Successful application of dietary ketogenic metabolic therapy in patients with glioblastoma: a clinical study

Abstract

Introduction: Glioblastoma multiforme (GBM) ranks as one of the most aggressive primary malignant tumor affecting the brain. The persistent challenge of treatment failure and high relapse rates in GBM highlights the need for new treatment approaches. Recent research has pivoted toward exploring alternative therapeutic methods, such as the ketogenic diet, for GBM.

Methods: A total of 18 patients with GBM, 8 women and 10 men, aged between 34 and 75 years participated in a prospective study, examining the impact of ketogenic diet on tumor progression. The pool of patients originated from our hospital during the period from January 2016 until July 2021 and were followed until January 2024. As an assessment criterion, we set an optimistic target for adherence to the ketogenic diet beyond 6 months. We considered the therapeutic combination successful if the survival reached at least 3 years.

Results: Among the 18 patients participating in the study, 6 adhered to the ketogenic diet for more than 6 months. Of these patients, one patient passed away 43 months after diagnosis, achieving a survival of 3 years; another passed away at 36 months, narrowly missing the 3-year survival mark; and one is still alive at 33 months post-diagnosis but has yet to reach the 3-year milestone and is, therefore, not included in the final survival rate calculation. The remaining 3 are also still alive, completing 84,43 and 44 months of life, respectively. Consequently, the survival rate among these patients is 4 out of 6, or 66.7%. Of the 12 patients who did not adhere to the diet, only one reached 36 months of survival, while the rest have died in an average time of 15.7 ± 6.7 months, with a 3-year survival rate of 8.3%. Comparing the survival rates of the two groups, we see that the difference is 58.3% (66.7% versus 8.3%) and is statistically significant with p < 0.05 (0.0114) and X² = 6.409.

Discussion: The outcomes observed in these patients offer promising insights into the potential benefits of the ketogenic diet on the progression of glioblastoma multiforme when compared to those who did not follow the diet consistently.

Keywords: brain; diet; glioblastoma; ketogenic; metabolic; multiforme; tumor.

Figure 1

(A) Simplified scheme of glucose and ketone metabolism in a normal brain cell. Under anaerobic conditions, normal cells perform glycolysis in the cytoplasm, generating minimal but rapid energy. In aerobic conditions, normal cells perform the slower but more efficient oxidative phosphorylation in mitochondria for energy production. In a fed state, cellular energy is derived from glucose metabolism (illustrated with a solid line), undergoing glycolysis in the cytoplasm to form pyruvate, which then enters the mitochondrion. Inside the mitochondria, pyruvate is converted into acetyl-CoA, initiating the citric acid cycle (Krebs cycle), leading to the production of reducing equivalents. NADH/FADH are subsequently oxidized to generate ATP (solid line). In a fasted state, when glucose availability is low, the cell uses alternative ketone bodies that pass into the cell through monocarboxylate transporters (MCTs, indicated with a dotted line). Ketone bodies are converted into acetyl-CoA, prompting the citric acid cycle to proceed, similarly producing NADH (+H), which is oxidized to produce ATP (dotted line). (B) Ketogenic diet impact in normal brain cells. Due to the ketogenic diet-induced competition for available glucose, the primary source of acetyl-CoA switches to ketone bodies. These ketone bodies enter the cell via MCTs, leading to the production of acetyl-CoA. This initiates the citric acid cycle (Krebs cycle), resulting in the generation of NADH (+H). NADH is then oxidized, producing ATP.

Figure 2

(A) Simplified schema of glucose and fat metabolism in a cancer cells. In addition to their reliance on glycolysis, most tumors, including those in the brain, exhibit abnormalities in the number and function of their mitochondria. Functional mitochondria are essential for utilizing ketones as an energy source. Consequently, for malignant cells, glycolysis becomes the primary source of ATP through the Embden–Meyerhof–Parnas pathway, regardless of oxygen availability. This glycolytic process is much less efficient than oxidative phosphorylation, as it generates less ATP per glucose molecule metabolized. Thus, conversion of glucose into lactic acid, bypassing oxidative phosphorylation, leads to reduced ATP production. To fulfill the elevated energy needs necessary for rapid tumor growth, cancer cells escalate glycolytic activity. The accumulation of lactate in cancer cells promotes lactate transport to the blood and extracellular fluid via proton-linked MCTs. This accumulation of lactic acid contributes to acidosis in both the blood and extracellular spaces, promoting angiogenesis, metastasis, and notably, immunosuppression, which is associated with worse clinical prognosis. (B) Ketogenic diet impact in cancer cells. The adoption of the ketogenic diet leads to an increase in hepatic ketogenesis, which in turn inhibits glucose uptake by cells, positioning ketones as the primary energy substrate. However, the reduced ability of cancer cells to oxidize ketones efficiently, compounded by glucose deprivation, may result in reduced proliferation rates.

Figure 3

Patient 1: (A) Pre-operative brain MRI (T2/FLAIR) (B) Pre-operative brain MRI (T1 with contrast) (C) 38-month follow-up brain MRI (T1 with contrast) (D) 80-month follow-up brain MRI (T1 with contrast).

Figure 4

Histopathology: Patient 1 (A) Typical Morphology of Glioblastoma (H&E x200). (B) Significant endothelial hyperplasia (H&E x200). (C) Extensive Coagulative Necrosis with Thrombotic Vessels (H&E x100). (D) Tumor cells negative for IDH-1 Mutant (IHC x200). Patient 2: (A) Typical morphology of glioblastoma with endothelial hyperplasia (H&E x200). (B) Severe endothelial hyperplasia (X100). (C) Palisading necrosis (H&E x200). (D) Tumor cells are negative for IDH-1 mutant (IHC x200). Patient 3 (A) Typical morphology of glioblastoma with endothelial hyperplasia (H&E x200). (B) Palisading necrosis (H&E x200). (C) Extensive coagulative necrosis with thrombotic vessels (H&E x200). (D) Tumor cells are negative for IDH-1 mutant (IHC x200). Patient 4 (A) Region of tumor necrosis (H&Ex40). (B) Endothelial hyperplasia (H&Ex100). (C) Pleomorphic glial cells (H&E x400). (D) GFAP+ neoplastic cells and gemistocytes (H&Ex400). Patient 5 (A) Region of tumor necrosis (H&E x40). (B) Neoplastic cells surrounding central necrosis (H&E x100). (C) Glial cells with gemistocytic features and microvascular proliferation (H&E x200). (D) Endothelial hyperplasia and microvascular proliferation (H&E x200). Patient 6 (A) Typical morphology of glioblastoma (H&E x200). (B) Area of geographic necrosis (H&E x200). (C) Endothelial hyperplasia (H&E X200). (D) Tumor cells negative for IDH-1 Mutant (IHC x200).

Figure 5

Patient 2: (A) pre-operative brain MRI (T2/FLAIR) (B) pre-operative brain MRI (T1 with contrast) (C) 20-month follow-up brain MRI (T1 with contrast) (D) 40-month follow-up brain MRI (T1 with contrast).

Figure 6

Patient 3: (A) brain MRI on diagnosis (T2/FLAIR) (B) brain MRI on diagnosis (T1 with contrast) (C) 9-month follow up brain MRI (T1 with contrast) (D) GBM relapse, 12-month follow up brain MRI (T1 with contrast) (E) 30-month follow up brain MRI (T1 with contrast).

Figure 7

Patient 4: (A) brain MRI on diagnosis (T2/FLAIR) (B) brain MRI on diagnosis (T1 with contrast) (C) 24-month follow-up brain MRI (T1 with contrast) (D) 32-month follow up brain MRI. GBM relapse (T1 with contrast) (E) 41-month follow up brain MRI (T1 with contrast).

Figure 8

Patient 5: (A) pre-operative brain MRI (T2/FLAIR) (B) pre-operative brain MRI (T1 with contrast) (C) 34-month follow up brain MRI (T1 with contrast) (D) GBM relapse 40-month follow up brain MRI (T1 with contrast).

Figure 9

Patient 6: (A) brain MRI on diagnosis (T2/FLAIR) (B) brain MRI on diagnosis (T1 with contrast) (C) 18-month follow up brain MRI (T1 with contrast) (D) 24-month follow-up brain MRI (T1 with contrast).

Figure 10

Study flow chart. pd, post diagnosis; ECOG, Eastern Cooperative Oncology Group.