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

  • Clinical Study
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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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Availability of data and material

The data that support the findings of this study are available on request from the corresponding author (Y.R.L).

Abbreviations

KD:

Ketogenic diet

ModAD:

Modified Atkins diet

HGG:

High-grade gliomas

AMPK:

AMP-activated protein kinase

LDL:

Low-density lipoprotein

MCT:

Medium chain triglyceride

β-OHB:

β-hydroxybutyrate

VMAT:

Volumetric modulated arc therapy

HbA1C:

hemoglobin A1C

IGF1:

Insulin like growth factor1

TRAM:

Treatment response assessment maps

BMI:

Body mass index

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Acknowledgements

We gratefully acknowledge the encouragement and assistance of Prof Raphael Catane and Prof Ohad Cohen in the design and opening of the trial.

Funding

The trial was supported by the EU FP7 Marie Curie program FP7-MC-CIG 303795 awarded to YRL, and the Rosetrees Trust (grant reference A680). The MCT oil was generously provided by Nutricia, Netherlands.

Author information

Author notes

  1. Leor Zach and Yaacov R. Lawrence have contributed equally to this work.

Authors and Affiliations

  1. Department of Radiation Oncology, Sheba Medical Center, Tel HaShomer, Israel

    Yael Shpatz, Orit Furman, Ariel Shimoni-Sebag, Zvi Symon, Uri Amit, Elisheva Jan, Hili Genssin, Leor Zach & Yaacov R. Lawrence

  2. Sackler School of Medicine, Tel Aviv University, 5265601, Tel Aviv, Israel

    Keren Porper, Zvi Symon, Uri Amit, Yael Mardor, Yair Anikster, Leor Zach & Yaacov R. Lawrence

  3. Pediatric Neurology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hashomer, Israel

    Luba Plotkin & Ronit Goldman Pechthold

  4. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA

    Colin E. Champ

  5. Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, Tel HaShomer, Israel

    Rina Hemi & Hannah Kanety

  6. The Advanced Technology Center, Sheba Medical Center, Tel HaShomer, Israel

    Yael Mardor

  7. Department of Neurosurgery, Sheba Medical Center, Tel HaShomer, Israel

    Zvi R. Cohen

  8. Metabolic Disease Unit, Sheba Medical Center, Tel HaShomer, Israel

    Yair Anikster

  9. Department of Radiation Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, USA

    Yaacov R. Lawrence

  10. Institute of Oncology, Sheba Medical Center, Tel HaShomer, Israel

    Keren Porper & Alisa Talianski

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Contributions

Keren Porper, Leor Zach, Colin E. Champ, and Yaacov R Lawrence designed the study, wrote the manuscript, and analyzed the data. All authors implemented the research protocol, contributed to the interpretation of the data, read and approved the final manuscript.

Corresponding author

Correspondence to Yaacov R. Lawrence.

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Conflict of interest

Yaacov Lawrence: Research funding: Karyopharm Therapeutics, Checkmate Pharmaceuticals, Bristol-Myers Squibb and pending from Merck Serono. Honoria/consultancy fees: Bristol-Myers Squibb, Clinigen Group and Roche Genetech. Stock ownership: Protean Biodiagnostics Inc. Colin E. Champ receives compensation for his dietary books, Leor Zach is an advisor of Trail-IN Pharma. Scientific advisory board for Atkins, and scientific advisory board for Biosense. The other authors declare that they have no competing interests.

Ethical approval

This study was performed in line with the principles of the Declaration of Helsinki. The trial was approved by the local Institutional Review Board (IRB) - SMC 0712 − 13, and registered on Clinicaltrials.gov NCT02149459.

Consent to participate

All patients signed an IRB approved informed consent form, in accordance with the principals of Good Clinical Practice (GCP).

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Porper, K., Shpatz, Y., Plotkin, L. et al. A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma. J Neurooncol 153, 487–496 (2021). https://doi.org/10.1007/s11060-021-03786-8

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