Metabolic therapies in Cancer Treatment: A Research Summary

MaxLove Project is committed to evidence-based integrative therapies that help fight pediatric cancer. One of the most important of these metabolic therapies like the nutritional ketosis. Below, we provide summaries of important research publications on the role of nutritional ketosis and blood sugar control in cancer treatment. The goal of this research summary is that parents and caregivers will be able to use it to discuss metabolic therapies with their medical team.

TERMINOLOGY:

Carbohydrate: The quickest source of energy for the body. They are commonly characterized as sugar, starch and cellulose. Foods generally classified as carbohydrates are: sugar, starchy vegetables, grains, milk and fruit. All carbohydrates reduce to some form of glucose in the body. Sugar and starch forms affect blood glucose levels, but cellulose (fiber) does not. 

Glucose: Blood sugar. A primary fuel for our bodies' energy needs. In cancer cells, there is a much higher uptake of glucose.

Protein: Sequences of amino acid that aid in almost every bodily function. There are a variety of types of protein such as enzymes and antibodies, but protein from food is categorized as animal and plant protein. Animal proteins (meat, poultry, fish, milk, and cheese) are considered high-quality protein by containing all the amino acids needed by the body. Plant proteins are considered low-quality proteins because they each lack one or more amino acids needed by the body making it a less efficient process in the body. 

Macronutrient: A nutrient needed in large amounts for proper growth and development. In the human body these are fat, protein, carbohydrate and macro minerals (calcium, phosphorus, magnesium, sodium, potassium, chloride). These minerals are sometimes included in macronutrient lists because although the amount needed for each bodily function is small, the number of bodily functions requiring these minerals is very high. 

Micronutrient: A nutrient needed in very small amounts for proper growth and development. These are all vitamins (water and fat soluble) and micro-minerals such as: iron, cobalt, chromium, copper, iodine, manganese, selenium, zinc, and molybdenum. 

Ketogenic Diet: A very low-carbohydrate, high-fat, adequate protein diet. Properly administered, it will decrease circulating glucose and increase ketone bodies, which are a good alternative source of fuel for our bodies and are produced when the liver breaks down fat.

Metabolism: The process of converting a fuel source into energy. Most often it refers to the body's mechanisms of converting the food and beverages we consume into energy, body tissue, waste, and fat (adipose tissue). 

Warburg Effect: Discovered by the German scientist and Nobel Prize winner Otto Warburg in the 1920s. It describes the unique characteristic of cancer cells to consume glucose at much higher rates and in a much different way than normal cells.

BROAD REVIEW ARTICLES (CHRONOLOGICAL ORDER)

Allen B., et al. (2014) Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biology, 2(4), 963-970.

In this review article, the authors review the ketogenic diet as a therapy that can be added to conventional cancer treatment. They briefly review mouse and human studies that have examined the KD in conjunction, but focus most of the article on the potential mechanisms of action in the ketogenic diet in cancer therapy. One potential mechanism is the difference in mitochondria (the cell’s “powerhouse”) between healthy cells and cancer cells. In cancer cells, mitochondria often show mutations and disfunctions. Ketogenic diets exploit this difference by placing stress on these cells with malfunctioning mitochondria. Healthy cells adapt just fine. Another potential mechanism is the difference in glucose (blood sugar) dependence between healthy cells and cancer cells. Cancer cells take in glucose at 30 to 43 times the rate that normal cells do. It’s this massive increase that allows PET scans to be effective at detecting cancer. But they don’t take in ketones at nearly the same rate or as efficiently. Bottom line: ketogenic diets allow the body to take advantage of many different mechanisms to make cancer cells less viable. 

Myers, A. P., & Cantley, L. C. (2012). Sugar free, cancer free? Nutrition, 28(10), 1036.

In this letter to the editor, two well known cancer researchers discuss the study by Eugene Fine, et al, which examined carbohydrate restriction in advanced cancer patients. They believe that the study is very provocative because it showed a strong negative association between ketosis and glucose uptake of tumors, as measured by PET scans. Bottom line: Dietary and pharmacological strategies for lowering glucose are promising new avenues for fighting cancer.

Klement, R. J., & Kämmerer, U. (2011). Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutrition and Metabolism, 8:75.

In this review, two German oncologists and cancer researchers review studies on cancer metabolism and dietary strategies for lowering blood glucose and insulin. They review the research on the Warburg effect, cancer metabolism, and the importance of glucose and insulin in cancer cell proliferation. They also describe potential mechanisms for cachexia and argue that a low-carbohydrate, high-fat (LCHF) diet that produces ketone bodies may inhibit cachexia. They also review and summarize the literature on ketogenic diets (KDs) and cancer, and find that the body of research supports vigorous testing on human subjects. Bottom line: a LCHF diet may suppress tumor growth while also inhibiting side effects of cancer and its conventional treatments.

Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009). Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science, 324(5930), 1029-33.

In this review article, the authors examine the Warburg effect, which describes the characteristic of most cancer cells to generate energy through aerobic glycolysis even in the presence of oxygen, which is inefficient, rather than mitochondrial oxidative phosphorylation, which is what normal cells do. The authors speculate that cancer cells exhibit the Warburg effect in order to proliferate faster, rather than aiming for efficient use of metabolic fuels. They conclude by calling for further research on fighting cancer through manipulating its distinct metabolic characteristics. Bottom line: cancer cells’ abnormal use of glucose provides a very attractive target for new anticancer therapies, diet included.

Blood Sugar (Glucose) and Cancer

Tieu MT, et al. Impact of glycemia on survival of glioblastoma patients treated with radiation and temozolomide. Journal of Neuro-Oncology. 2015;124(1):119-126.

Researchers compared glioblastoma patients with higher and lower average levels of blood sugar. They found that in patients with average blood sugar above 113 mg/dl survived 3 months less than patients with average blood sugar below 113 mg/dl. Even when the researchers factored in many treatment and patient characteristics all together, they found that average glucose was significant predictor of survival time. Bottom line: keeping blood sugar in a normal to low range may increase survival time in patients with malignant brain tumors.

Mathews EH, et al. Tumor cell culture survival following glucose and glutamine deprivation at typical physiological concentrations. Nutrition. 2014;30(2):218-227. 

Researchers looked at tumor cells in petri dishes to see how they would respond with 1) normal human levels of blood sugar and glutamine (a naturally occurring amino acid in the human body); 2) ketogenic levels of blood sugar and glutamine; and 3) zero levels of blood sugar and glutamine. At ketogenic levels, only 63% of tumor cells survived after 2 hours. Bottom line: Tumor cells are hurt by a sustained decrease blood sugar.

Derr RL, Ye X, Islas MU, Desideri S, Saudek CD, and Grossman SA. Association between hyperglycemia and survival in patients with newly diagnosed glioblastoma. J Clin Oncol. 2009;27(7):1082-6. doi:10.1200/JCO.2008.19.1098.

Researchers took many different measures of blood sugar from GBM patients and calculated the average blood sugar of each patient. They then divided all the patients into four different groups depending on their blood sugar level (lowest to highest). They then recorded average survival times for patients in each group and found that a clear association between blood sugar and survival time. The group with the lowest blood sugar survived the longest at 14.6 months, while the group with the highest survived the shortest at 9.1 months. That came out to a 57% increase in risk of dying for patients with very high blood sugar (>137 mg/dl). But even for patients with blood sugar in the normal range of 94 to 109 mg/dl, the risk of dying was raised by 29% when compared to those with blood sugar under 94 mg/dl.

McGirt, M. J., et al. (2008). Persistent outpatient hyperglycemia is independently associated with decreased survival after primary resection of malignant brain astrocytomas. Neurosurgery63(2), 286-91.

The records of 367 patients who had craniotomies for malignant astrocytomas were examined for outpatient hyperglycemia (>180 mg/dl). The researchers found that patients who had one or more readings of hyperglycemia had a median survival of 5 months, compared with patients with normal glucose levels who had a media survival of 11 months. Even when adjusted for age, tumor grade, resection status, and chemotherapy, researchers still found hyperglycemia to be independently associated with decreased survival time. Bottom line: high blood sugar decreases survival time in high-grade glioma patients. 

Spitz, D.R.. et al. (2006). Glucose deprivation-induced oxidative stress in human tumor cells: A fundamental defect in metabolism? Annals of the New York Academy of Sciences899(1), 349-362.

This in vitro study showed that glucose-deprivation damaged cancer cells more than normal cells. The authors present a theoretical model to explain the results and call for further research on metabolic strategies for fighting cancer. Bottom line: glucose deprivation may be an important therapy in damaging cancer cells.

Ketogenic Diets AND CANCER

Morscher RJ, et al. Combination of metronomic cyclophosphamide and dietary intervention inhibits neuroblastoma growth in a CD1-nu mouse model. Oncotarget. 2016. In press. 

Mice were separated into 5 different groups: 1) standard diet with no chemo (cyclophosphamide); 2) standard diet with chemo; 3) calorie-restricted standard diet with chemo; 4) ketogenic diet not calorie-restricted with chemo; and 5) calorie-restricted ketogenic diet with chemo. The researchers found all mice that received chemo did significantly better than the mice who did not. But they also found that mice on the experimental diets reacted significantly better to chemotherapy than mice on the standard diet. The best combination was the calorie-restricted ketogenic diet with chemo. ottom line: Combining ketogenic diets with chemotherapy may be a very effective strategy against neuroblastoma. 

Ma, D.C., et al. Ketogenic diet sensitizes FaDu human head and neck cancer xenografts to cisplatin as well as ionizing radiation combined with cetuximab (Conference Abstract). Cancer Research. 2015;75(15 Supplement):1177.

Researchers used mice with head and neck cancer and separated them into 4 groups 1) mice given chemotherapy (cetuximab and cisplatin) and fed normal mice food; 2) mice given chemo and fed a KD; 3) mice given chemo plus radiation and normal mice food; and 3) mice given chemo, radiation, and a KD. They found that mice given chemo plus KD did better than mice only given chemo. But the mice given chemo, radiation, and KD all together significantly outperformed all other groups. Bottom line: Combing the ketogenic diet with chemotherapy and radiation may be a very effective anti-cancer strategy.

Woolf EC, et al. The ketogenic diet enhances immunity in a mouse model of malignant glioma (Conference Abstract). Cancer Research. 2015;75(15 Supplement):1344.

Mice with malignant glioma were separated into two groups: one was given standard mice food and the other was given a ketogenic diet. The tumor cells in the mice on the KD showed several markers for reduced immune suppression (in other words, they couldn’t hide from the body’s immune system as well). Also certain immune cells showed better functioning. This led the authors to say that this study suggested that the KD improves the body’s immune response to cancer. Bottom line: One of the mechanisms of KDs is to increase the effectiveness of the body's immune system. 

Rossi AP, et al. The ketone body β-hydroxybutyrate increases radiosensitivity in glioma cell lines in vitro (Conference Abstract). Cancer Research. 2015;75(15 Supplement): 3346.

This group of researchers had previously shown that feeding mice with malignant gliomas a KD and giving them radiation led to a complete removal of the tumor for many of the mice. They wanted to see whether it was the ketones that were responsible for this remarkable effect. So, in this study, mouse glioma cells were tested in petri dishes. Groups of cells received different levels of ketones (specifically betahydroxybutyrate) and were given radiation. The researchers found that more tumor cells died under radiation if they were surrounded by ketones than if they did not. And the more ketones that were present, the more effective was the radiation. This led to the researchers to suggest that the ketones themselves could be a potential reason why the KD is therapeutically effective in radiation. Bottom line: Ketone bodies themselves may have a direct anti-tumor effect, especially with radiation therapy.  

Martuscello RT, A Supplemented High-Fat Low-Carbohydrate Diet for the Treatment of Glioblastoma. Clin Cancer Res. 2015. In press.

This study looks at the efficacy of a diet less stringent than the classical ketogenic diet but still ketone-producing. Called the “Supplemented High-Fat Low-Carbohydrate” (sHFLC) diet, it contains 60% of calories from fat, 30% of calories from protein, and 10% of calories from carbohydrates. They compared the sHFLC diet to the classical ketogenic diet and the normal diet in mice with glioblastoma (GB). They found that both sHFLC and the KD reduced tumor size and improved survival over the normal diet, and there was not a significant difference between sHFLC and KD in efficacy. This led the authors to suggest that the sHFLC diet is a viable alternative to the KD as an adjuvant cancer therapy. Bottom line: Patients may not have to do a calorie-restricted or classic ketogenic diet to get anti-cancer benefits. A more lenient supplemented high-fat, low-carb diet may be sufficient. 

Poff AM, et al. Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy. PLOS ONE. 2015;10(6):e0127407.

Mice with metastatic cancer were separated into four groups: 1) normal mouse diet, no treatment; 2) ketogenic diet; 3) ketogenic diet plus supplemental ketones; 4) ketogenic diet plus supplemental ketones plus hyperbaric oxygen therapy (HBOT). They showed that mice on the normal diet lived an average of 31 days. Mice on a KD lived 44.6% longer; mice on KD plus supplemental ketones lived 65.4% longer; mice on KD plus ketone supplements plus HBOT lived an average 103.2% longer. The authors remarked that this large improvement over the normal diet with non-toxic therapies “could be readily implemented clinically if their effects hold up in human trials.” Bottom line: Ketone supplementation and hyperbaric oxygen treatment may boost the anticancer effectiveness of ketogenic diets. 

Morscher RJ, et al. Inhibition of Neuroblastoma Tumor Growth by Ketogenic Diet and/or Calorie Restriction in a CD1-Nu Mouse Model. PLoS One. 2015;10(6):e0129802.

Two groups of mice given genetically different types of neuroblastoma (SH-SY5Y and SK-N-BE(2)) and were separated into four separate groups: 1) standard diet [SD]; 2) a calorie-restricted (2/3 of regular calories) standard diet [SD]; 3) a ketogenic, normal calorie diet [KD]; and 4) a calorie-restricted ketogenic diet [CR-KD]. Researchers found that with one type of neuroblastoma (SH-SY5Y), there was a significant difference in tumor load and survival between the normal diet and all experimental diets (CR, CR, and CR-KD; 100% survival in CR-KD vs. 0% survival in SD at day 33). In the other type of neuroblastoma (SK-N-BE(2)), only calorie-restricted diets (CR and CR-KD) significantly improved tumor load and survival (100% survival in CR-KD vs. 36% survival in SD at day 33). Bottom line: Ketogenic diets may have direct anti-cancer effects on neuroblastoma. 

Woolf EC, et al. The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model. PLOS ONE. 2015;10(6):e0130357.

Mice were given malignant gliomas and separated into two groups 1) standard diet (SD) and 2) ketogenic diet (KD). They showed that in mice on the KD, several important markers of tumor malignancy (lack of oxygen, tumor blood vessel growth, and swelling around the tumor) were all significantly lower than mice on a standard diet. Bottom line: Ketogenic diets have anticancer effects on tumors through increasing oxygen, restricting tumor blood vessel growth, and reducing swelling around the tumor.  

Champ, C. E. et al. (2014). Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. Journal of Neuro-oncology. 117(1), 125-131 .

Researchers followed 6 GBM patients undergoing radiation therapy and chemotherapy who followed a ketogenic diet for 14 months and compared their blood work to 47 other GBM patients not on the KD. Their main goal was to assess the safety of a KD during cancer treatment. There first finding was that there was a very large difference in average non-fasting glucose levels between the KD and non-KD group (84 mg/dl and 122 mg/dl, respectively), which shows that even in the midst of treatment (and steroids), a KD can drastically lower blood glucose. They also found that the diet is safe. No patients experienced significant toxicity. One patient experienced significant fatigue. Bottom line: The KD is safe for cancer patients and can decrease average non-fasting blood sugar even during chemotherapy and radiation treatment.

Poff, M. et al. (2014). Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. International Journal of Cancer, 135(7), 1711-1720.

Mice were implanted with cancer cells and placed into four groups: 1) standard diet (SD) and NOT given ketone supplements; 2) calorie-restricted diet (CR) NOT given ketone supplements; 3) standard diet supplemented with butenediol (BD) which gets converted into ketone bodies; 4) standard diet with ketone esters (KE) which get converted into ketone bodies as well. Researchers found that group 2 survived 18.7% longer than the control group (#1), group 3 survived 50.6% longer, and group 4 survived 69.2% longer. Bottom line: even on a standard high-carbohydrate diet that produces high blood sugar, ketones can have a significant anticancer effect.

Klement, R. J. & Champ, C. E. (2014). Calories, carbohydrates, and cancer therapy with radiation: Exploiting the five R's through dietary manipulation. Cancer Metastasis Reviews, 33(1), 217-229.

This is a review in which two radiation oncologists discuss the potential biochemical mechanisms that make the ketogenic diet an ideal adjunct to radiation therapy. They argue that the KD may: 1) improve DNA repair in normal cells, but not tumor cells; 2) make it harder for tumor cells to regrow because of a decrease in insulin and insulin-like growth-factor 1 (IGF-1); 3) change the life cycle of normal cells to become more resistant to radiation but not tumor cells; 4) make the tumor support structure more normal, thus decreasing the likelihood of tumor progression; 5) increase the ability of normal cells to resist radiation through the use of ketone bodies as a fuel while decreasing the viability of tumor cells that are dependent on glucose. Bottom line: there are very good biochemical reasons for believing that the KD works synergistically with radiation therapy.

Rieger, J. et al. (2014). ERGO: A pilot study of ketogenic diet in recurrent glioblastoma. International Journal of Oncology, 44(6), 1843-52.

This is the result of a phase I trial conducted in Germany that investigates the feasibility and safety of a ketogenic diet for recurrent GBM patients. A secondary objective was progression free survival. Patients were educated on the principles of ketogenic diets and told to restrict carbohydrates to 60 g/day. Patients were also given fermented yoghurt drinks and “plant oils” (the research article doesn’t say which types). Ketones were measured by urine ketostix. No serum ketones were measured. Researchers found that a majority of patients (85%, 17 of 20) reported no difficulty in transitioning to maintaining the diet. 12 of 20 patients were able to achieve ketosis (as measured in urine) at least once. No serious adverse events were reported in any of the patients. The 3 who initially dropped out said that the diet negatively affected their quality of life. GBM recurred in all patients on the KD. Compared to the control group, the KD staved off recurrence by about 2 weeks. But once they were put on a chemotherapy drug (bevacizumab) they had significantly better response than the non-KD control group (85% response rate for KD, 65% response rate for non-KD; mean of 20 weeks PFS for KD, 16 for non-KD). Bottom line: Even though this study has serious flaws (no tracking of blood ketones, little evidence of glucose or insulin control; potentially too high carbohydrate limit), it found that KD is safe and feasible even in patients with advance brain cancer. More importantly, they showed that the KD in conjunction with conventional therapy can produce significantly better outcomes than conventional therapy alone. Bottom line: The KD is safe even in advanced cancer patients, and it is also works synergistically with chemotherapy.

Husain, Z. et al. (2013). Tumor-Derived lactate modifies antitumor immune response: Effect on myeloid-derived suppressor cells and NK cells. The Journal of Immunology, 191(3), 1486-1495.    

This study takes a close look at micro-environment of tumors. They find that as tumors metabolize a high rate of glucose and thus produce a high level of lactate, they are able to “hide” themselves from immune cells. They found that lactate from tumors inhibits the bodies immune response both directly and indirectly. They also found that depletion of glucose levels through a ketogenic diet led to lower lactate production, an improved anti-tumor immune response, and smaller tumors. Bottom line: Diets that decrease blood glucose, like ketogenic diets, can improve the anticancer immune response in patients.

Poff, A. M. et al. (2013). The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PloS One8(6), e65522.

In this mouse study, the researchers examined the effects of a KD alone, hyperbaric oxygen therapy alone and a KD alongside hyperbaric oxygen therapy on systemic metastatic cancer. They found that the KD alone increased mean survival time by 56.7%, hyperbaric oxygen therapy alone had no effect on survival time, but together they increased survival time by 77.9%. Bottom line: While the KD alone may have anticancer effects, it is most effective when used in conjunction with other therapies such as hyperbaric oxygen therapy.

Navrátilová, J. et al. (2013). Low-glucose conditions of tumor microenvironment enhance cytotoxicity of tetrathiomolybdate to neuroblastoma cells. Nutrition and Cancer65(5), 702–710.

This is an in vitro study of the reaction of neuroblastoma cells to a combination of chemotherapy (tetrathiomolybdate) and low glucose conditions (the result of a carbohydrate-restricted diet). Researchers found that at very low levels of glucose (40mg/dl), chemotherapy had a significantly greater cytotoxic effect on cancer cells than when glucose levels were normal (100 mg/dl). Unfortunately the researchers did not measure more physiologically achievable levels of 60 or 70 mg/dl. But there was a large difference between the anticancer effect of chemo at 40 mg/dl and 100 mg/dl that it could be assumed that there would be benefit in the more achievable low-glucose ranges. It should also be noted, that nutritional ketosis allows for symptom-free mild hypoglycemia because ketone bodies are used as alternative metabolic fuels. Bottom line: there may be a synergistic effect between the KD and chemotherapy for neuroblastoma.

Allen, B. G. et al. (2013). Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts. Clinical Cancer Research 19(14), 3905-3913.

This mouse study looks at the combined effects of the ketogenic diet with radiation and chemotherapy on lung cancer. The researchers found that the ketogenic diet alone did not outperform the control group (no treatment). But the ketogenic diet significantly enhanced chemotherapy and radiation treatments. Bottom line: The KD can increase the effectiveness of conventional cancer treatment.

Abdelwahab, M. G. et al. (2012). The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PloS One7(5), e36197.

Similar to Allen (2013), researchers induced mice with cancer, this time with malignant gliomas. Rats were put in three groups: No KD/no radiation; KD (ketocal) and no radiation, and KD (Ketocal) and radiation. Rats with KD and no radiation survived 5 days longer than rats on no treatments. But 9 of 11 rats that received both radiation and KD were tumor-free and after 101 days were switched to standard diet. No cancer recurrence for over 200 days. Truly amazing study. Bottom line: The KD might cause tumor regression and full remission when used with standard radiation treatment for high-grade gliomas.

Fath, M. A. F. et al. (2012). Enhancement of cancer therapy using ketogenic diet. In D. R. Spitz, et al (Eds.), Oxidative stress in cancer biology and therapy. (pp. 47-58). Humana Press.

Similar to Allen (2013) and Abdelwahab (2012), Fath et al found that KD (ketocal) improved the effects of conventional treatments radiation and chemotherapy (cisplatin). Here researchers looked at squamous cell head and neck cancer in mice. Mice were separated into 5 groups: control, chemotherapy/no-KD, chemotherapy/KD, radiation/KD, and KD only. First, they found that while ketone levels significantly increased in the mice on the KD, blood glucose did not fall. Second, they found that the weight in mice on the KD did not significantly differ from mice on standard chow. The mice given chemotherapy did drop in weight in the middle of chemotherapy treatment but quickly regained weight when returned to standard chow. It would’ve been interesting to see if the mice would’ve regained weight if they had remained on the KD. Third, they found that chemo (cisplatin) was significantly more effective when paired the KD. Radiation did not have the same increase in effectiveness overall. However. one mouse had a complete regression of the tumor on the KD and radiation treatment. Bottom line: chemotherapy was significantly more effective when paired with KD.

Fine, E. J. et al. (2012). Targeting insulin inhibition as a metabolic therapy in advanced cancer: A pilot safety and feasibility dietary trial in 10 patients. Nutrition28(10), 1028-35.

This is the largest and most comprehensive human trial on the KD’s effect on cancer published to date. 10 subjects were put on a calorie-modified, ketogenic diet (although author’s refrain from using the term “ketogenic” and use “insulin-inhibiting diet” instead). Patients were educated on the diet and a individualized caloric intake goal was calculated to maintain body weight. Researchers asked patients to limit their CHO intake to 5% of total caloric intake. Fat and protein could be eaten to satiety. First, they found that most patients were able to adhere to the diet with 9 out of 10 keeping CHO intake below 10% of total caloric intake, with the 10th patient at 14.7%. Although some overweight patients lost weight, those who had normal BMI maintained weight. No one on the diet was seen to lose an unhealthy amount of weight. Second, they were also able to greatly increase the production of ketone bodies, but in absolute numbers, only one patient achieved significant ketosis. They did not however achieve the same results with glucose. On average patients only dropped around 3 mg/dl in fasting glucose. This could be due to the very high protein intake of patients on the diet. Third, and most importantly they saw a significant positive association between level of ketones and disease-stability/partial-remission. One patient achieved partial remission at the end of the 28-day study and this patient had the highest recorded levels of ketones (~4.5 mml/l) in the study. Bottom line: The KD is safe in humans with advanced cancer and the higher ketone levels are raised, the better the odds are that disease will remain stable.

Scheck, A. C. et al. (2012). The ketogenic diet for the treatment of glioma: Insights from genetic profiling. Epilepsy Research100(3), 327-37.

This is an exploratory study of the effects of a KD on gene expression in mice with and without tumors. The authors found that the KD altered the expression of genes implicated in epilepsy and other neurodegenerative diseases. The authors argue, “These data suggest that there may be genes or gene cascades that play a role in the initiation, progression and/or symptomatology of a variety of apparentlydisparate neurological diseases ranging from neurodegenerative diseases to brain tumors.” Bottom line: The KD’s anticancer effect could be partially due to the way it alters gene expression in the brain.

Schmidt, M. et al. (2011). Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial. Nutrition & Metabolism, 8(1), 54.

Patients with advanced metastatic cancer were instructed to follow a KD of less than 70 g of CHO/day for 3 months. The primary measurement was quality of life. 10 of the participants dropped out before the end of the 3 month trial. Those that remained reported improved emotional functioning and less insomnia, with other QOL measurements remaining stable or worsening (likely due to the advancement of their disease). All the patients who remained on the diet till the end of the study had stable disease. The blood labs showed no significantly adverse effects from the diet, however, it is odd that HBA1c didn’t change and LDL went down, HDL went down, and triglycerides went up, which is the opposite of what is commonly found in non-cancer subjects on a KD. Authors conclude that the KD is suitable for cancer patients for whom their disease has not affected eating and digestion. Bottom line: the KD is safe for advanced cancer patients. If followed strictly, it may increase survival time.

Maurer, G. D. et al. (2011). Differential utilization of ketone bodies by neurons and glioma cell lines: A rationale for ketogenic diet as experimental glioma therapy. BMC Cancer11(1), 315.

This study of high-grade glioma cells in vitro showed that normal neurons can adjust to low glucose levels easily by metabolizing ketone bodies, but glioma cells cannot. However, they found that if the mice were on a unrestricted-calorie diet, the tumor was unaffected by the diet. They hypothesize that this could be due to the fact the KD did not affect glucose or IGF-1 levels. Bottom line: ketones can be used by normal cells but not glioma cells.

Stafford, P. et al. (2010). The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutrition & Metabolism7(1), 74.

In this mouse study, researchers found that the KD significantly reduced the rate of glioma tumor growth and prolonged survival. Mice on the KD survived 25 days, non-KD mice survived 19. The KD also reduced reactive oxygen species production in tumor cells. They found that the “genes modulating ROS levels and oxidative stress were altered” by the diet. Bottom line: The KD alone may increase survival time in glioma patients

 

Zuccoli, G. et al. (2010). Brief communication metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case reportNutrition & Metabolism. 7(1), 33.

 

This is a single case study in which a 65 year old woman with GBM went on a strict, calorie-restricted KD immediately after partial resection and before standard treatment. After two months on the KD, the disease was examined with a PET scan and MRI. No evidence of disease was found. The patient continued for several months on the diet and eventually discontinued the diet after a second clean MRI scan. 10 weeks after discontinuing the diet, tumor recurrence was detected. Bottom line: the KD if followed very strictly, may potentially be a primary treatment for some GBM patients. 

Skinner, R. et al. (2009). Ketone bodies inhibit the viability of human neuroblastoma cells. Journal of Pediatric Surgery44(1), 212-216.

This in vitro study showed that neuroblastoma cell viability was significantly reduced in the presence of the ketone bodies betahydroxybutyrate and acetoacetate (62% and 51%, respectively). Viablity of normal cells were unaffected. Bottom line: Ketones may have an anticancer effect apart from allowing for glucose deprivation. 

Derr, R. L., et al. (2009). Association between hyperglycemia and survival in patients with newly diagnosed glioblastoma. Journal of Clinical Oncology27(7), 1082-6.

The records of 191 GBM patients were examined for glucose measurements (adjusted for steroid administration). They were grouped into quartiles according to patients’ mean glucose levels (<94 mg/dl; 94 to 109 mg/dl; 110 to 137 mg/dl; >137 mg/dl). Researchers found that median survival times for the quartiles were, from lowest glucose levels to highest, 14.5, 11.6, 11.6, and 9.1. Bottom line: the higher the average glucose levels in GBM patients the shorter their survival time. 

Fine, E. J. et al. (2009). Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2. Cancer Cell International9(1), 14.

This in vitro study showed that in the same amount of glucose, cancer cell viability is significantly decreased if the ketone body acetoacetate is present. Bottom line: Ketones may have an anticancer effect apart from allowing for glucose deprivation. 

Nebeling, L. C. & Lerner, E. (1995). Implementing A ketogenic diet based on medium-chain triglyceride oil in pediatric patients with cancer. Journal of the American Dietetic Association95(6), 693 - 697.

This is a review of the first known study of the ketogenic diet used in a humans to fight cancer. Two pediatric patients with advanced astrocytomas were put on a strict but calorie-unrestricted ketogenic diet. The diet consisted of 10% CHO, 20% protein, and 60% Medium-Chain Triglyceride oil, and 10% other fats. They found after 8 weeks a 21.8% decline in glucose uptake at the tumor site. Weight remained stable and no adverse side effects were detected. Bottom line: the KD is well tolerated in a children and a noticeable change in tumor metabolism can be detected after two months on the diet.

CARBOHYDRATE RESTRICTION AND BRAIN INJURY/PROTECTION

Prins, M. & Matsumoto, J. (2014). The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. Journal of Lipid Research. Published online: http://www.jlr.org/content/early/2014/04/10/jlr.R046706.

In this review article, the authors explain the apparent mechanisms behind the neuroprotective effect of KDs in traumatic brain injury (TBI). TBI alters glucose metabolism in the brain and ketones can provide efficient and effective alternative fuel for the brain in this state. To date, “preclinical studies employing both pre-and post-injuryimplementationoftheketogenicdiethavedemonstratedimprovedstructuraland functional outcome in traumatic brain injury models, mild TBI/ concussion models, and spinal cord injury.” Bottom line: KDs may have an important role to play for patients undergoing procedures that could negatively impact the brain, such as surgery, radiation, and chemotherapy.

Masino, S. A. & Ruskin, D. N. (2013). Ketogenic diets and pain. Journal of Child Neurology. 28(8), 993-1001.

In this review article, the authors examine the research to date on pain and ketosis. All of the studies mentioned in the review are mouse studies. First, the authors find that KDs decrease inflammation and thus may have some anti-pain effects. Second, the authors found that KDs decreased thermal pain in rats after 10 days on the diet. Third, the authors found that KDs did not decrease pain in two models of neuropathic pain, but they did not rule out KD efficacy in other models. Finally, the authors speculate that because the KD seems to work synergistically with conventional therapies in epilepsy and cancer, it may also work synergistically with pharmacologic agents to reduce pain. Bottom line: Because the KD is safe, non-toxic, non-addictive, and decreases inflammation and thermal pain, it should be further explored as an adjunct treatment for pain. 

Stafstrom, C. E. & Rho, J. M. (2012). The ketogenic diet as a treatment paradigm for diverse neurological disorders. Frontiers in Pharmacology, 59(3), 1-8.

In this review article, the authors summarize the research to date on the KD in the treatment of a diverse range of neurological disorders, from epilepsy to TBI to autism. They find that there are only a limited number of studies that look at this but the findings are promising. The authors ask how it might be possible that such a diverse range of neurological disorders could be ameliorated through a dietary intervention. They speculate that alterations in energy metabolism are the key. Bottom line: The KD is a promising non-toxic therapy for a variety of neurological disorders.

Deng-Bryant, Y. et al. (2011). Ketogenic diet prevents alterations in brain metabolism in young but not adult rats after traumatic brain injury. Journal of Neurotrauma, 28(9), 1813-1825.

 

Maalouf, M. et al. (2009). The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies. Brain Research Reviews, 59(2), 293 - 315.

CARBOHYDRATE RESTRICTION AND METABOLIC HEALTH (OBESITY AND DIABETES)

Saslow, L. R. et al. (2014). A randomized pilot trial of a moderate carbohydrate diet compared to a very low carbohydrate diet in overweight or obese individuals with type 2 diabetes mellitus or prediabetes. PloS One9(4), e91027.

 

Kapetanakis, M. et al. (2014). Effects of ketogenic diet on vascular function. European Journal of Pediatric Neurology. In press.

 

Yamada, Y. et al. (2013). A non-calorie-restricted low-carbohydrate diet is effective as an alternative therapy for patients with type 2 diabetes. Internal Medicine (Tokyo, Japan)53(1), 13-19.

 

Ruskin, D. N. & Masino, S. A. (2012). The nervous system and metabolic dysregulation: Emerging evidence converges on ketogenic diet therapy. Frontiers in Neuroscience, 6(33).

 

CARBOHYDRATE RESTRICTION AND GENERAL HEALTH

Kapetanakis, M. et al. (2014) Effects of Ketogenic Diet on Vascular Function. European Journal of Pediatric Neurology. 18(4), 489-494.

 

Chowdhury, R. et al. (2014). Association of dietary, circulating, and supplement fatty acids with coronary risk: A systematic review and meta-analysis. Annals of Internal Medicine, 160(6).

 

Hallböök, T. et al. (2012). The effects of the ketogenic diet on behavior and cognition. Epilepsy Research, 100(3), 304 - 309.