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 Of these, four were unable to comply with the diet and withdrew, two completed the study, and one was withdrawn due to a dose limiting toxicity.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 Of these, one completed the study and the other was withdrawn due to a dose limiting toxicity.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.
Background
High‐dose cisplatin (Cis) is a preferred systemic agent for concurrent chemoradiation (CRT) in locally advanced head and neck squamous cell cancer (LAHNSCC) patients. As some patients are unable to tolerate Cis, this study compares the toxicity and efficacy of weekly cisplatin‐paclitaxel (CP) regimen with Cis.
Methods
Patients with LAHNSCC receiving definitive chemoradiation either with Cis (Cisplatin—100 mg/m2 q3w x 3) or CP (Cisplatin—20 mg/m2; Paclitaxel—30 mg/m2qw x7) were included.
Results
Cis and CP groups were comprised of 114 and 111 subjects, respectively. Complete response for Cis versus CP groups was 88% versus 88%, respectively. Median follow‐up for the study was 58.5 months. After adjusting for potential treatment selection bias, no significant differences were evident between Cis and CP groups for overall survival (hazard ratios [HR] 0.85, 95% CI 0.59‐1.21, P = 0.36), progression free survival (HR 0.88, 95% CI 0.62‐1.24, P = 0.46), locoregional control (HR 0.77, 95% CI 0.52‐1.15, P = 0.21), and distant control (HR 0.87, 95% CI 0.61‐1.23, P = 0.42). Patients in the CP group had less acute and chronic toxicities.
Conclusions
Weekly CP regimen can serve as an alternative systemic therapy with radiation in patients with LAHNSCC who are not fit for Cis.
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