Introduction
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a median survival of approximately 15-20 months. This dismal prognosis has led patients to explore health-related behaviors within their control, particularly diet and exercise. The ketogenic diet (KD), a high-fat, low-carbohydrate diet, has garnered significant interest in the brain tumor community for its potential anti-cancer effects. Initially developed as a treatment for epilepsy, its use continues to this day with proven benefits. Interest in the anti-cancer effects of a low-carbohydrate diet dates back to the 1920s, when Otto Warburg observed that cancer cells exhibit increased glycolysis even under aerobic conditions. More recent research has demonstrated that many cancers, including GBM, depend on glycolysis for oncogenesis.
Given the confluence of clinical urgency, scientific rationale, lackluster conventional treatment, and the perception of a low barrier to entry, many neuro-oncologists have patients who have implemented KD in some form without dietitian support. Yet, beyond anecdotes, clinical evidence to support the use of KD for brain tumor patients is limited. This article aims to provide a comprehensive overview of the current research on ketogenic diets and their potential role in the treatment of glioblastoma multiforme.
The Rationale Behind Ketogenic Metabolic Therapy (KMT)
Cancer as a Mitochondrial Metabolic Disease
The rationale for using KD in GBM treatment stems from the understanding of cancer as a mitochondrial metabolic disease. Two major biochemical processes generate energy in eukaryotic animal cells: substrate-level phosphorylation (SLP), also known as fermentation, and mitochondrial oxidative phosphorylation (OXPHOS). Non-tumoral cells are metabolically flexible, relying on OXPHOS in the presence of oxygen and SLP only under certain physiological conditions. Cancer cells, including GBM, are largely dependent on increased SLP flux of glucose and glutamine through the glycolysis and glutaminolysis pathways, regardless of the presence of oxygen.
The functional definition of SLP dependency is the comparatively limited capacity of malignant cells to sustain long-term proliferation when forced to use OXPHOS-exclusive metabolism (e.g., deprivation of glucose and glutamine). Insufficient or “dysfunctional” OXPHOS in cancer cells, as compared to normal cells, is hypothesized to arise from abnormalities in the number, structure, dynamics, and collective functional efficiency of the mitochondrial population.
There are no models of cancer that retain aggressive and limitless replicative capacity in the simultaneous absence of glycolysis and glutaminolysis, despite substitution with non-fermentable OXPHOS fuels (e.g., ketone bodies, fatty acids, pyruvate, lactate). Similarly, neither basic nor clinical research to date supports the notion that tumors with certain mutations (e.g., BRAF V600E) can effectively metabolize fatty acids or ketone bodies to maintain constant growth after effective dual targeting of glucose and glutamine, even if they may do so over short experimental endpoints as long as SLP flux is maintained.
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"Respiratory insufficiency" or "insufficient OXPHOS" is the therapeutically exploitable fact that cancer cells, unlike normal cells, appear unable to proliferate exclusively via OXPHOS when SLP is absent, not by the relative degree of mitochondrial function they may still retain. Residual OXPHOS is a quantifiable category but, from a purely utilitarian point of view, it may not be able to support long-term proliferation in the absence of sufficient SLP flux, representing a targetable difference between non-tumoral and tumoral cells.
Targeting Glycolysis and Glutaminolysis
GBM cells exhibit increased glycolysis even under aerobic conditions. More recent research has demonstrated that many cancers, including GBM, depend on glycolysis for the biosynthetic, bioenergetic, and signaling needs of oncogenesis.
Glioblastoma (GBM) cells utilize aerobic fermentation of glucose in the cytosol for energy supply instead of mitochondrial oxidative phosphorylation (the “Warburg effect”). 18F-fluoro-2-deoxyglucose positron emission tomography (PET) shows that human GBMs have much higher glucose utilization than normal cortex. In states of prolonged glucose deprivation, such as fasting or starvation, normal brain cells metabolize ketone bodies derived from fatty acids for energy instead of glucose. Tumor cells are poorly able to do so. They depend on glucose and glycolysis for survival. This makes tumor cells vulnerable to therapies of glucose restriction.
Two main scientific theories attempt to explain the phenomenon of carcinogenesis. The somatic mutation theory of cancer predicts that mutations in tumor-suppressor genes and proto-oncogenes are recognized as the main culprits of the unregulated growth of tumor cells. In fact, according to this theory, cancer is known as a genetic disease. The mitochondrial metabolic theory, on the other hand, proposes that cancer is best explained as a metabolic, hence nongenetic, disease in which proliferating tumor cells cannot survive or grow without the carbon and nitrogen needed for the synthesis of metabolites and ATP.
The Metabolic Mitochondrial Theory would seem to be the most accredited, also because it would be able to provide an explanation for the oncogenic paradox that was first introduced by Albert Szent-Gyorgyi to describe a seemingly contradictory phenomenon in cancer biology. This paradox refers to the fact that a specific malignant transformation, leading to cancer formation, can be triggered by a wide range of nonspecific events. So, despite the diversity of these triggers, they can all lead to the same outcome: the transformation of normal cells into cancer cells. Researchers believe they have solved the oncogenic paradox by identifying a single pathophysiological mechanism for the origin of cancer, namely the prolonged loss of oxidative phosphorylation, following damage to the mitochondria. The ketogenic diet, high in fat and low in carbohydrates, forces the body to use lipid substrates as the main source of energy, producing ketones. These are usable by healthy cells as an alternative fuel but not easily usable by tumor cells, in which the mitochondria are damaged.
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The Role of Ketone Bodies
In states of prolonged glucose deprivation, such as fasting or starvation, normal brain cells metabolize ketone bodies derived from fatty acids for energy instead of glucose. Healthy brain cells are able to modify their metabolism to accommodate fasting. This would cause metabolic stress in tumor cells, making them more vulnerable to treatment and possibly increasing the efficacy of conventional treatments like chemotherapy and radiotherapy.
The action of the ketogenic diet is not limited to glycometabolic regulation alone, since the ketone bodies released can themselves be considered metabolites with neuroprotective action and to counteract oxidative stress. In favor of healthy brain tissue, the ketogenic diet could probably improve the protection of non-diseased parenchyma of the central nervous system from malignant transformation and attenuate the cytotoxic side effects of conventional treatments.
Among all ketone bodies, it is beta-hydroxybutyrate that carries out the most interesting actions. Its effect is twofold: on one hand, it appears to protect healthy cells by easily transforming into Acetyl-CoA, allowing it to physiologically enter the Krebs cycle. On the other hand, it can hinder the metabolic functioning of unhealthy cells because impaired mitochondrial function prevents the formed Acetyl-CoA from entering the Krebs cycle and producing energy. Another intracellular mechanism worthy of mention of ketone bodies concerns the action they exert on monocarboxylate transporters. These transporters vehicle molecules such as lactate, pyruvate, and ketone bodies across cells through a competition mechanism. As part of the ketogenic diet, they can therefore regulate both the access of ketone bodies to the cellular environment and the extrusion of lactate.
Ketogenic Metabolic Therapy (KMT) Defined
Winter and colleagues coined the term “Ketogenic Metabolic Therapy” (KMT) to describe the systemic metabolic changes induced by very low carbohydrate (ketogenic) diets, calorie restriction, and/or fasting. In the current framework, KMT is redefined and expanded as an “umbrella” term that includes long-term dietary, physical activity, and lifestyle.
KMT leverages diet-drug combinations that inhibit glycolysis, glutaminolysis, and growth signaling while shifting energy metabolism to therapeutic ketosis. The glucose-ketone index (GKI) is a standardized biomarker for assessing biological compliance, ideally via real-time monitoring. KMT aims to increase substrate competition and normalize the tumor microenvironment through GKI-adjusted ketogenic diets, calorie restriction, and fasting, while also targeting glycolytic and glutaminolytic flux using specific metabolic inhibitors. Non-fermentable fuels, such as ketone bodies, fatty acids, or lactate, are comparatively less efficient in supporting the long-term bioenergetic and biosynthetic demands of cancer cell proliferation. The proposed strategy may be implemented as a synergistic metabolic priming baseline in GBM as well as other tumors driven by glycolysis and glutaminolysis, regardless of their residual mitochondrial function.
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Clinical Trials and Studies
Phase 1 Clinical Trial: Safety and Feasibility
A phase 1 clinical trial was conducted at Cedars-Sinai Medical Center to assess the safety of a 16-week KD in patients with recently diagnosed glioblastoma receiving Standard of Care (SOC) treatment. The diet would be considered unsafe if, after 1 month on the diet, 20% of study participants experienced a 10% decrease in weight or BMI resulting in a BMI < 18.5. Assessment of feasibility was a major secondary objective, operationally defined as > 50% of patients being able to maintain blood ketone levels > 0.3 mM for over 50% of days on study, starting 2 weeks after KD initiation. Other secondary objectives included assessments of progression-free survival (PFS) and overall survival (OS), health-related quality-of life (QOL), cognitive function, and physical activity.
Patients > 18 years of age with newly or recently diagnosed GBM were eligible for this study. Patients were eligible to enroll at any point from the time of initial diagnosis until the initiation of post-radiation adjuvant chemotherapy (3-4 weeks after the completion of radiation), providing a window of approximately 3 months from the time of diagnosis for patients to enroll.
All patients received standard-of-care treatment consisting of maximal safe surgical resection, followed by involved field radiation therapy with concurrent temozolomide chemotherapy (~ 6 weeks), followed by adjuvant cycles of temozolomide given Days 1-5 of a 28-day cycle beginning 3-4 weeks after the completion of radiation. All patients were supervised by a KD-trained research dietitian, providing necessary support throughout the study period. Prior to KD implementation, the study dietitian performed an initial evaluation of each patient, assessing for factors that may affect adherence such as weight, nutritional status, performance status, psychosocial support, age, sex, weight trends, and BMI. Patients were provided with glucose/ketone meters and test strips for home use and were instructed to check blood glucose and ketone levels twice daily. Patients were converted from their baseline diet to a supervised KD with a goal of a 3:1 ratio between grams of fat to grams of carbohydrates plus protein.
From April 2018 until February 2021, 21 patients with recently diagnosed GBM consented to participate in the trial and 17 patients were eligible for analysis. In order to qualify for data analysis, patients had to have been on trial for 4 consistent weeks, therefore, four patients voluntarily withdrew before the 4 week threshold. Median age at enrollment for the 17 evaluable patients was 55 years old, with median KPS of 85. Sex was evenly distributed in this population with nine (53%) females and 8 males (47%) participating in the study.
Total Meal Replacement (TMR) Program Study
A pilot study evaluated the feasibility, safety, tolerability, and efficacy of GBM treatment using a total meal replacement (TMR) program with “classic” 4:1 KD. GBM patients were treated in an open-label study for 6 months with 4:1 [fat]:[protein + carbohydrate] ratio by weight, 10 g CH/day, 1600 kcal/day TMR. Patients were either newly diagnosed (group 1) and treated adjunctively to radiation and temozolomide or had recurrent GBM (group 2). Patients checked blood glucose and blood and urine ketone levels twice daily and had regular MRIs. Primary outcome measures included retention, treatment-emergent adverse events (TEAEs), and TEAE-related discontinuation. Secondary outcome measures were survival time from treatment initiation and time to MRI progression.
Recruitment was slow, resulting in early termination of the study. Eight patients participated, 4 in group 1 and 4 in group 2. Five (62.5%) subjects completed the 6 months of treatment, 4/4 subjects in group 1 and 1/4 in group 2. Three subjects stopped KD early: 2 (25%) because of GBM progression and one (12.5%) because of diet restrictiveness. Four subjects, all group 1, continued KD on their own, three until shortly before death, for total of 26, 19.3, and 7 months, one ongoing. The diet was well tolerated. TEAEs, all mild and transient, included weight loss and hunger (n = 6) which resolved with caloric increase, nausea (n = 2), dizziness (n = 2), fatigue, and constipation (n = 1 each). No one discontinued KD because of TEAEs. Seven patients died. For these, mean (range) survival time from diet initiation was 20 months for group 1 (9.5-27) and 12.8 months for group 2 (6.3-19.9). One patient with recurrent GBM and progression on bevacizumab experienced a remarkable symptom reversal, tumor shrinkage, and edema resolution 6-8 weeks after KD initiation and survival for 20 months after starting KD.
The study concluded that treatment of GBM patients with 4:1 KD using a total meal replacement program with standardized recipes was well tolerated.
Ongoing Randomized Study
A Phase 2, randomized two-armed, multi-site study of 170 patients with newly diagnosed glioblastoma multiforme is currently underway. Patients will be randomized 1:1 to receive Keto Diet, or Standard Anti-Cancer Diet. All patients will receive standard of care treatment for their glioblastoma. The Keto Diet intervention will be for an 18-week period and conducted by trained research dietitians. Daily ketone and glucose levels will be recorded to monitor Keto Diet adherence. This two-armed randomized multi-site study aims to provide evidence to support the hypothesis that a Keto Diet vs.
Mechanisms of Action
Modulation of Epigenetic Variables
The modulation of epigenetic variables is the subject of yet another theory that was just recently uncovered. This theory suggests that the ketogenic diet might have a positive impact on malignancies. The ketogenic diet has been discovered to have both direct and indirect effects on the genome and the expression of genes, according to Boison and colleagues’ findings. This indicates that it can exert a positive influence on the expression of oncogenes and tumor suppressors during the course of the disease. The authors, who indicate that the KD has a direct inhibitory effect on DNA methylation, state that this effect is achieved via raising the levels of adenosine. Another key component of the ketogenic diet that is highly intriguing is its role in the epigenetic control of GBM and other types of cancer, particularly in relation to microRNAs. On the other hand, these are non-coding RNA molecules that have the ability to create associations with messenger RNA sequences that are complementary to one another, which can lead to the suppression or destruction of gene translation. Alterations in the expression of microRNAs are brought about by the tumor, which results in a reduction in tumor suppressors and an increase in oncogenes.
Insulin Modulation
Insulin modulation is another consequence that has been suggested to be caused by the ketogenic diet, which is related to intracellular pathways. The ketogenic diet is responsible for a reduction in blood sugar levels, which in turn leads to a reduction in the activation of the Akt/mTOR and Ras/MAPK signaling pathways. These pathways are driven by insulin and are thought to play a role in the development of cancer. Apoptosis is triggered in mouse models of astrocytomas when glucose restriction is present, and the ketogenic diet is responsible for activating the AMPK sensor, which is responsible for apoptosis.
Immune Adjuvant
According to Lussier et al., on their study conducted on murine models, the ketogenic diet could be considered an “immune adjuvant”, so much so that it can be used in combinatorial approaches. In fact, it would inhibit tumor growth and proinflammatory environmental conditions, promoting the survival of mice.
Impact on Glucose Metabolism
Research that was conducted in living creatures (in vivo), as well as in laboratory conditions (in vitro), has shown that glioma cells are highly dependent on glucose as a source of energy. Because of this, these cells go through a state of energy deprivation if there is an absence of glucose. In contrast, glioma cells do not possess the metabolic capacity to adjust to fasting and make use of ketone bodies as an alternative source of energy.
Currently, research is being conducted to determine whether or whether the ketogenic diet can influence pyruvate kinase, an enzyme that plays a vital role in glycolysis, as an intracellular target in malignant tumors. To facilitate the conversion of phosphoenolpyruvate and ATP into pyruvate and ATP, pyruvate kinase is a necessary enzyme. A phenomenon that is generally known as the Warburg effect is characterized by changed cells exhibiting a tendency to activate the glycolysis and lactate production pathways while simultaneously reducing oxygen intake. It has been established that the M2 isoform of the phosphokinase PKM2 plays a significant role in the promotion of the Warburg effect as well as cancer. According to Ji et al., the ketogenic diet showed in in vitro culture systems of GBM-infected cells the reduction of the activity of PKM2, the Glut1 transporter and other key enzymes in the process of glycolysis. From this, an energy crisis of the neoplastic cells could develop, due to the strict dependence of the cells on the glycolysis pathway, also demonstrated by a reduction in the production of ATP by them in situations of ketosis.
Challenges and Considerations
Diet Adherence and Feasibility
Studies with > 2 patients reported difficulty with doing the diet and, in 3/4 studies, continuing it beyond 3 months. In these 3 studies, the diet duration was limited to 6 weeks-3 months because the investigators thought that patients could not tolerate longer periods. In one study, treatment continued for 14 weeks, but increased CH content after 8 weeks and required “intense counseling”. There are three main problems with the “classic” 3:1 or 4:1 ketogenic diet: (1) it is complicated to do; (2) it is not palatable; and (3) it is done individually by each patient, and thus differs between patients in a study, and between studies.
To address these challenges, a novel program of total meal replacement (TMR) of ready-made 4:1 and 3:1 KD meals was developed to simplify and standardize the diet in order to make it easier to do and adhere to, and to make it uniform across a study and comparable between studies. The program delivers patients ready-made meals using a large palette of recipes in a TMR program with 4:1 KD with 10 g CH and 1600 kcal/day, with no other food consumed.
Potential Adverse Effects
Treatment-emergent adverse events (TEAEs), all mild and transient, included weight loss and hunger which resolved with caloric increase, nausea, dizziness, fatigue, and constipation.
Standard of Care Considerations
Regrettably, standard GBM therapeutics are not designed to take advantage of the metabolic vulnerabilities of cancer cells; instead, they focus on DNA repair mechanisms. In fact, as an unintended consequence of non-specific cell damage, radiotherapy has been shown to induce detrimental metabolic changes and inflammation in the tumor microenvironment, impacting the phenotype of recurrence, which should be weighed against the desirable short-term cytotoxic or immune-potentiation effects. In a similar fashion, temozolomide may increase systemic inflammation and tumor-driver mutations. Both brain-directed radiotherapy and systemic antineoplastic therapy can result in neurological complications (including brain tissue necrosis, brain atrophy, and neurocognitive impairment), which should be prevented if long-term survival is expected.
Furthermore, as part of supportive therapy, patients with brain cancer often receive corticosteroids (e.g., dexamethasone) to reduce vasogenic edema. The injudicious use of corticosteroids has been questioned due to correlations with reduced survival via dysregulated glucose metabolism, increased insulin signaling and immune suppression. Current recommendations specify that “the lowest dose of steroids should be used for the shortest time possible,” in contrast with the “traditional, often uncritical use of steroids”. Finally, bevacizumab, a second-line anti-angiogenic therapy, may harbor unwanted adverse effects by facilitating distal tumor invasion through the neural parenchyma and perivascular network, without offering improvements to long-term survival.
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