Efficacy and Safety of Ketogenic Diet in Glioblastoma: An Updated Systematic Review

Background: Glioblastoma (GBM) remains the most common and lethal primary central nervous system tumor, with a median survival of only 14.6 months under standard care. The tumor’s characteristic "Warburg effect"—a dependency on aerobic glycolysis for energy—creates a metabolic vulnerability. This review evaluates the efficacy and safety of the ketogenic diet (KD) as an adjunctive metabolic therapy aimed at exploiting this glucose dependency. Methods: This PRISMA-compliant systematic review updates clinical evidence by synthesizing data from database inception through September 2025. We searched PubMed, Embase, Cochrane, and Web of science for human studies assessingthe ketogenic diet in glioblastoma and high-grade gliomas. Primary outcomes included overall survival (OS), progression-free survival (PFS), feasibility, and adverse events. Results: Forty-one studies were included, ranging from randomized trials to case series and abstracts, utilizing interventions such as the classic 4:1 ketogenic diet, Modified Atkins Diet, and calorie restriction. Adherence was high, with over 75% of patients maintaining nutritional ketosis. Recent data indicate significant survival benefits; adherent cohorts achieved a median OS of 29.4 months compared to historical controls, with some studies reporting a 66.7% 3-year survival rate. The diet was well-tolerated, with adverse events limited to mild gastrointestinal symptoms and fatigue, and no Grade 3/4 diet-related toxicities reported. Conclusion: Current evidence supports the ketogenic diet as a safe, feasible, and biologically rational adjunct to standard glioblastoma treatment. It demonstrates potential to prolong survival and maintain quality of life without severe toxicity, highlighting the need for standardized Phase III trials to establish clinical guidelines.