Abstract LB-252: Ketogenic diet with concurrent chemoradiation in head and neck squamous cell carcinoma: Pre-clinical and phase I trial results

Abstract

Abstract Purpose: A ketogenic diet (KD) is a high fat, low carbohydrate diet that forces cells to utilize mitochondrial fatty acid oxidation for energy production. It has been previously shown that cancer cells have defects in mitochondrial oxidative metabolism resulting in increased oxidative stress relative to non-malignant cells. Because radiation and platinum based chemotherapy also induce oxidative damage, we hypothesized that a KD may enhance radiation and platinum chemotherapy efficacy in head and neck cancer. The KD's ability to enhance radiation and chemotherapy efficacy were assessed in murine head and neck cancer xenograft models. The safety and tolerability of a KD in combination with standard of care radiation and platinum-based chemotherapy in head and neck cancer patients was assessed in a phase I clinical trial. Methods: Mice bearing FaDu human head and neck cancer xenografts were fed either standard mouse chow or commercially prepared KD and treated with varying combination of cetuximab (CTX), cisplatin, and/or radiation (IR) and tumor growth was measured via calipers. Tumor homogenates and mice serum were harvested to test for markers including glutathione, 4HNE, PCNA, and IL6. Based on this study and other previously published pre-clinical studies, a phase I clinical trial in locally advanced head and neck cancer combining standard radiation and chemotherapy while consuming a KD was initiated. Subjects consumed a KD by PEG or nasogastric-tube and were also allowed to orally consume water, sugar-free drinks approved by the dietician, and approved snacks and meals approved by the dietician. Oxidative stress markers including protein carbonyl and glutathione were assessed. Results: Mice bearing xenografts treated with KD + IR + CTX had significantly increased survival relative to mice treated with IR + CTX. Collected tumor homogenates in KD + IR + CTX treated mice demonstrated increased 4HNE modified proteins relative to tumor homogenates from IR +CTX mice. In the phase I clinical trial, a total of twelve subjects were enrolled in the study. Four subjects completed five weeks of the KD as per protocol. Median follow-up from completion of RT was 13.1 months (range 8.0-26.7 months). Of the eight subjects that did not tolerate the diet, median number of days subjects stayed on diet was 5.5 (range: 2-8 days). Reasons for discontinuation included “stress of diet compliance” (1), grade 2 nausea (3), and grade 3 fatigue (1). Three subjects were removed for dose limiting toxicities: grade 4 hyperuricemia (2) and grade 3 acute pancreatitis (1). Median weight loss was 2.95% for the KD group and 7.92% for subjects that did not tolerate the diet. Subject serums demonstrated increased oxidative stress as they continued the diet. Conclusions: KD shows promise as adjuvant treatment in mouse xenograft model of head and neck cancer but in our small study there was difficulty with compliance and tolerability when combined with standard of care radiation and chemotherapy. Citation Format: Daniel MA, Carryn Anderson, Samuel N. Rodmann, Kayla Follmer, Visarut Buranasudja, Kellie Bodeker, Jessica R. Parkhurst, Michael McCormack, Andrew Davis, Douglas R. Spitz, John Buatti, Bryan G. Allen, Melissa A. Fath. Ketogenic diet with concurrent chemoradiation in head and neck squamous cell carcinoma: Pre-clinical and phase I trial results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-252.