Ketogenic diets are low in
carbohydrates and high in fat, which forces cells to rely more heavily upon mitochondrial oxidation of
fatty acids for energy. Relative to normal cells,
cancer cells are believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in
glucose metabolism to generate reducing equivalents. In this study we tested the hypothesis that a
ketogenic diet concurrent with radiation and
chemotherapy would be clinically tolerable in locally advanced
non-small cell lung cancer (NSCLC) and
pancreatic cancer and could potentially exploit
cancer cell oxidative metabolism to improve therapeutic outcomes. Mice bearing MIA PaCa-2
pancreatic cancer xenografts were fed either a
ketogenic diet or standard rodent chow, treated with conventionally fractionated radiation (2 Gy/fraction), and
tumor growth rates were assessed daily.
Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modfied
proteins as a marker of oxidative stress. Based on this and another previously published preclinical study, phase 1 clinical trials in locally advanced NSCLC and
pancreatic cancer were initiated, combining standard radiation and
chemotherapy with a
ketogenic diet for six weeks (NSCLC) or five weeks (
pancreatic cancer). The xenograft experiments demonstrated prolonged survival and increased 4HNE-modfied
proteins in animals consuming a
ketogenic diet combined with radiation compared to radiation alone. In the phase 1 clinical trial, over a period of three years, seven NSCLC patients enrolled in the study. Of these, four were unable to comply with the diet and withdrew, two completed the study and one was withdrawn due to a dose-limiting toxicity. Over the same time period, two
pancreatic cancer patients enrolled in the trial. Of these, one completed the study and the other was withdrawn due to a dose-limiting toxicity. The preclinical experiments demonstrate that a
ketogenic diet increases radiation sensitivity in a
pancreatic cancer xenograft model. However, patients with locally advanced NSCLC and
pancreatic cancer receiving concurrent
radiotherapy and
chemotherapy had suboptimal compliance to the oral
ketogenic diet and thus, poor tolerance.