Ketogenic Diet in the Treatment of Malignant Gliomas: A Systematic Review

Background: The Ketogenic Diet (KD) has been proposed as an adjunct to standard therapy for gliomas by targeting tumor glycolysis. We systematically reviewed evidence on KD interventions in patients with glioma across multiple outcomes. Methods: Following Cochrane guidelines, we searched MEDLINE, Embase, and Cochrane Library (until 1 February 2025) for studies on humans with glioma treated with any KD versus usual care or other diets. Outcomes included overall survival (OS) and progression-free survival (PFS), quality of life (QoL), biochemical markers (glucose, ketones, glucose-ketone index GKI), anthropometric measures, safety, and tolerability. All study designs were eligible. The quality of the studies was assessed with JBI tools. Data were narratively synthesized due to heterogeneity. The PROSPERO registration is CRD42024547388. Results: Twenty-three studies (306 patients) were included: two RCTs, 11 quasi-experimental studies, six case series, and four case reports. Dietary interventions included classic KD, modified KD, medium-chain triglyceride KD, and Modified Atkins Diet, sometimes combined with fasting. The overall dropout was 20.3%, mainly due to dietary restrictiveness, disease progression, adverse effects, or QoL concerns. Survival results were inconsistent: RCTs showed no significant OS/PFS differences versus controls, although exploratory analyses suggested better outcomes with lower glucose levels. Ketosis was commonly achieved; glucose reductions were variable, and GKI was rarely reported, with target values seldom reached outside fasting periods. Weight/BMI generally decreased modestly or remained stable; adverse events were mostly mild and tolerability was acceptable. Conclusions: Evidence for KDs in glioma patients is heterogeneous and limited. Although ketosis and safety are achievable, survival or QoL benefits remain unproven. Given the methodological challenges, the clinical complexity, and the promising potential of the Ketogenic Diet, further well-designed studies are needed to clarify its clinical utility in glioma treatment.