The Ketogenic Diet for Glioblastoma

 Glioblastoma multiforme (GBM) is one of the most aggressive brain tumors, with the average 5-year survival rate being less than 10% with aggressive treatment.1 Treatment often includes surgery, radiation, chemotherapy, and steroids1. Researchers are currently investigating the efficacy of using the ketogenic diet (KD) in patients with GBM as an adjuvant form of treatment. Historically, the Ketogenic Diet (KD) has been used to improve clinical outcomes for intractable epilepsy across the age spectrum when other traditional treatments have failed.2 The KD has also showed improved cognition and behavioral outcomes, and patients have been able to taper down epilepsy medications as a result of following the KD.2 


The KD is a high-fat, low carbohydrate diet which focuses on creating a state of ketosis in the body by reducing the use of glucose metabolism.1 This can only occur in the setting of a carbohydrate deficit and lipid surplus. There are multiple variations of the KD to follow, with the traditional and most restrictive diet being the 4:1 fat:carbohydrate + protein ratio, which consists of 90% of total calories coming from long-chain fatty acids.2 Other variations of the KD include 3:1 (87% of total calories from fat), 2:1, (82% of total calories from fat), and 1:1, (70% of total calories from fat).2 A typical American diet may consist of 50-60% of total energy from carbohydrate sources, whereas the KD only consists of ~2% of energy from carbohydrates.3 When following the KD, patients must be very restrictive and cautious, as non-food sources can be a significant source of carbohydrates and must be accounted for in the meal plan such as liquid medications, beverages, lotions, toothpaste, and artificial sweeteners. When a patient who follows the KD is hospitalized, it is crucial to only administer NS, and avoid IV dextrose, as this source of carbohydrates may increase the patient’s carbohydrate sources past the daily limit, pushing the patient out of ketosis. 


The Ketogenic Diet and Tumor Metabolism


Glucose is a necessary biomolecule for energy metabolism. Unlike other cells in the body, most brain tumor cells are not able to metabolize ketones due to genetic and mitochondrial differences.1,6 The typical process for energy metabolism with oxygen present is the conversion of glucose to pyruvate through glycolysis, followed by oxidative phosphorylation.5 When glucose is not present, most normal cells (except RBC’s and sperm cells) can utilize ketone bodies for energy production through oxidative phosphorylation, a process that is impaired in tumor cells.5 The role of the KD is to reduce the presence of glucose available in the blood for energy production. Therefore, the KD may help to reduce the growth of tumor cells in the brain because of the need for glucose for energy. 
The idea behind the use of the KD and cancer progression revolves around the Warburg effect. The Warburg effect describes the tumor cell’s ability to use aerobic glycolysis for energy, regardless of the presence of oxygen.6 Normal cells typically undergo oxidative phosphorylation, which is a more efficient way to produce ATP (energy). However, even despite the presence of oxygen, cancer cells will undergo aerobic glycolysis, followed by lactic acid fermentation to produce ATP. The fermentation process that cancer cells utilize with glucose after undergoing aerobic glycolysis produces high levels of lactic acid, which may increase inflammation and disease progression.2

 

Using the Ketogenic Diet as Adjuvant Therapy


While human studies are ongoing and results are currently limited, the KD has been used in conjunction with radiation therapy in the animal model, and has been shown to enhance the antitumor effect of radiation therapy in mice.5 One case report in 2010 was done on a 65-year-old female with GBM (WHO grade IV) receiving the restricted 4:1 KD (~ 600 kcal/day) and radiation therapy. The outcomes demonstrated reduced body weight and serum glucose levels, with no evidence of tumor or progression.7 This patient received steroid therapy, anti-epileptic therapy and underwent right frontal temporal craniotomy for partial excision at time of diagnosis. When chemotherapy (temozolomide) with concomitant radiation was initiated, the patient was taken off steroids.7 The results of this case study showed a significant 20% reduction in body weight and no evidence of tumor growth (based on FDG-PET and MRI). These results indicate potential success in the use of the restricted KD in targeting metabolism of brain cancer cells, as tumor recurrence occurred for this patient only 10 weeks after stopping the restricted KD. Limitations of this case report include sample size, and the fact that the patients followed both a calorie-restricted and a carbohydrate-restricted diet, blurring which element, or if both elements of the diet, may have contributed to a positive effect. In addition, steroids are frequently prescribed throughout treatment of GBM to manage symptoms, but this patient was not using steroids throughout the KD period, and therefore, therefore, the results may have been associated with the lack of steroid use rather than the success from the KD implementation.7 


Steroid use and the Effect on Glucose Metabolism


Treatment or symptom management for patients with a brain tumor often involves the use of corticosteroids to reduce vasogenic edema.2,7 Steroids induce hyperglycemia, ultimately creating the ideal environment for the tumor cells in the brain to thrive. Research indicates that the KD is beneficial even in those who are using high-dose steroids, as the average glucose level in patients following the KD was less than 94 mg/dL.9 Lower average blood glucose levels have been correlated with greater survival rates in patients with GBM, with the greatest survival being in patients with blood glucose levels below 94 mg/dL.9


Benefits of the Ketogenic Diet 


●    Ketone bodies, specifically Beta-Hydroxybutyrate (BHB) and acetoacetate may help to prevent cellular injury as a result of oxidative stress.3
●    Cancer cachexia syndrome is a common problem in patients undergoing treatment, and due to the nature of the KD, the high fat intake may help provide adequate energy for the body to maintain weight and prevent further weight loss.4 
●    Research shows that elevated blood glucose levels during GBM treatment have decreased survival rates. The KD results in lower serum glucose levels as a result of the low carbohydrate intake. 
●    Reducing the availability of glucose in the body decreases the fermentation process and results in less lactic acid build-up. This reduces inflammation within the body and slows progression of the tumor.2 
●    The KD combined with current treatments such as radiation therapy has to the potential to improve treatment outcomes.9 Additional research is needed.
●    While research remains limited on the efficacy of the KD as an adjuvant therapy for GBM in humans, studies to date show that the diet can be administered safely in non-insulin-dependent patients with GBM for those who desire to trial it. Patients in Ketone Link Trial9 showed minimal weight loss, no episodes of hypoglycemia, and no reported adverse effects from patients.

Challenges with the Ketogenic Diet
●    The KD is a very restrictive diet, requiring intense meal planning and measuring food for each meal and snack. It can be difficult to follow and difficult to achieve a state of ketosis. Patients who desire to implement such a diet should be followed closely by a qualified dietitian.
●    This diet is usually not meant as a long-term lifestyle change. Patients may begin the diet prior to treatment and should be transitioned to a modified Atkins type diet following treatment.
●    Patients may have difficulty with eating at restaurants or social gatherings, as food will likely not be measured out/the appropriate fat: carbohydrate ratio. 
●    Side effects of the diet include GI, risk for kidney stone formation, micronutrient deficiency and constipation. These effects can be mitigated with adequate monitoring and treatment by the veteran’s oncology team, increased fluid intake, prophylactic multivitamin administration, and stool softeners in most cases.
●    While a variety of patients may desire to trial this or similar diets, a KD should not be implemented in most other malignancies. It may be specifically contraindicated in extremely hypermetabolic cancers such as pancreatic, head and neck or lung cancers, as it may contribute to undesirable weight loss in these cancers. It should also not be encouraged in GI malignancies, as many elements of a KD are known to increase risk for these cancers (i.e. inadequate fiber, possibly increased in red/processed meat, possibly pro-inflammatory, low in fruits/vegetables). 

Evidence for a KD is very limited. However, preliminary findings have demonstrated safety for patients with GBM. It is too early to judge whether or not such a diet might be effective in reducing cancer risk. However, it may be reasonable to support patients with GBM who wish to follow such a dietary pattern throughout the course of their treatment. When considering the use of the KD for a patient, it is important to note that this diet is not a long-term solution, and has a risk of a variety of side effects. Therefore, it is crucial to discuss these side effects with the patient and address the involvement of the diet with the patient, prior to initiating.

References
1.    Woolf EC, Scheck AC. The ketogenic diet for the treatment of malignant glioma. J Lipid Res. 2015;56(1): 5-10. 
2.    Zupec-Kania B, Abrams J, Pietsch-Escuada S. Proceedings of ketogenic diet therapies symposium. The Charlie Foundation for Ketogenic Therapies. Manhattan Beach, CA. 2015: 1-23. 
3.    Plogsted S. The ketogenic diet. Infant, Child and Adolescent Nutrition. 2010;2(6):370-376. 
4.    Klement RJ. Calorie or carbohydrate restriction? The ketogenic diet as another option for supportive cancer treatment. The Oncologist. 2013;18:1056. 
5.    Vidali S, Aminzadeh S, Lambert B, Rutherford T, Sperl W, Kofler B, Fiechtinger RG. Mitochondria: The ketogenic diet - A metabolism-based therapy. The International Journal of Biochemistry & Cell Biology. 2015; 63: 55-59. 
6.    Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, Scheck AC. The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PLoS ONE. 2012;7(5):e36197
7.    Zuccoli G, Marcello N, Pisanelloa A, Servadei F, Vaccaro S, Mukherjee P, et al. Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: a case report. Nutr Metab (Lond). 2010;7:33. 
8.    Plogsted S. The ketogenic diet. Infant, Child and Adolescent Nutrition. 2010;2(6):370-376. 
9.    Champ CE, Palmer JD, Volek JS, Werner-Wasik M, Andrews DW, Evans JJ, Glass J, Kim L, Shi Wenyin. Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. J Neuro-Onc. 2014; 117:125-131. 

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