Abstract
The ketogenic diet (KD) was initially used in 1920 for drug-resistant epileptic patients. From this point onward, ketogenic diets became a pivotal part of nutritional therapy research. To date, KD has shown therapeutic potential in many pathologies such as Alzheimer's disease, Parkinson's disease, autism, brain cancers, and multiple sclerosis. Although KD is now an adjuvant therapy for certain diseases, its effectiveness as an antitumor nutritional therapy is still an ongoing debate, especially in Neuroblastoma. Neuroblastoma is the most common extra-cranial solid tumour in children and is metastatic at initial presentation in more than half of the cases. Although Neuroblastoma can be managed by surgery, chemotherapy, immunotherapy, and radiotherapy, its 5-year survival rate in children remains below 40%. Earlier studies have proposed the ketogenic diet as a possible adjuvant therapy for patients undergoing treatment for Neuroblastoma. In this study, we seek to review the possible roles of KD in the treatment of Neuroblastoma.
Abstract from Makuku R, Sinaei Far Z, Khalili N, Moyo A, Razi S, Keshavarz-Fathi M, Mahmoudi M, Rezaei N. The Role of Ketogenic Diet in the Treatment of Neuroblastoma. Integr Cancer Ther. 2023;22:15347354221150787.
Knowledge Transfer of Fiona McCullough (Nottingham)
Background
The ketogenic diet has been explored for its therapeutic potential in an increasing number of conditions since 1920 when it was originally proposed for the management of epilepsy, with autism and brain cancer more recently investigated.
Study Result
This paper provides a comprehensive narrative-style review of the current situation in relation to the use of the ketogenic diet in the treatment of neuroblastoma.
The paper emphasises the importance of the consideration of neuroblastoma, since it is the most commonly occurring extracranial solid tumour in childhood [1]. It is responsible for approximately 6–10% of malignancies in children under 15 years of age and 15% of paediatric cancer deaths [2, 3]. Neuroblastoma originates in nerve cells known as neuroblasts. The cells, which usually form into working nerve cells, grow uncontrollably and form a solid tumour. The cause for the occurrence of the acquired mutations in neuroblastoma is unknown. The International Neuroblastoma Risk Group Staging System differentiates between 4 stages, and there are 3 graded risk groups – low, intermediate, and high, with the latter being hard to cure. The age of the child is relevant, with children 12–18 months usually developing a more aggressive form of the disease. Diet-relevant symptoms include anaemia and bleeding, severe and persistent diarrhoea (as well as abdominal mass, neck mass, muscle twitching, bone pain.)
The paper reports that based on epidemiological analyses, lifestyle factors including diet play an important role in the initiation, promotion, and progression of cancer. Of particular interest is the metabolic reprogramming at the cellular level that has a direct effect on the energy demand and neoplastic transformation profile of cells.
The paper indicates that in preclinical, clinical, and review studies the ketogenic diet has been shown to reduce tumour growth, increase the survival rate (especially in low- and intermediate-risk neuroblastoma), and enhance therapeutic effects – for example by increasing the sensitivity of malignant glioma to radiotherapy and of lung cancer to chemoradiation. The mechanisms are angiogenesis suppression, decreased oxidative damage to normal cells, and reduced levels of insulin, IGF1, and plasma amino acids.
The ketogenic diet is a high-fat, medium-protein, and very low-carbohydrate diet. Reduced carbohydrate consumption (below 50 g/day) depletes glucose reserves for both normal fat oxidation and the supply of glucose to the central nervous system. This stimulates ketogenesis which produces high levels of ketone bodies from the breakdown of fat. There is a range of different types of ketogenic diet – classic or supplemented, e.g. with medium chain triglycerides (MCT). The paper tabulates the following general categories of ketogenic diet (Table 1):
Other nutritional interventions of more recent interest include a calorie-reduced ketogenic diet and combination effects with metformin, vitamin D, omega 3, genistein, vitamin A/E, and phytochemicals.
The paper weighs the potential benefits of the ketogenic diet against established adverse effects, including its unsuitability in hypoglycaemia-prone patients or patients with diabetes mellitus. Side effects include nausea, vomiting, headache, fatigue, dizziness, and constipation, although in most patients these resolve within a few days to weeks. Hence consideration needs to be on a patient-centred, case-by-case basis.
The paper also includes a section on recommended future studies and makes the point that this research approach is inexpensive compared to other interventions.
The paper concludes that ketogenic diets may enhance the antitumor effects of classic chemotherapy and radiotherapy with acceptable safety, tolerability, and quality of life. However, the cellular and molecular mechanisms underlying the antitumour effects of the ketogenic diet need further investigation.
Conclusion
So what are the potential benefits and impact from a dietetic perspective? The growing evidence base of the benefit of the ketogenic diet as an adjuvant therapy to chemoradiation or integrated with immunotherapy is encouraging. A major point of note and a limitation of this paper is that the role of the nutritionist/dietitian is not discussed. Many children dislike the taste of ketogenic meals, and dietetic input can offer support with tube feeding which has been shown to assist with compliance. Additionally, since there are many stresses for families including concerns about the safety of the diet, risk of deficiencies, and organising the supply of the diet, the dietitian’s counselling skills are very helpful. It is well recognised that while some families will not want to put their child through any more upset than is necessary, many parents and carers wish to explore dietary treatments in order to provide their child with every possible treatment that may be helpful. Dietitians can ensure that resources are appropriate and culturally adapted, as well as signpost to wider support networks and organisations such as Matthew’s Friends which have a range of resources available (matthewsfriends.org) [5]. Hence, in the future, we need to work towards understanding the barriers and ensuring the involvement of more dietitians in this emerging evidence base as has been recently explored in the USA for dietitians specialising in ketogenic diet therapies for epilepsy [6].
Disclosure Statement
I hereby declare that there are no conflicts of interest with regard to this commentary.