Plain language summary
Radiation therapy is standard care for cancer patients alongside surgery and chemotherapy. However, there are still some cancers which seem to withstand this treatment. This study looks at whether calorie reduction (CR) and carbohydrate restriction can have any impact on treatment outcomes. The reason for exploring this idea comes from data showing a high level of ‘glycolysis’ (a need for sugar) in cancer cells. Calorie reduction is defined as 30-50% less calories per day achieved either by intermittent fasting or a fixed calorie regime. Carbohydrate restriction is defined as a ketogenic diet (KD); a diet which removes carbohydrate foods and sugars and focuses on high fat foods and limited protein. Both nutritional protocols have been shown to have similar metabolic effects of reducing blood sugar levels and insulin activity, and thus reducing the ability of cancer cells to communicate. The 5R principle of radiotherapy tries to exploit the differences between cancer cells and healthy tissue. The 5Rs are Repair to DNA damage, Repopulation of the tumour, Redistribution of cells, Reoxygenation of the tumour area and Radio resistance in cells which do not respond to treatment. The concern with restricting calories and carbohydrates is triggering detrimental weight loss in cancer patients, although some fat loss may be beneficial in overweight patients with hormonal cancers. Intermittent fasting seems to fit well with typical radiation treatment schedules over 2-3-month periods. Trials of ketogenic diets on healthy volunteers have shown it encourages muscle mass which is a strong predictor of survival in cancer patients. Of the two, a carbohydrate-restricted, ketogenic diet appears the most viable adjunct to radiation therapy.
Abstract
Aggressive tumors typically demonstrate a high glycolytic rate, which results in resistance to radiation therapy and cancer progression via several molecular and physiologic mechanisms. Intriguingly, many of these mechanisms utilize the same molecular pathways that are altered through calorie and/or carbohydrate restriction. Furthermore, poorer prognosis in cancer patients who display a glycolytic phenotype characterized by metabolic alterations, such as obesity and diabetes, is now well established, providing another link between metabolic pathways and cancer progression. We review the possible roles for calorie restriction (CR) and very low carbohydrate ketogenic diets (KDs) in modulating the five R's of radiotherapy to improve the therapeutic window between tumor control and normal tissue complication probability. Important mechanisms we discuss include (1) improved DNA repair in normal, but not tumor cells; (2) inhibition of tumor cell repopulation through modulation of the PI3K-Akt-mTORC1 pathway downstream of insulin and IGF1; (3) redistribution of normal cells into more radioresistant phases of the cell cycle; (4) normalization of the tumor vasculature by targeting hypoxia-inducible factor-1α downstream of the PI3K-Akt-mTOR pathway; (5) increasing the intrinsic radioresistance of normal cells through ketone bodies but decreasing that of tumor cells by targeting glycolysis. These mechanisms are discussed in the framework of animal and human studies, taking into account the commonalities and differences between CR and KDs. We conclude that CR and KDs may act synergistically with radiation therapy for the treatment of cancer patients and provide some guidelines for implementing these dietary interventions into clinical practice.
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