Glucose and glutamine are suggested to facilitate tumor progression. Recent evidence suggests that many glioblastoma GBMs are infected with cytomegalovirus, which could further enhance glucose and glutamine metabolism in the tumor cells. Emerging evidence also suggests that neoplastic macrophages/microglia, arising through possible fusion hybridization, can comprise an invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells, as well as for the more rapidly proliferating cancer stem cells. Therapies that increase inflammation and energy metabolites in the GBM microenvironment can enhance tumor progression. In contrast to current GBM therapies, metabolic therapy is designed to target the metabolic malady common to all tumor cells (aerobic fermentation), while enhancing the health and vitality of normal brain cells and the entire body. The calorie restricted ketogenic diet (KD-R) is an anti-angiogenic, anti-inflammatory and pro-apoptotic metabolic therapy that also reduces fermentable fuels in the tumor microenvironment. Metabolic therapy, as an alternative to the standard of care, has the potential to improve outcome for patients with GBM and other malignant brain cancers 1).

There are two ongoing clinical trials set to be completed by 2016 studying the efficacy of a Ketogenic Diet (KD) in Glioblastoma (GBM) patients: a Phase 1 randomized controlled trial/Phase 2 randomized controlled trial and a Phase II trial. In the Phase I/II trial, GBM patients will be administered a traditional 4:1 ratio of fat to carbohydrate KD while being treated chemoradiotherapy for six weeks. Monthly chemotherapy will be given afterwards. Patients will have an initial MRI scan, weekly blood tests to monitor ketone levels and a final MRI test 2).

In the Phase II trial, recurrent GBM will be treated with a similar KD as the previous trial, along with chemoradiation. Following the treatment, bevacizumab may be administered 3).

Both studies aim to determine the tolerability and safety of a KD, along with its efficacy as a tumor-shrinking agent. Preclinical and clinical studies have both been able to suggest the effectiveness and tolerability of the KD and the KD-UR; however, the precise success of tumor shrinkage exhibited in the preclinical trials has not been explicitly carried over into the clinic. It is difficult to draw conclusions based on these studies given their lack of large cohorts—the largest being a group of six patients being treated with a KD 4).

Moreover, the exact scientific mechanisms of how the KD works are still unclear. Studies dissecting the aspects of a KD and finding the exact attribute of a KD that provides benefits are warranted. Furthermore, larger cohort studies to show a more conclusive and statistically significant improvement of KD therapy on GBM patient prognosis are needed 5).

A program was developed (Glucose Ketone Index Calculator, GKIC) that tracks the ratio of blood glucose to ketones as a single value. We have termed this ratio the Glucose Ketone Index (GKI).

The GKIC was used to compute the GKI for data published on blood glucose and ketone levels in humans and mice with brain tumors. The results showed a clear relationship between the GKI and therapeutic efficacy using ketogenic diets and calorie restriction.

The GKIC is a simple tool that can help monitor the efficacy of metabolic therapy in preclinical animal models and in clinical trials for malignant brain cancer and possibly other cancers that express aerobic fermentation 6).

Seyfried TN, Flores R, Poff AM, D'Agostino DP, Mukherjee P. Metabolic therapy: a new paradigm for managing malignant brain cancer. Cancer Lett. 2015 Jan 28;356(2 Pt A):289-300. doi: 10.1016/j.canlet.2014.07.015. Epub 2014 Jul 25. Review. PubMed PMID: 25069036.
Ketogenic Diet With Radiation and Chemotherapy for Newly Diagnosed Glioblastoma. [Oct;2014 ];St. Joseph's Hospital and Medical Center. 2013
Ketogenic Diet as Adjunctive Treatment in Refractory/End-stage Glioblastoma Multiforme: A Pilot Study. [Oct;2014 ];Mid-Atlantic Epilepsy and Sleep Center, LLC LLC. 2013
Targeting metabolism with a ketogenic diet during the treatment of glioblastoma multiforme. Champ CE, Palmer JD, Volek JS, et al. J Neurooncol. 2014;117:125–131.
Varshneya K, Carico C, Ortega A, Patil CG. The Efficacy of Ketogenic Diet and Associated Hypoglycemia as an Adjuvant Therapy for High-Grade Gliomas: A Review of the Literature. Cureus. 2015 Feb 27;7(2):e251. doi: 10.7759/cureus.251. eCollection 2015 Feb. Review. PubMed PMID: 26180675; PubMed Central PMCID: PMC4494562.
Meidenbauer JJ, Mukherjee P, Seyfried TN. The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer. Nutr Metab (Lond). 2015 Mar 11;12:12. doi: 10.1186/s12986-015-0009-2. eCollection 2015. PubMed PMID: 25798181; PubMed Central PMCID: PMC4367849.
  • ketogenic_diet_in_glioblastoma.txt
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