Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma

Abstract

It has been hypothesized that persistent ketotic hypoglycemia represents a potential therapeutic strategy against high-grade gliomas. Perillyl alcohol (POH) is a non-toxic, naturally-occurring, hydroxylated monoterpene that exhibits cytotoxicity against temozolomide-resistant glioma cells, regardless of O6-methylguanine-methyltransferase promoter methylation status. The present study aimed to evaluate the toxicity and therapeutic efficacy of intranasal POH when administered in combination with a ketogenic diet (KD) program for the treatment of patients with recurrent glioblastoma. The 32 enrolled patients were divided into two groups, KD or standard diet, with intranasal POH treatment (n=17 and n=15, respectively). The nutritional status and anthropometric parameters of the patients were measured. Patients that adhered to the KD maintained a strict dietary regimen, in addition to receiving 55 mg POH four times daily, in an uninterrupted administration schedule for three months. Neurological examination and magnetic resonance imaging analysis were used to monitor disease progression. A total of 9/17 patients in the KD group survived and maintained compliance with the KD. After three months of well-tolerated treatment, a partial response (PR) was observed for 77.8% (7/9) of the patients, stable disease (SD) in 11.1% (1/9) and 11.1% (1/9) presented with progressive disease (PD). Among the patients assigned to the standard diet group, the PR rate was 25% (2/8 patients), SD 25% (2/8) and PD 50% (4/8 patients). The patients assigned to the KD group presented with reduced serum lipid levels and decreased low-density lipoprotein cholesterol levels. These results are encouraging and suggest that KD associated with intranasal POH may represent a viable option as an adjunct therapy for recurrent GBM.

Keywords: combination therapy; intranasal administration; ketogenic diet; perillyl alcohol; recurrent glioblastoma.

Figure 1.

Brain magnetic resonance images of three patients, with images prior to (A,C,E) and following (B,D,F) the commencement of treatment. (A) Axial flair shows part of the expansive lesion and the extensive perilesional edema in the left temporoparietal region, which extends along the left cerebral peduncle. (B) Axial flair in the control shows reduction of lesion dimension. (C) Axial T1W contrast-enhanced image demonstrates lesion with peripheral and irregular enhancement and perilesional edema. (D) Axial T1W contrast-enhanced image of the control with reduction of tumor volume following therapy. Postoperative changes in correspondence. (E) Axial flair demonstrates a heterogeneous lesion with hyperintense area. (F) Axial flair of the control shows reduction in the dimensions of the heterogeneous lesion with extensive perilesional edema. Magnetic susceptibility artefact by previous biopsy.

Figure 2.

Tumor area (cm²). Tumor area was significantly smaller in the ketogenic diet group at 90 days compared with the baseline (P=0.035), but not in the control group (P=0.687).

Figure 3.

Total cholesterol (mg/dl). There was a statistically significant difference (P=0.003) between the total cholesterol level in the initial and final evaluations of the ketogenic diet group, with values significantly lower at 90 days.