The Ketogenic Diet & Brain Cancer: An Evidence-Based Review

It is hard to mention the ketogenic diet and expect objectivity, or even rationality. There is something deeply emotive about the role of fat in the human diet, and high fat diets either have rabid supporters or dogmatic detractors.

Lost in all of the crusading is the only thing that should really matter in the discussion: the evidence.

The ketogenic diet has been the standard clinical nutrition therapy for children with drug-refractory epilepsy since the 1930’s, and is an effective treatment to prevent seizures (Martin et al., 2016). This is a very important point to hammer home at the outset: the ketogenic diet is a clinical nutrition diet.

Why stress that? Because the ketogenic diet is often portrayed as a “fad”, “alternative”, dangerous, and second only to Donald Trump as an existential threat to global security.

Am I being pedantic? Yeah. Again, the only thing that should be considered is the evidence, yet most of the discussion around the ketogenic diet is rhetoric and hyperbole.

This article focus on brain cancer for two reasons. First, there is more research on the ketogenic diet in this form of cancer. Secondly, the purpose of the post is to help you with more of an understanding of why and how it may have therapeutic application specific to cancer.

What is the Ketogenic Diet?

The ketogenic diet is a high-fat, lower protein and carbohydrate diet. The classic epilepsy ketogenic diet consists of 80% energy from fat, with 10% each from protein and carbs: a 4:1 ratio of fat to protein+carbs. Recently, other forms have emerged including modified ratios i.e. 3:1, or the MCT ketogenic diet, in which 60% of energy is provided by medium-chain triglycerides, allowing for higher protein and carb intake and greater sustainability.

Going to get geeky here for a sec: when the body undergoes extended periods in the fasted state, or with carbohydrate restriction, the main mechanism of aerobic energy production, known as the Krebs Cycle, is unable to continue producing energy through this pathway. This is because the first step in this cycle relies on a byproduct of carbohydrate breakdown known as oxaloacetate. As stored glycogen and fats continue to be broken down and form Acetyl-CoA, in the absence of oxaloacetate there is an excess buildup of ACoA outside of the Krebs Cycle.

The liver detects this and uses the excess ACoA molecules to form ketone bodies, which can then be used by the brain and other body tissues (like the heart and skeletal muscles) as energy. Thus, this mechanism is a unique evolutionary alternate fuel tank. Whether it is our “optimal” fuel source, as ketogenic advocates will insist, is a matter of speculative debate. The evidence doesn’t support the use of the ketogenic diet, for example, in sports performance as I’ve written about previously.

However, the anti-seizure effects of the ketogenic diet suggest that the altered energy metabolism which defines the diet alter neurological dysregulation, and may have therapeutic application in other neurological diseases, including cancer (Danial et al., 2013).

Cancer Metabolism and Ketogenic Diets

Brian tumours exhibit characteristic features of cancer, including increased reliance on glycolysis and decreased mitochondrial oxidative phosphorylation [“the Warburg Effect” – reliance on the breakdown of glycogen in aerobic conditions], and reduced suppression of apoptosis [programmed cell death] (Rieger et al., 2014).

High blood glucose levels activate the IGF-1/PI3K/Akt/Hif-1a signalling pathways, which stimulate tumour growth, promote angiogenesis and prevent apoptosis (Ziccoli et al., 2010).

The ketogenic diet has generated interest as an adjunct therapy to brain tumour treatment due to its potential to lower blood glucose levels, while providing an alternate fuel source for healthy brain cells that tumorous cells lack the flexibility to metabolise for energy (Woolf & Scheck, 2014; Maurer et al., 2011).

This is the core concept underlying the theory of why the ketogenic diet may be effective, which very much centres on a concept of “cancer as a metabolic disease.” However, it is worth bearing in mind that it is a theory, and cancer is not simply a metabolic disease. It is epigenetic, metabolic, environmental, and sometimes nutritional.

Pre-Clinical Data – The Evidence from Animal Models

When glucose is unavailable, metabolism of the ketone beta-hydroxybutyrate [β-OHB] requires the expression of mitochondrial enzymes that tumour cells may not express (Stafford et al., 2010; Zhou et al., 2007). This “metabolic inflexibility” forms the basis for the potential benefit of the ketogenic diet in cancer, and suggests a metabolic advantage to ketosis by reducing fuel for tumour growth (Zhou et al., 2007). A recent study in rats did find that tumour cells could oxidise ketones, casting doubt on the theory of metabolic inflexibility (De Feyter et al., 2016). This may, however, be a result of the chosen animal model. There are metabolic differences  which allow rat brains to use ketones as an alternate energy source, in contrast to mouse and human malignant brain cells (Maurer et al., 2011; Zhou et al., 2007).

The generation of reactive oxygen species [ROS] is increased in cancer cells, which induces angiogenesis and tumour growth (Woolf & Scheck, 2014). In a mouse model of glioma, a ketogenic diet decreased ROS in tumour cells, attenuating tumour growth and increasing survival time (Stafford et al., 2010). This may be an advantage of a ketogenic diet, as expression of genes involved in oxidative stress were overexpressed in a standard control diet, while the ketogenic diet shifted genetic expression toward that found in non-tumorous tissue (Stafford et al., 2010).

Using a ketogenic diet adjuvant to radiotherapy eradicated cancerous brain cells in 9 of 11 mice compared to 0 of 11 on a standard diet (Abdelwahab et al., 2012). β-OHB levels were highest in animals on a combination of the ketogenic diet and radiation, indicating a potentiating effect of the ketogenic diet on radiation/chemotherapy treatment (Abdelwahab et al., 2012). It is possible that a ketogenic diet may thus confer an advantage by increasing sensitisation of tumour cells to treatment (Abdelwahab et al., 2012).

Blood glucose appears to be a critical factor. An unrestricted calorie ketogenic diet failed to reduce blood glucose in mice, and had no effect on survival time or tumour growth (Maurer et al., 2011). Meta-analysis of unrestricted ketogenic diets in mice has found no significant difference in blood glucose levels compared to a standard diet with >50% carbohydrate (Klement et al., 2016). Comparing an unrestricted ketogenic diet, a standard diet, and a calorie-restricted ketogenic diet, only the restricted ketogenic diet reduced blood glucose levels and inhibited tumour growth (Zhou et al., 2007).

A major disadvantage to this observation is the reluctance in oncology to restrict calorie intake in patients (Woolf & Scheck, 2014). However, if calorie restriction is a mediator of effect, then the ketogenic diet may in fact be a more advantageous means of achieving restriction due to its anorexigenic, appetite-suppressing effects (Paoli et al., 2015).

The Evidence in Humans

In an early case study, two paediatric females with high-grade tumours were maintained in stable remission for 4 and 5 years, respectively, with a medium-chain triglyceride ketogenic diet (Nebeling et al., 1995). The ERGO trial found that subjects on a combination therapy of ketogenic diet and bevacizumab had a 50% longer progression-free survival time than a control group undergoing treatment but not on the ketogenic diet (Rieger et al., 2014). Consistent with the preclinical data, no reduction in blood glucose was observed with an unrestricted ketogenic diet in the ERGO trial, but urinary ketones were measured and the longer progression-free survival time correlated with achieving a state of stable ketosis (Rieger et al., 2014).

Caloric restriction may augment the efficacy of the ketogenic diet due to reductions in blood glucose. In a case report of a 65-year old lady with glioblastoma multiforme [GBM], the most aggressive form of brain cancer, a 600kcal/day restricted ketogenic diet adjuvant to chemotherapy and radiation decreased blood glucose to 60mg/dl, and no tumour was discernible on MRI after 8-weeks treatment (Ziccoli et al., 2010). The glucose-ketone index [GKI], a more precise analysis of the metabolic environment conducive to tumour management, provides support for the synergistic effect of the ketogenic diet and caloric restriction in reducing blood glucose while increasing ketones (Meidenbauer, Mukherjee & Seyfried, 2015). While more accurate prescription is an advantage, there remains an ethical reluctance to restrict calorie intake in a palliative care scenario (Rieger et al., 2014).

This may disadvantage the potential therapeutic application of the ketogenic diet. A case study of two patients using a restricted ketogenic diet as monotherapy for malignant glioma found that, while one patient remained in ketosis, blood glucose couldn’t be maintained <80mg/dl and tumour growth progressed after an initial stable period (Schwartz et al., 2015). In 6 patients undergoing a restricted ketogenic diet for GBM who averaged a blood glucose level of 84mg/dl, progression-free survival was 10.3 months (Champ et al., 2014). That these subjects were on steroids, which increase gluconeogenesis and blood glucose levels, indicates that a restricted ketogenic is an effective intervention to decrease blood glucose levels (Champ et al., 2014). Whether this correlates to any clinical significance is open to question. A review of the available data noted that if blood glucose is a key mediator of efficacy, the sole case study that managed to achieved a level of 60mg/dl used a 600kcal/day RKD intervention, which is unfeasible for long-term tumour management (Schwartz et al., 2015).

While concern has been expressed about tolerability of the ketogenic diet, the literature does not support this concern overall (Nebeling et al., 1995; Ziccoli et al., 2010; Champ et al., 2014; Rieger et al., 2014; Schwartz et al., 2015). There are, however, inter-individual differences in response and some patients fail to reach ketosis, indicating the need for further understanding of the mechanisms behind this metabolic shift (Rieger et al., 2014). More particularly, there is evidence from one individual case of increased expression for ketolytic mitochondrial enzymes, indicating that malignant human hippocampal cells may be able to metabolise ketones in certain individuals (Schwartz et al., 2015). While cumulatively the weight of current data supports the metabolic inflexibility hypothesis (Stafford et al., 2010; Maurer et al., 2011; Abdelwahab et al., 2012; Ziccoli et al., 2010; Meidenbauer, Mukherjee & Seyfried, 2015), more data is needed in this crucial aspect of clinical efficacy.

Conclusions – Safety, Efficacy and Synergy

The small body of human data demonstrates that a ketogenic diet is clinically safe and effective (Nebeling et al., 1995; Ziccoli et al., 2010; Champ et al., 2014; Rieger et al., 2014; Schwartz et al., 2015).

Employing a calorie-restricted ketogenic diet in lieu of high dose steroids, adjuvant to chemo/radiotherapy, may be more effective in tumour management, due to the glucogenic effects of steroids (Ziccoli et al., 2010). There appears to be a synergistic effect between increased hypoxia from anti-angiogenic drugs and the ability of the ketogenic diet to reduce energy availability to hypoxic tissue (Rieger et al., 2014).

This is a point of crucial importance to oncologists, dieticians, and anyone skeptical about the therapeutic use of the ketogenic diet in cancer. No one with a grasp of the literature is suggesting it – or any dietary treatment – should be used as monotherapy.

The evidence for the efficacy of the ketogenic diet is solely as a combination, adjuvant therapy with chemo/radiotherapy and anti-angiogenic drugs.

The additive effect of the ketogenic diet plus treatment is consistent across preclinical and human data, supporting the advantage of combined treatment over monotherapy (Klement et al., 2016; Schwartz et al., 2015).

There are gaps, however, in the literature: the optimal level of calorie intake required for a treatment effect; further elucidation of the ‘metabolic zone’ for glucose and ketones; and more data on inter-individual differences in ketone metabolism (Schwartz et al., 2015).

The concerns and questions, insofar as safety and efficacy are concerned, are not well founded: the advantage of the ketogenic diet is its safety and efficacy as an adjunct to chemo/radiotherapy in attenuating tumour growth.

The disadvantages are the apparent degree of caloric restriction required for full therapeutic effect, together with lack of data from well controlled trials. There is one other, obvious and very limiting disadvantage: the fact that the only effect is slightly increased survival time. The ketogenic diet is often portrayed, incorrectly, as a highly effective treatment, but to date it is impossible to separate the effects from that of calorie restriction per se, and ultimately it has not led to any survival. This is certainly a reflection of a majority of the literature in the realm of brain cancer, which is terminal in any event.

I will end this with a musing that I’ve had, a question I can’t quite answer: Why is there an inability to have an objective discussion about this topic? Eventually, the evidence – pro or con – should win out.


References

Abdelwahab, M., Fenton, K., Preul, M., Rho, J., Lynch, A., Stafford, P. and Scheck, A. (2012). The Ketogenic Diet Is an Effective Adjuvant to Radiation Therapy for the Treatment of Malignant Glioma. PLoS ONE, 7(5), p.e36197.

Champ, C., Palmer, J., Volek, J., Werner-Wasik, M., Andrews, D., Evans, J., Glass, J., Kim, L. and Shi, W. (2014). Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neurooncol, 117(1), pp.125-131.

Danial, N. N., Hartman, A. L., Stafstrom, C. E., & Thio, L. L. (2013). How Does the Ketogenic Diet Work? Four Potential Mechanisms. Journal of Child Neurology, 28(8), 1027–1033. http://doi.org/10.1177/0883073813487598

De Feyter, H., Behar, K., Rao, J., Madden-Hennessey, K., Ip, K., Hyder, F., Drewes, L., Geschwind, J., de Graaf, R. and Rothman, D. (2016). A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth. Neuro-Oncology, 18(8), pp.1079-1087.

Klement, R., Champ, C., Otto, C. and Kämmerer, U. (2016). Anti-Tumor Effects of Ketogenic Diets in Mice: A Meta-Analysis. PLOS ONE, 11(5), p.e0155050.

Martin K, Jackson CF, Levy RG, Cooper PN. (2016). Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev. Feb 9;2:CD001903

Maurer, G., Brucker, D., Bahr, O., Harter, P., Hattingen, E., Walenta, S., Mueller-Klieser, W., Steinbach, J. and Rieger, J. (2011). Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy. BMC Cancer, 11(1).

Meidenbauer, J., Mukherjee, P. and Seyfried, T. (2015). The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer. Nutrition & Metabolism, 12(1), p.12.

Nebeling, L., Miraldi, F., Shurin, S. and Lerner, E. (1995). Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. Journal of the American College of Nutrition, 14(2), pp.202-208.

Paoli, A., Bosco, G., Camporesi, E. and Mangar, D. (2015). Ketosis, ketogenic diet and food intake control: a complex relationship. Frontiers in Psychology, 6.

Rieger, J., Bähr, O., Maurer, G., Hattingen, E., Franz, K., Brucker, D., Walenta, S., Kämmerer, U., Coy, J., Weller, M. and Steinbach, J. (2014). ERGO: A pilot study of ketogenic diet in recurrent glioblastoma. Int J Oncol.

Schwartz, K., Chang, H., Nikolai, M., Pernicone, J., Rhee, S., Olson, K., Kurniali, P., Hord, N. and Noel, M. (2015). Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Metab, 3(1).

Stafford, P., Abdelwahab, M., Kim, D., Preul, M., Rho, J. and Scheck, A. (2010). The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutrition & Metabolism, 7(1), p.74.

Woolf, E. and Scheck, A. (2014). The ketogenic diet for the treatment of malignant glioma. J. Lipid Res., 56(1), pp.5-10.

Zhou, W., Mukherjee, P., Kiebish, M., Markis, W., Mantis, J. and Seyfried, T. (2007). The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutrition and Metabolism, 4(2007), p.5.

Zuccoli, G., Marcello, N., Pisanello, A., Servadei, F., Vaccaro, S., Mukherjee, P. and Seyfried, T. (2010). Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case Report. Nutrition & Metabolism, 7(1), p.33.