Background

Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that the metabolic stress induced by a KD combined with metformin would enhance radiation’s efficacy. We sought to assess the tolerability and feasibility of this approach.

Methods

A single-institution phase I clinical trial. Radiotherapy was either 60 or 35 Gy over 6 or 2 weeks, for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a Modified Atkins Diet (ModAD) supplemented with medium chain triglycerides (MCT). There were three cohorts: Dietary intervention alone, and dietary intervention combined with low-dose or high-dose metformin; all patients received radiotherapy. Factors associated with blood ketone levels were investigated using a mixed-model analysis.

Results

A total of 13 patients were accrued, median age 61 years, of whom six had newly diagnosed and seven with recurrent disease. All completed radiation therapy; five patients stopped the metabolic intervention early. Metformin 850 mg three-times daily was poorly tolerated. There were no serious adverse events. Ketone levels were associated with dietary factors (ketogenic ratio, p < 0.001), use of metformin (p = 0. 02) and low insulin levels (p = 0.002). Median progression free survival was ten and four months for newly diagnosed and recurrent disease, respectively.

Conclusions

The intervention was well tolerated. Higher serum ketone levels were associated with both dietary intake and metformin use. The recommended phase II dose is eight weeks of a ModAD combined with 850 mg metformin twice daily.

中文翻译：

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剂量递增代谢疗法联合伴随放疗治疗高级别胶质瘤的 I 期临床试验

背景

动物脑肿瘤模型已证明放射治疗和生酮饮食 (KD) 之间存在协同作用。二甲双胍通过 AMPK 激活和 mTOR 抑制具有体外抗癌活性。我们假设由 KD 与二甲双胍联合引起的代谢压力会提高放疗的疗效。我们试图评估这种方法的耐受性和可行性。

方法

单机构 I 期临床试验。对于新诊断的和复发的神经胶质瘤，放疗分别为 60 或 35 Gy，时间为 6 周或 2 周。饮食干预包括添加中链甘油三酯 (MCT) 的改良阿特金斯饮食 (ModAD)。共有三个队列：单独饮食干预，饮食干预联合低剂量或高剂量二甲双胍；所有患者均接受放射治疗。使用混合模型分析研究了与血酮水平相关的因素。

结果

共纳入 13 名患者，中位年龄 61 岁，其中 6 名新诊断，7 名复发。所有完成的放射治疗；5 名患者提前停止了代谢干预。二甲双胍 850 毫克，每日 3 次，耐受性差。没有严重的不良事件。酮水平与饮食因素（生酮比率，p < 0.001）、二甲双胍的使用（p = 0. 02）和低胰岛素水平（p = 0.002）相关。新诊断和复发疾病的中位无进展生存期分别为 10 个月和 4 个月。

结论

干预的耐受性良好。较高的血清酮水平与饮食摄入和二甲双胍的使用有关。推荐的 II 期剂量是八周的 ModAD 联合 850 毫克二甲双胍每天两次。