No abstract

There is increasing interest in the use of a ketogenic diet for various adult disorders; however, the ability of adults to generate ketones is unknown. Our goal was to challenge the hypothesis that there would be no difference between adults and children regarding their ability to enter ketosis. Methods: Two populations were studied, both treated with identical very low-carbohydrate high-fat diets: a retrospective series of children with epilepsy or/and metabolic disorders (2009–2016) and a prospective clinical trial of adults with glioblastoma. Dietary intake was assessed based upon written food diaries and 24-h dietary recall. Ketogenic ratio was calculated according to [grams of fat consumed]/[grams of carbohydrate and protein consumed]. Ketone levels (β-hydroxybutyrate) were measured in blood and/or urine. Results: A total of 168 encounters amongst 28 individuals were analyzed. Amongst both children and adults, ketone levels correlated with nutritional ketogenic ratio; however, the absolute ketone levels in adults were approximately one quarter of those seen in children. This difference was highly significant in a multivariate linear regression model, p < 0.0001. Conclusions: For diets with comparable ketogenic ratios, adults have lower blood ketone levels than children; consequently, high levels of nutritional ketosis are unobtainable in adults.

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 sought to assess the feasibility of combined radiation, KD and metformin in adults with high grade gliomas. METHODS A prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin combined with dietary intervention and 3) high-dose metformin combined with dietary intervention. Clinicaltrials.gov NCT02149459. RESULTS A total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4 / 5 adverse events, and only one grade 3 event (nausea). The median level of ketones during the intervention was 0.5 mM. Ketone levels were associated with dietary factors (high fat, low carbohydrates, MCT intake), use of metformin and low insulin levels. Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease. CONCLUSIONS The intervention was fairly well tolerated, however only moderate ketones levels were obtained. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a low-carbohydrate diet combined with 850mg metformin twice daily.

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 metabolic stress (moderate hypoglycemia) would enhance the anti-tumor efficacy of concurrent DNA damage. We further hypothesized that concurrent metformin would decrease insulin resistance and consequently elevate ketone blood level. We performed a formal prospective phase I dose-escalation trial to assess the tolerability and feasibility of this approach. Methods A prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin (850mg twice-daily) combined with dietary intervention and 3) high-dose metformin (850mg three-times daily) combined with dietary intervention. Statistics: The prediction of blood ketones levels was performed using a mixed-model univariate analysis methodology. Clinicaltrials.gov NCT02149459. Results A total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4/5 adverse events. Median levels of β-hydroxybutyrate increased from 0.09 mmol/l at baseline to 0.59 mmol/l during the trial (p=0.006). Ketone levels were associated with dietary factors (ketogenic ratio, p &lt; 0.001), use of metformin (p = 0.02) and low insulin levels (p = 0.002). Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease. Conclusions The intervention was fairly well tolerated. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a KD combined with 850mg metformin twice daily. The trial was supported by the EU FP7 Marie Curie program FP7-MC-CIG 303795, and the Rosetrees Trust. The MCT oil was provided by Nutricia, Netherlands. Citation Format: Yaacov Lawrence, Keren Porper, Yael Shpatz, Uri Amit, Zvi Symon, Leor Zach. A phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-004.

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 metabolic stress (moderate hypoglycemia) would enhance the anti-tumor efficacy of concurrent DNA damage. We further hypothesized that concurrent metformin would decrease insulin resistance and consequently elevate ketone blood level. We performed a formal prospective phase I dose-escalation trial to assess the tolerability and feasibility of this approach. Methods A prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin (850mg twice-daily) combined with dietary intervention and 3) high-dose metformin (850mg three-times daily) combined with dietary intervention. Statistics: The prediction of blood ketones levels was performed using a mixed-model univariate analysis methodology. Clinicaltrials.gov NCT02149459. Results A total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4/5 adverse events. Median levels of β-hydroxybutyrate increased from 0.09 mmol/l at baseline to 0.59 mmol/l during the trial (p=0.006). Ketone levels were associated with dietary factors (ketogenic ratio, p &lt; 0.001), use of metformin (p = 0.02) and low insulin levels (p = 0.002). Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease.Conclusions The intervention was fairly well tolerated. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a KD combined with 850mg metformin twice daily. The trial was supported by the EU FP7 Marie Curie program FP7-MC-CIG 303795, and the Rosetrees Trust. The MCT oil was provided by Nutricia, Netherlands. Citation Format: Yaacov R. Lawrence, Keren Porper, Yael Shpatz, Luba Plotkin, Ronit Pechthold, Alisa Talianski, Zvi Symon, uri Amit, Zvi Cohen, Hili Gnessin, Yair Anikster, Yael Mardor, Leor Zach. A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT142.