Adjuvant effect of low-carbohydrate diet on outcomes of patients with recurrent glioblastoma under intranasal perillyl alcohol therapy

Abstract

Background: Standard of care for glioblastoma (GB), consisting of cytotoxic chemotherapy, steroids, and high-dose radiation, induces changes in the tumor microenvironment through its effects on glucose availability, which is a determinant for tumor progression (TP). Low-carbohydrate diet (LCD) reduces the glucose levels needed to drive the Warburg effect.

Methods: To investigate LCD's effect on GB therapy, we have begun a clinical trial using LCD as an addition to intranasal perillyl alcohol (POH) for recurrent GB (rGB) patients. This study involved 29 individuals and evaluated, over a period of 1 year, the adjuvant effect of LCD associated with POH therapy in terms of toxicity, extent of peritumoral edema, reduced corticosteroid use, seizure frequency, and overall survival. POH group (n = 14) received solely intranasal POH without specific diet regimen, whereas POH/LCD group (n = 15) received intranasal POH in combination with nutritional intervention. Patients' assessment was based on clinical reviews and magnetic resonance data.

Results: In the 1-year follow-up, the POH/LCD group showed a 4.4-fold decrease in the proportion of patients who needed treatment with corticosteroids, as well as a reduction in tumor size and peritumoral edema, as compared to the POH group. While 75% of patients undergoing POH treatment experienced seizures, this fraction was reduced to 56% in the POH/LCD group. A 2.07-fold increase in the proportion of patients with stable disease, along with a 2.8-fold decrease in the proportion of patients with TP, was seen in the POH/LCD group.

Conclusion: The results presented in this study show that the LCD associated with intranasal POH therapy may represent a viable option as adjunctive therapy for rGB to improve survival without compromising patients' quality of life. Prospective cohort studies are needed to confirm these findings and validate the efficacy of this novel therapeutic strategy.

Keywords: Intranasal administration; Low carbohydrate diet; Perillyl alcohol; Recurrent glioblastoma.

Graph 1:

Kaplan–Meier graphical plots of perillyl alcohol (POH)+Diet group (black line) show a tendency (P = 0.232) for higher survival probability of recurrent glioblastoma patients compared to POH control groups (red line) especially after the 3rd month of intervention onward.

Graph 2:

Effect of the diet in recurrent glioblastoma (rGB) patients under perillyl alcohol (POH) therapy. Compared to POH group with only intranasal POH therapy, LCD/POH group caused a 2.07-fold increase in the proportion of patients with stable disease and 2.81-fold reduction in the proportion of rGB patients with tumor progression.

Figure 1:

Magnetic resonance imaging (MRIs) of representative patients before and after treatment. (a-d) shows MRIs from four different patients (all treated with intranasal perillyl alcohol concomitant with low-carbohydrate diet) that were taken before (left image labeled “i”) and after (right image labeled “ii”) treatment. (a) MRI scan after 12 months of treatment (ii) shows 24% reduction of tumor size (4.36 cm² total area) as compared to the image obtained before the treatment (5.74 cm², i). (b and c) Additional examples of patients responding favorably to treatment, with reduction in tumor size after treatment (ii) as compared to the MRIs before treatment (i). (d) Example of patient not responding to treatment. First image (i; axial FLAIR) shows an expansive oval, isointense lesion in the right thalamus, with perilesional edema, causing a mass effect with distortion of the posterior horn of the right lateral ventricle, and slight compression of the third ventricle. Four months later, axial FLAIR (ii) shows irregular enhancement, indicating lack of response to treatment.