Gliomas are tumours that originate from glial cells in the central nervous system. The
most common histological subtype is GBM, which accounts for nearly 50% of all malignant
brain tumours. Despite aggressive multimodal treatment, the median survival for GBM is
poor (8-15 months).
Although cancer is regarded as a genetic disease, it may be perceived as a metabolic
disorder. The majority of human cancers, including GBM, display low numbers of
mitochondria, most of which are structurally damaged, resulting in defective cell
respiration. To compensate, cancer cells greatly increase their uptake of glucose, which
is fermented (regardless of oxygen concentration, a process known as the Warburg Effect)
to generate energy. Cancer cells also rely on increased growth signaling pathways
involving insulin, insulin-like growth factor-1, and mammalian target of rapamycin to
support their unbridled growth and proliferation. Cancer cells may therefore be
vulnerable to interventions that selectively target their abnormal metabolism.
Metabolic interventions, such as fasting and ketogenic diets, target cancer cell
metabolism and may be effective alongside standard treatments in advanced cancers.
Fasting is a voluntary abstinence from food and drink for a controlled period of time
(typically, 12 hours to 3 weeks in humans), whereas ketogenic diets are high-fat,
adequate-protein, low-carbohydrate diets that stimulate the body to create a fasting-like
metabolic state. Fasting and ketogenic diets stimulate mitochondria biogenesis, decrease
blood glucose, increase liver production of fat-derived ketones (which serve as a major
alternative energy source for most normal cells within the body, but cannot be utilized
by cancer cells), and decrease growth factor availability. Thus, fasting and ketogenic
diets provide an advantage for normal cells but a disadvantage to cancer cells by
enhancing mitochondria biogenesis and function, depriving cancer cells of their major
fuel, and creating a cell environment unfavourable for unbridled growth and
proliferation.
Preliminary experience at Waikato Hospital has shown that a metabolic therapy program
(MTP) consisting of fasting and/or a ketogenic diet is feasible, safe, and may be
effective in patients with advanced cancer, including GBM. In a recent case report, a
metabolic strategy (7-day fast every 1-2 months, with a ketogenic diet between fasts)
resulted in the near-complete regression of a stage IVA metastatic thymoma after 2 years.
Moreover, we are currently observing 8 glioblastoma patients who voluntarily consented to
undergo fasting and ketogenic diet therapy in a manner similar to what we propose to use
in this study; at an average of 4-5 months, all patients have completed the fasts and
adhered to their ketogenic diet, experiencing only mild adverse effects.
On this background, we aim to determine whether using an MTP concurrently with standard
oncological treatment (chemoradiation followed by adjuvant chemotherapy) is feasible and
safe, and has treatment outcomes consistent with greater overall treatment efficacy than
in published trials, in patients with GBM.