Intensive multimodal ketogenic metabolic therapy in glioblastoma: A clinical trial

Abstract Background Glioblastoma (GBM), isocitrate dehydrogenase (IDH)-wildtype, has a median overall survival of 11-14 months despite standard treatment. Ketogenic metabolic interventions that lower the glucose ketone index (GKI) may improve outcomes. We evaluated the feasibility, tolerability, and potential clinical benefit of integrating standard treatment with an intensive multimodal metabolic therapy program (MTP) in newly diagnosed IDH-wildtype GBM. Methods Patients received standard chemoradiation and adjuvant chemotherapy alongside an MTP comprising prolonged fasting, time-restricted feeding, and a ketogenic diet. The primary outcome was the proportion sustaining a mean daily GKI ≤6 during chemoradiation. Secondary outcomes included GKI control throughout chemotherapy, body weight, body mass index, adverse events, performance, exercise, quality of life, and survival, compared with contemporary controls using unadjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results Among 32 eligible patients, 18 commenced chemoradiation with the MTP (intention-to-treat), and 15 completed it (per-protocol). In the intention-to-treat population, 15 of 18 patients (83%) sustained a mean daily GKI ≤6 during chemoradiation. Among per-protocol patients, the GKI was 1.88 ± 0.56 during chemoradiation and 2.53 ± 0.86 throughout chemotherapy. Intentional weight loss averaged 17%, normalizing body mass index. MTP-related adverse events were mild or moderate. Exercise activity and quality of life improved. Median overall survival was 21.5 months versus 14.7 months in controls (HR = 0.42, 95% CI 0.18-0.97, P = .027), with 3-year survival of 27% versus 7%. Conclusions Intensive multimodal metabolic therapy was feasible, well-tolerated, and associated with improved exercise activity, quality of life, and survival outcomes, including higher 3-year survival.