Management of Glioblastoma Multiforme in a Patient Treated With Ketogenic Metabolic Therapy and Modified Standard of Care: A 24-Month Follow-Up

Abstract

Few advances have been made in overall survival for glioblastoma multiforme (GBM) in more than 40 years. Here, we report the case of a 38-year-old man who presented with chronic headache, nausea, and vomiting accompanied by left partial motor seizures and upper left limb weakness. Enhanced brain magnetic resonance imaging revealed a solid cystic lesion in the right partial space suggesting GBM. Serum testing revealed vitamin D deficiency and elevated levels of insulin and triglycerides. Prior to subtotal tumor resection and standard of care (SOC), the patient conducted a 72-h water-only fast. Following the fast, the patient initiated a vitamin/mineral-supplemented ketogenic diet (KD) for 21 days that delivered 900 kcal/day. In addition to radiotherapy, temozolomide chemotherapy, and the KD (increased to 1,500 kcal/day at day 22), the patient received metformin (1,000 mg/day), methylfolate (1,000 mg/day), chloroquine phosphate (150 mg/day), epigallocatechin gallate (400 mg/day), and hyperbaric oxygen therapy (HBOT) (60 min/session, 5 sessions/week at 2.5 ATA). The patient also received levetiracetam (1,500 mg/day). No steroid medication was given at any time. Post-surgical histology confirmed the diagnosis of GBM. Reduced invasion of tumor cells and thick-walled hyalinized blood vessels were also seen suggesting a therapeutic benefit of pre-surgical metabolic therapy. After 9 months treatment with the modified SOC and complimentary ketogenic metabolic therapy (KMT), the patient's body weight was reduced by about 19%. Seizures and left limb weakness resolved. Biomarkers showed reduced blood glucose and elevated levels of urinary ketones with evidence of reduced metabolic activity (choline/N-acetylaspartate ratio) and normalized levels of insulin, triglycerides, and vitamin D. This is the first report of confirmed GBM treated with a modified SOC together with KMT and HBOT, and other targeted metabolic therapies. As rapid regression of GBM is rare following subtotal resection and SOC alone, it is possible that the response observed in this case resulted in part from the modified SOC and other novel treatments. Additional studies are needed to validate the efficacy of KMT administered with alternative approaches that selectively increase oxidative stress in tumor cells while restricting their access to glucose and glutamine. The patient remains in excellent health (Karnofsky Score, 100%) with continued evidence of significant tumor regression.

Keywords: Warburg effect; calorie restriction; chloroquine; epigallocatechin gallate; glioblastoma; hyperbaric oxygen; ketogenic diet; therapeutic ketosis.

Figure 1

(A) Timeline of clinical course with dates of dietary treatments, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and hyperbaric oxygen therapy (HBOT). (B) Glucose/ketone index indicates the ratio of circulating glucose to urinary ketones at all eight clinical assessments during the 15 months period from February 2016 to April 2017.

Figure 2

(A) Preoperative radiology, (A) magnetic resonance imaging (MRI) contrast enhanced images axial and sagittal view revealed cystic lesion with perifocal edema “blue arrow” and midline shift “red arrow”; (B) magnetic resonance spectroscopy (MRS) of the lesion revealed high choline value (28) and low N-acetylaspartate (NAA) value (2.7); (C) Functional MRI showed affection of motor and sensory functions; (D) MRI tractography showed displaced motor and sensory fibers. (B) 3 months postoperative radiology (A) MRI contrast enhanced images axial and sagittal view revealed reduction in tumor size and perifocal edema with less midline shift; (B) MRS of the lesion revealed reduction of choline value (21) and elevation of NAA value (3.5) compare to preoperative study. (C) 12 months postoperative radiology (A) MRI contrast enhanced images axial and sagittal view revealed stationary or slightly decrease in tumor size and less perifocal edema with less midline shift; (B) MRS of the lesion revealed reduction of choline value (19) and elevation of NAA value (4) compare to previous study. (D) Postoperative radiology at 20 months. MRI contrast enhanced images for axial, sagittal, and coronal views revealed further reduction in tumor size, with no perifocal edema or midline shift.

Figure 2

(A) Preoperative radiology, (A) magnetic resonance imaging (MRI) contrast enhanced images axial and sagittal view revealed cystic lesion with perifocal edema “blue arrow” and midline shift “red arrow”; (B) magnetic resonance spectroscopy (MRS) of the lesion revealed high choline value (28) and low N-acetylaspartate (NAA) value (2.7); (C) Functional MRI showed affection of motor and sensory functions; (D) MRI tractography showed displaced motor and sensory fibers. (B) 3 months postoperative radiology (A) MRI contrast enhanced images axial and sagittal view revealed reduction in tumor size and perifocal edema with less midline shift; (B) MRS of the lesion revealed reduction of choline value (21) and elevation of NAA value (3.5) compare to preoperative study. (C) 12 months postoperative radiology (A) MRI contrast enhanced images axial and sagittal view revealed stationary or slightly decrease in tumor size and less perifocal edema with less midline shift; (B) MRS of the lesion revealed reduction of choline value (19) and elevation of NAA value (4) compare to previous study. (D) Postoperative radiology at 20 months. MRI contrast enhanced images for axial, sagittal, and coronal views revealed further reduction in tumor size, with no perifocal edema or midline shift.

Figure 3

(A) Histopathological features of the patient glioblastoma multiforme (GBM). (A) Classic GBM area with pseudopalisading necrosis. (B) Regressive changes in the form of variable background fibrosis. (C) Glomeruloid thick-walled blood vessels. (D) Tumor edge showing limited brain infiltration (haematoxylin and eosin, 200×). (B) Immunohistochemical features of the patient GBM. (A,B) Diffuse positive staining for glial fibrillary acidic protein (100× and 200×, respectively). (C) Moderately high proliferative activity (Ki67, 200×). (D) Numerous blood vessels highlighted by cluster of differentiation 31 immunostaining (100×), negative staining for epithelial markers: CK [(E) 200×] and epithelial membrane antigen [(F) 200×], respectively.

Figure 4

(A) Comparison between tumor metabolism over 20 months. Choline indicates cell membrane turnover and reflects tumorigenesis. N-acetylaspartate (NAA) is a marker for neuronal integrity that decreases with brain malignancy and radio necrosis. Creatine is a marker for cellular energy that decreases significantly with malignancy and radio necrosis. Hunter angle (blue arrow) reflects the choline/NAA ratio. (B) Comparison between tumor size and midline shift (red line) over 20 months.