Consuming a Ketogenic Diet while Receiving Radiation and Chemotherapy for Locally Advanced Lung Cancer and Pancreatic Cancer: The University of Iowa Experience of Two Phase 1 Clinical Trials

Abstract

Objective Ketogenic diets (KD) are low in carbohydrates and high in fat which force cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Cancer cells, relative to normal 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. The current study tests the hypothesis that consuming a KD while receiving concurrent radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes. Methods Mice bearing MIA PaCa-2 pancreatic cancer xenografts were fed either a KD or standard rodent chow, treated with conventionally fractionated radiation (2 Gy / fx), and tumor growth rates were assessed daily. Tumors were assessed for immuno-reactive 4-hydroxy-2-nonenal-(4HNE) modified proteins as a marker of oxidative stress. Based on this and another previously published pre-clinical study, phase I clinical trials in locally advanced NSCLC and pancreatic cancer were initiated combining standard radiation and chemotherapy with a KD (lung 6 weeks duration; pancreas 5 weeks duration). Results Xenograft experiments demonstrated prolonged survival and increased 4HNE modified proteins in animals consuming a KD combined with radiation compared to radiation alone. In the phase I clinical trial, over a period of three years, seven NSCLC subjects 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 Of these, four were unable to comply with the diet and withdrew, two completed the study, and one was withdrawn due to a dose limiting toxicity.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 Of these, one completed the study and the other was withdrawn due to a dose limiting toxicity. Conclusion The pre-clinical experiments demonstrate that a KD increases radiation sensitivity in a pancreatic cancer xenograft model. However, subjects with locally advanced NSCLC and pancreatic cancer receiving concurrent radiation and chemotherapy had suboptimal oral KD compliance and hence poor tolerance.

Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer

“…Similar results were obtained using a pancreatic cancer xenograft model treated with 6 × 2 Gy [101]. In 2 clinical trials, the same working group had measured increases in plasma protein carbonyl content in lung and pancreatic cancer patients who adhered to a strict KD while receiving chemo-RT [101]. However, the small sample size (n = 4) and the lack of a control group did not allow any conclusion as to whether the KD contributed to this increase of oxidative protein damage or whether it was solely due to the chemo-RT.…”

“…Tumor samples harvested from mice on the KD at the end of the hypofractionation experiment exhibited significantly higher levels of protein modifications with the lipid peroxidation marker 4-hydroxy-2-nonenal (4HNE), consistent with increased KD-mediated oxidative stress in tumor cells [100]. Similar results were obtained using a pancreatic cancer xenograft model treated with 6 × 2 Gy [101]. In 2 clinical trials, the same working group had measured increases in plasma protein carbonyl content in lung and pancreatic cancer patients who adhered to a strict KD while receiving chemo-RT [101].…”

A systematic review of the use of ketogenic diets in adult patients with cancer

“…All studies investigated the effect of oral KD; however, there was considerable variation in how the diet was delivered. Three studies followed a traditional KD with a 4 : 1 or 3 : 1 fat (F) to carbohydrate CHO) + protein (P) kg m –2 (F : CHO + P) , two studies used a ratio of F : CHO + P between 0.7 : 1 and 1.8 : 1 , three studies used a modified Atkins diet (20–40 g day −1 CHO) , two studies used a low glycaemic index diet (<70 g day −1 CHO) and one study used a Paleolithic KD with a F : P ratio of 2 : 1 .…”

“…Ten studies assessed blood glucose at baseline and follow‐up. Four studies reported a decrease in blood glucose , five reported no significant changes and one study showed problems with maintenance of glucose below 80 mg dL −1 . Two studies reported on correlation between β‐hydroxylbutyrateand glucose concentration.…”

Foods as a Novel Treatment for Glioblastoma

“…The other preclinical and clinical studies also described the anti-cancer effects of combination therapy including caloric reduction diet with radiation and chemotherapy. [33][34][35][36] Mechanism of ketogenic diet DNA damage might be the reason of tumor cell death by radiation while the normal cells can repair themselves and tumor cell cannot. [37] In addition, Insulin-like Growth Factor-1 (IGF-1) and glucose have been reduced in tumor cells in response to genotoxic stress.…”