Ketogenic Diet with Concurrent Chemoradiation in Head and Neck Squamous Cell Carcinoma: Preclinical and Phase 1 Trial Results

Abstract

Ketogenic diets (KD) are high in fat and low in carbohydrates, forcing cells to utilize mitochondrial fatty acid oxidation for energy production. Since cancer cells demonstrate increased mitochondrial oxidative stress relative to normal cells, we hypothesized that a KD may selectively enhance metabolic oxidative stress in head and neck cancer cells, sensitizing them to radiation and platinum-based chemotherapy without causing increased toxicity in surrounding normal tissues. This hypothesis was tested in preclinical murine xenografts and in a phase 1 clinical trial (NCT01975766). In this study, mice bearing human head and neck cancer xenografts (FaDu) were fed either standard mouse chow or KetoCalt KD (90% fat, 8% carbohydrate, 2% protein) and exposed to ionizing radiation. Tumors were harvested from mice to test for glutathione, a biomarker of oxidative stress. In parallel, patients with locally advanced head and neck cancer were enrolled in a phase 1 clinical trial where they consumed KD and received radiation with concurrent platinum-based chemotherapy. Subjects consumed KetoCal KD via percutaneous endoscopic gastrostomy (PEG) tube and were also allowed to orally consume water, sugar-free drinks, and foods approved by a dietitian. Oxidative stress markers including protein carbonyls and total glutathione were assessed in patient blood samples both pre-KD and while consuming the KD. Mice bearing FaDu xenografts that received radiation and KD demonstrated a slight improvement in tumor growth rate and survival compared to mice that received radiation alone; however a variation in responses was seen dependent on the fatty acid composition of the diet. In the phase 1 clinical trial, a total of twelve patients were enrolled in the study. Four patients completed five weeks of the KD as per protocol (with variance in compliance). Eight patients did not tolerate the diet with concurrent radiation and platinum-chemotherapy (5 were patient decision and 3 were removed from study due to toxicity). The median number of days consuming a KD in patients who did not complete the study was 5.5 (range: 2-8 days). Reasons for discontinuation

Impact of a ketogenic diet intervention during radiotherapy on body composition: V. Final results of the KETOCOMP study for head and neck cancer patients

“…In an uncontrolled phase I study, Ma et al. found that two thirds of HNSCC patients did not manage to consume a KD during 5 weeks of radiochemotherapy [ 25 ]. Thereby, all patients had received a PEG tube prior to the study, which was used to provide a ketogenic formula that accounted for the main calories of the KD.…”

“…Thereby, all patients had received a PEG tube prior to the study, which was used to provide a ketogenic formula that accounted for the main calories of the KD. Reasons for discontinuation included fatigue, nausea, and vomiting, two cases of grade 4 hyperuricemia, and one case of acute grade 3 pancreatitis; the attribution of these side effects to the KD was unclear in all cases [ 25 ]. Thus, a KD—even if applied via a PEG tube—may not be feasible in the general HNC population.…”

“…Ma et al. also showed that the combination of a ketogenic formula with ionizing radiation significantly prolonged the survival time of HNC xenograft-bearing mice compared to irradiation alone [ 25 ]. However, the survival benefit vanished when a new version of the formula with another fatty acid composition was given.…”

“…In oncological settings, KDs can be defined as high-fat (usually ≥ 65% of energy intake), low-carbohydrate (≤ 50 g and day) diets ideally providing an adequate protein supply (≈ 1.5 g/kg per day) and leading to an elevation of circulating ketone bodies into the mM range (≥ 0.5 mmol/L). Preclinical research has shown that KDs may not only impair tumor cell metabolism and growth, but also fight cachexia and therapy-induced side effects [ 23 – 25 ]. However, data showing whether HNC patients can comply to KDs are sparse.…”

Efficacy of Glucose Starvation of Cancer Cells in the Progress of Oral Squamous Cell Carcinoma Induced in Hamster

“…KD might selectively enhance metabolic oxidative stress in head and neck cancer cells, and sensitize them to radiation and platinum chemotherapy without causing increased toxicity in surrounding normal tissues. This hypothesis was tested in preclinical murine xenografts in a previous study, mice bearing human head and neck cancer xenografts were fed either standard mouse chow or (a glucose-free diet) and exposed to ionizing radiation, Mice-bearing xenografts that received radiation and a glucose-free diet showed a slight improvement in tumor growth rate and survival compared to mice that received radiation alone (Ma et al, 2021), This is consistent with the conclusion of our research that showed that a glucose-free diet slightly prevents oral squamous cell carcinoma.…”