Despite remarkable improvements in screening, diagnosis, and targeted therapies, cancer remains the second leading cause of death in the United States. It is increasingly clear that diet and lifestyle practices play a substantial role in cancer development and progression. As such, various dietary compositions have been proposed for reducing cancer risk and as potential adjuvant therapies. In this article, we critically assess the preclinical and human trials on the effects of the ketogenic diet (KD, i.e., high-fat, moderate-to-low protein, and very-low carbohydrate content) for cancer-related outcomes. The mechanisms underlying the hypothesized effects of KD, most notably the Warburg Effect, suggest that restricting carbohydrate content may impede cancer development and progression via several pathways (e.g., tumor metabolism, gene expression). Overall, although preclinical studies suggest that KD has antitumor effects, prolongs survival, and prevents cancer development, human clinical trials are equivocal. Because of the lack of high-quality clinical trials, the effects of KD on cancer and as an adjunctive therapy are essentially unknown. We propose a set of research recommendations for clinical studies examining the effects of KD on cancer development and progression.

Carbohydrate-restricted ketogenic diets (KD) were introduced in the mid-19th century as a weight loss method with a resurgence of its use in epilepsy treatment in the 1920’s. Research conducted over the last several years provides evidence that KD’s can confer beneficial effects for several chronic metabolic diseases, including obesity, type-2 diabetes, and polycystic ovary syndrome. In recent years, emerging evidence suggests KD’s may also have therapeutic benefits for some cancers and for neurological conditions such as Alzheimer's disease, Parkinson's' disease, multiple sclerosis, traumatic brain injury, and spinal cord injury. Finally, as the physiological mechanisms by which a KD operates become increasingly understood, we speculate that several other health conditions (e.g., autism, cystic fibrosis, COVID-19) that may improve from consuming a KD. The potential to reduce or eliminate long-term pharmaceutical treatments and their potential adverse effects by modifying diet patterns justifies additional research, particularly rigorously conducted clinical trials with long-term follow-up. This brief review describes a selection of the recent studies of KD as applied to chronic metabolic diseases, and provides an estimate of the quality of the evidence for KD’s effects. We also describe and appraise some of the risks and misconceptions attributed to KD which may limit the widespread use of KD’s among physicians and healthcare providers.