Sarah Rice BSc. (Hons), MCOptom (UK), MHP, NNP
The role of the ketogenic diet in cancer treatment is a controversial topic that requires a sensitive and nuanced discussion. Different metabolic phenotypes of tumour tissue and individual responses, along with heterogeneity amongst study types and dietary interventions, have made progress in this area a challenge.
One such cancer type that responds favourably to a ketogenic diet is the glioblastoma (GBM). A recent paper deserves particular attention as it is the most comprehensive overview that I have seen to date (1). A global team of researchers experienced in ketogenic diet and cancer research collaborated on this paper to develop an extensive consensus treatment protocol covering the mechanisms and the biochemistry of cancer as a mitochondrial metabolic disease, the chemistry of ketone metabolism and how that affects tumour energetics, as well as implementation and troubleshooting protocols.
The Duraj et al. paper serves as a framework for an evidence-driven development of observational and interventional studies that are critical to the advancement of this field. In this paper, they use the term ketogenic metabolic therapy (KMT) to reflect that this approach is not the same as an ad libitum isocaloric ketogenic diet that may be utilised for other clinical conditions like obesity or type 2 diabetes. The approach is distinct and part of a ‘press-pulse’ therapeutic strategy.
The press-pulse concept has its roots in an evolution model of extinction survival where, in this example, tumour cells can be thought of in comparison to healthy cells (2). A ‘press’ describes an environmental pressure, such as loss of habitat, that favours one species (or cell type) best able to adapt to change. A ‘pulse’ event is brief and focused, causing high mortality; in this context, in the more vulnerable cell type. This concept in cancer treatment pertains to energy metabolism preferences, which are leveraged to increase the susceptibility of the tumour to therapeutic interventions. KMT creates a ‘press’ environment by reducing the availability of preferred fuels for the GBM tumour type. The mitochondrial metabolic theory of cancer underpins the press-pulse theory of metabolic cancer treatment. In the damaged mitochondria of tumour cells, energy metabolism is impaired and ATP synthesis via oxidative phosphorylation (OxPhos) gradually reduces, forcing a switch to ATP synthesis via the fermentation pathway, which upregulates as the OxPhos pathway fails. This fermentation pathway reflects ‘survival mode’ as OxPhos is the preferred energy pathway.
Cancer cells, like those in GBM, are dependent on the fermentation pathway, which utilises fermentable fuels like glucose and glutamine, to produce energy. The tumour microenvironment tends to have increased levels of these substrates.
Ketogenic therapies are showing promise due to the shift in metabolism that occurs when individuals enter ketosis. Tumour cells are less likely to utilise non-fermentable fuels such as ketone bodies, fatty acids, and lactate. This reduction in the preferred fuels may inhibit tumour growth. This is the ‘press’ component.
Using ketogenic diets (the ‘press’) alongside other therapies like drug treatments and radiation (the ‘pulse’) may make the tumour more susceptible to these treatments, helping to reduce tumour burden. The presence of non-fermentable ketone bodies are readily utilised by healthy cells; in fact, ketone body metabolism offers additional resilience and an advantage for normal cells over tumour cells. Through these mechanisms, the tumour microenvironment becomes less favourable, while healthy cells are more protected.
Individual nutritional needs, treatment type, cancer stage, and personal preference should guide the formulation of a ketogenic approach. KMT may include different variations of a ketogenic diet, caloric restriction, fasting, or a combination approach.
The glucose-ketone index (GKI) is a biomarker that assesses the adherence and biological effects of the ketogenic therapy and denotes the ratio of glucose to beta-hydroxybutyrate (ketones). This marker, along with other metrics of metabolic and tumour responses, enables the ketogenic intervention to be adjusted for the best therapeutic effect. Suggested targets for GKI are < 2.0, with an optimal goal being close to 1.0. It is important to recognise KMT should be personalised as clinically indicated and according to patient needs and preferences.
Key features of the KMT approach suggested by Duraj et al. include:
- Carbohydrate < 20–50 g/day
- Steady BG levels < 5 mmol/L (90 mg/dl) (aim for the lowest achievable physiologically safe glucose and insulin levels)
- Target GKI ≤2.0, ideally ≤1.0
- Adequate protein intake (initially 0.8 g/kg & adjust up maintaining GKI: av ~ 1.2 and 1.5 g/kg)
- Monitor lean body mass & adjust nutrition as needed
- Adequate micronutrient and vitamin intake
- Focus on nutrient-dense foods, e.g. eggs, beef, oily fish, and offal
Support from a knowledgeable practitioner and consideration of patient preferences are important factors for success. Other significant lifestyle factors to consider include exercise and stress management.
In conclusion, focusing on energy metabolism, tumour cells may be energetically compromised through ketogenic interventions that reduce the preferred fuel availability and therefore reduce the energy available for tumour growth and survival.
In combination with standard therapies, the synergy of KMT with these other interventions holds potential for improving cancer treatment outcomes.
This article represents the collective experience of leading experts in KMT application for GBM, and its detailed framework for further research will hopefully bring much-needed clarity to the field. This paper is required reading for anyone interested in ketogenic therapies as complementary strategies for the management of cancer.
Further resources
The Nutrition Network reference resource has an extensive listing where you can read more about the application of therapeutic carbohydrate restriction (TCR) as an adjunctive therapy for cancer management (under the ‘metabolic component’ section). Look at our training options to learn how you can support others using this approach. If you have a special interest, the training ‘Cancer: a metabolic disease’ is a comprehensive program that includes lecturers who were coauthors of the paper discussed in this article.
References
- Duraj, T. et al. (2024) ‘Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma’, BMC Medicine, 22(1), p. 578. Available at: https://doi.org/10.1186/s12916-024-03775-4.
- Seyfried, T.N. et al. (2017) ‘Press-pulse: a novel therapeutic strategy for the metabolic management of cancer’, Nutrition & Metabolism, 14(1), p. 19. Available at: https://doi.org/10.1186/s12986-017-0178-2.