association of Naturopathic Physicians: Directory
- Nutritional Solutions
- ClinicalTrials.gov
- Winters N, Kelley JH. The Metabolic Approach to Cancer: Integrating Deep Nutrition, the Ketogenic Diet, and Nontoxic Bio-Individualized Therapies. Vermont: Chelsea Green Publishing. 2017.
- Kalamian M. Keto for Cancer. Vermont: Chelsea Green Publishing. 2017.
- Moss Reports (purchase required): Select from the list of cancers down the left side of the page for a report describing uses of conventional, complementary, alternative and integrative therapies related to that cancer. Ralph Moss is among the most knowledgeable and balanced researchers of integrative cancer therapies. The cost of his Moss Reports is not negligible, but many patients find them of considerable value. Moss is also available for consultations.
- Zick SM, Snyder D, Abrams DI. Pros and cons of dietary strategies popular among cancer patients. Oncology (Williston Park). 2018 Nov 15;32(11):542-7.
- Five to Thrive Live: Keto for Cancer
- Donald I. Abrams, MD, and Andrew T. Weil, MD: Integrative Oncology, 2nd Edition
- Dwight McKee, MD, editor: Clinical Pearls
- Barbara MacDonald, ND, LAc: The Breast Cancer Companion: A Complementary Care Manual: Third Edition
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