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 KetoCal® 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 included “stress of diet compliance” (1 patient), grade 2 nausea (3 patients), and grade 3 fatigue (1 patient). Three patients were removed from the trial due to dose-limiting toxicities including: grade 4 hyperuricemia (2 patients) and grade 3 acute pancreatitis (1 patient). Median weight loss was 2.95% for the KD-tolerant group and 7.92% for patients who did not tolerate the diet. In conclusion, the ketogenic diet shows promise as a treatment combined with radiation in preclinical mouse head and neck cancer xenografts. A phase 1 clinical trial evaluating the safety and tolerability of KD demonstrated difficulty with diet compliance when combined with standard-of-care radiation therapy and cisplatin chemotherapy.

生酮饮食 (KD) 脂肪含量高，碳水化合物含量低，迫使细胞利用线粒体脂肪酸氧化来产生能量。由于癌细胞表现出相对于正常细胞增加的线粒体氧化应激，我们假设 KD 可以选择性地增强头颈癌细胞的代谢氧化应激，使它们对放射和铂类化学疗法敏感，而不会增加周围正常组织的毒性。这一假设在临床前小鼠异种移植物和 1 期临床试验 (NCT01975766) 中得到检验。在这项研究中，携带人类头颈癌异种移植物 (FaDu) 的小鼠被喂食标准小鼠饲料或 KetoCal® KD（90% 脂肪、8% 碳水化合物、2% 蛋白质）并暴露于电离辐射。从小鼠身上采集肿瘤以测试谷胱甘肽，氧化应激的生物标志物。与此同时，局部晚期头颈癌患者参加了一项 1 期临床试验，他们服用了 KD 并接受了同步铂类化疗的放疗。受试者通过经皮内窥镜胃造口术 (PEG) 管食用 KetoCal KD，还允许口服水、无糖饮料和营养师批准的食物。包括蛋白质羰基化合物和总谷胱甘肽在内的氧化应激标志物在 KD 前和食用 KD 时的患者血液样本中进行了评估。与单独接受放射治疗的小鼠相比，接受放射治疗和 KD 的携带 FaDu 异种移植物的小鼠的肿瘤生长率和存活率略有提高；然而，反应的变化取决于饮食的脂肪酸组成。在 1 期临床试验中，共有 12 名患者参加了研究。四名患者按照协议完成了五周的 KD（依从性差异）。8 名患者不能耐受同步放疗和铂类化疗的饮食（5 名患者决定，3 名因毒性而退出研究）。未完成研究的患者服用 KD 的中位数天数为 5.5（范围：2-8 天）。停药原因包括“饮食依从性压力”（1 名患者）、2 级恶心（3 名患者）和 3 级疲劳（1 名患者）。由于剂量限制性毒性包括：4 级高尿酸血症（2 名患者）和 3 级急性胰腺炎（1 名患者），三名患者被排除在试验之外。KD 耐受组的体重减轻中位数为 2.95%，而 7. 92% 对于不能耐受饮食的患者。总而言之，生酮饮食在临床前小鼠头颈癌异种移植手术中与放疗相结合显示出前景。一项评估 KD 安全性和耐受性的 1 期临床试验表明，当与标准护理放射治疗和顺铂化疗相结合时，饮食依从性存在困难。