Journal article
A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma
Journal of neuro-oncology, v 153(3), pp 487-496
01 Jul 2021
PMID: 34152528
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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Details
- Title
- A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma
- Creators
- Keren Porper - Tel Aviv UniversityYael Shpatz - Sheba Medical CenterLuba Plotkin - College Station Medical CenterRonit Goldman Pechthold - Edmond and Lily Safra Children's HospitalAlisa Talianski - Sheba Medical CenterColin E. Champ - Duke Medical CenterOrit Furman - Sheba Medical CenterAriel Shimoni-Sebag - Sheba Medical CenterZvi Symon - Sheba Medical CenterUri Amit - Sheba Medical CenterRina Hemi - Sheba Medical CenterHannah Kanety - Sheba Medical CenterYael Mardor - Tel Aviv UniversityZvi R. Cohen - Sheba Medical CenterElisheva Jan - Sheba Medical CenterHili Genssin - Sheba Medical CenterYair Anikster - Tel Aviv UniversityLeor Zach - Tel Aviv UniversityYaacov R. Lawrence - Thomas Jefferson University
- Publication Details
- Journal of neuro-oncology, v 153(3), pp 487-496
- Publisher
- Springer Nature
- Number of pages
- 10
- Grant note
- FP7-MC-CIG 303795 / EU FP7 Marie Curie program A680 / Rosetrees Trust
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Radiation Oncology (and Nuclear Medicine)
- Web of Science ID
- WOS:000663987700001
- Scopus ID
- 2-s2.0-85109906834
- Other Identifier
- 991021897379604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Clinical Neurology
- Oncology