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A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma.

Publication ,  Journal Article
Porper, K; Shpatz, Y; Plotkin, L; Pechthold, RG; Talianski, A; Champ, CE; Furman, O; Shimoni-Sebag, A; Symon, Z; Amit, U; Hemi, R; Kanety, H ...
Published in: J Neurooncol
July 2021

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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Published In

J Neurooncol

DOI

EISSN

1573-7373

Publication Date

July 2021

Volume

153

Issue

3

Start / End Page

487 / 496

Location

United States

Related Subject Headings

  • Oncology & Carcinogenesis
  • Neoplasm Recurrence, Local
  • Middle Aged
  • Metformin
  • Ketones
  • Humans
  • Glioma
  • Combined Modality Therapy
  • Brain Neoplasms
  • 1112 Oncology and Carcinogenesis
 

Citation

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Porper, K., Shpatz, Y., Plotkin, L., Pechthold, R. G., Talianski, A., Champ, C. E., … Lawrence, Y. R. (2021). A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma. J Neurooncol, 153(3), 487–496. https://doi.org/10.1007/s11060-021-03786-8
Porper, Keren, Yael Shpatz, Luba Plotkin, Ronit Goldman Pechthold, Alisa Talianski, Colin E. Champ, Orit Furman, et al. “A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma.J Neurooncol 153, no. 3 (July 2021): 487–96. https://doi.org/10.1007/s11060-021-03786-8.
Porper K, Shpatz Y, Plotkin L, Pechthold RG, Talianski A, Champ CE, et al. A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma. J Neurooncol. 2021 Jul;153(3):487–96.
Porper, Keren, et al. “A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma.J Neurooncol, vol. 153, no. 3, July 2021, pp. 487–96. Pubmed, doi:10.1007/s11060-021-03786-8.
Porper K, Shpatz Y, Plotkin L, Pechthold RG, Talianski A, Champ CE, Furman O, Shimoni-Sebag A, Symon Z, Amit U, Hemi R, Kanety H, Mardor Y, Cohen ZR, Jan E, Genssin H, Anikster Y, Zach L, Lawrence YR. A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma. J Neurooncol. 2021 Jul;153(3):487–496.
Journal cover image

Published In

J Neurooncol

DOI

EISSN

1573-7373

Publication Date

July 2021

Volume

153

Issue

3

Start / End Page

487 / 496

Location

United States

Related Subject Headings

  • Oncology & Carcinogenesis
  • Neoplasm Recurrence, Local
  • Middle Aged
  • Metformin
  • Ketones
  • Humans
  • Glioma
  • Combined Modality Therapy
  • Brain Neoplasms
  • 1112 Oncology and Carcinogenesis