Feasibility and Biological Activity of a Ketogenic/Intermittent-Fasting Diet in Patients With Glioma

Abstract

Objective: To examine the feasibility, safety, systemic biological activity, and cerebral activity of a ketogenic dietary intervention in patients with glioma.

Methods: Twenty-five patients with biopsy-confirmed World Health Organization grade 2 to 4 astrocytoma with stable disease after adjuvant chemotherapy were enrolled in an 8-week Glioma Atkins-Based Diet (GLAD). GLAD consisted of 2 fasting days (calories <20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates ≤20 g/d) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, insulin-like growth factor-1, and magnetic resonance spectroscopy at baseline and week 8.

Results: Twenty-one patients (84%) completed the study. Eighty percent of patients reached ≥40 mg/dL urine acetoacetate during the study. Forty-eight percent of patients were adherent by food record. The diet was well tolerated, with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity, including hemoglobin A1c, insulin, and fat body mass, decreased significantly, while lean body mass increased. Magnetic resonance spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate [bHB] and acetone) in both lesional and contralateral brain compared to baseline. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB R s = 0.52, p = 0.05). Subgroup analysis of isocitrate dehydrogenase-mutant glioma showed no differences in cerebral metabolites after controlling for ketonuria.

Conclusion: The GLAD dietary intervention, while demanding, produced meaningful ketonuria and significant systemic and cerebral metabolic changes in participants. Ketonuria in participants correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records.

Trial registration information: ClinicalTrials.gov Identifier: NCT02286167.

© 2021 American Academy of Neurology.

Figures

Figure 1. Schema Depicting the Patients Screened and Enrolled in the Glioma Modified Atkins Diet Study

.

Figure 2. Effect of GLAD Dietary Intervention on Systemic Ketonuria and Cerebral Ketones and Metabolites

Urine ketone (acetoacetate [AcAc]) concentration measured (A) after fasting days and (B) after modified Atkins diet (MAD) days each week on study. Percentage of participants reporting data (N = 18–21) with moderate or greater ketosis after fasting days was 71% at week 2, 83% at week 4, 68% at week 6, and 78% at week 8. AcAc concentrations: trace 5 mg/dL, small 15 mg/dL, moderate 40 mg/dL, large 80 mg/dL, and extra-large 160 mg/dL. (C) Lesion (blue) and contralateral brain (gray) ketone and metabolite concentrations before and after 8 weeks of Glioma Atkins-Based Diet (GLAD) dietary intervention. Asterisks indicate significant differences between hemispheres at either time point. (D) Changes in lesion and contralateral brain ketone and metabolite concentrations before and after 8-week dietary intervention in the lesional (green) and contralateral (gray) brain. Asterisks indicate significant differences between time points (*p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001). Ace = acetone; bHB = β-hydroxybutyrate; Cho = phosphocholine; Gln = glutamine; Glu = glutamate; Glx = combination of Gln and Glu; Lac = lactate; NAA = N-acetylaspartic acid; tNAA = total NAA.

Figure 3. Change in BMI and WBC Count During the GLAD Intervention

(A) Body mass index (BMI) and (B) white blood cell count (WBC) over time shown as hashed line for each participant in the Glioma Atkins-Based Diet (GLAD) study. Healthy-weight BMI and physiologic normal WBC values are indicated by solid black line.