Treatment of glioblastoma multiforme with "classic" 4:1 ketogenic diet total meal replacement

Pavel Klein, Ivana Tyrlikova, Giulio Zuccoli, Adam Tyrlik, Joseph C Maroon, Pavel Klein, Ivana Tyrlikova, Giulio Zuccoli, Adam Tyrlik, Joseph C Maroon

Abstract

Introduction: Glioblastoma (GBM) has poor survival with standard treatment. Experimental data suggest potential for metabolic treatment with low carbohydrate ketogenic diet (KD). Few human studies of KD in GBM have been done, limited by difficulty and variability of the diet, compliance, and feasibility issues. We have developed a novel KD approach of total meal replacement (TMR) program using standardized recipes with ready-made meals. This pilot study evaluated feasibility, safety, tolerability, and efficacy of GBM treatment using TMR program with "classic" 4:1 KD.

Method: GBM patients were treated in an open-label study for 6 months with 4:1 [fat]:[protein + carbohydrate] ratio by weight, 10 g CH/day, 1600 kcal/day TMR. Patients were either newly diagnosed (group 1) and treated adjunctively to radiation and temozolomide or had recurrent GBM (group 2). Patients checked blood glucose and blood and urine ketone levels twice daily and had regular MRIs. Primary outcome measures included retention, treatment-emergent adverse events (TEAEs), and TEAE-related discontinuation. Secondary outcome measures were survival time from treatment initiation and time to MRI progression.

Results: Recruitment was slow, resulting in early termination of the study. Eight patients participated, 4 in group 1 and 4 in group 2. Five (62.5%) subjects completed the 6 months of treatment, 4/4 subjects in group 1 and 1/4 in group 2. Three subjects stopped KD early: 2 (25%) because of GBM progression and one (12.5%) because of diet restrictiveness. Four subjects, all group 1, continued KD on their own, three until shortly before death, for total of 26, 19.3, and 7 months, one ongoing. The diet was well tolerated. TEAEs, all mild and transient, included weight loss and hunger (n = 6) which resolved with caloric increase, nausea (n = 2), dizziness (n = 2), fatigue, and constipation (n = 1 each). No one discontinued KD because of TEAEs. Seven patients died. For these, mean (range) survival time from diet initiation was 20 months for group 1 (9.5-27) and 12.8 months for group 2 (6.3-19.9). Mean survival time from diagnosis was 21.8 months for group 1 (11-29.2) and 25.4 months for group 2 ( 13.9-38.7). One patient with recurrent GBM and progression on bevacizumab experienced a remarkable symptom reversal, tumor shrinkage, and edema resolution 6-8 weeks after KD initiation and survival for 20 months after starting KD.

Conclusion: Treatment of GBM patients with 4:1 KD using total meal replacement program with standardized recipes was well tolerated. The small sample size limits efficacy conclusions.

Trial registration: NCT01865162 registered 30 May 2013, and NCT02302235 registered 26 November 2014, https://clinicaltrials.gov/.

Keywords: Glioblastoma multiforme; Ketogenic diet; Low carb diet.

Conflict of interest statement

The authors declare that they have no competing interests.

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