The purpose of this review is to summarize our own experimental studies carried out over a 13-year period of time using the F98 rat glioma as model for high grade gliomas. We evaluated a binary chemo-radiotherapeutic modality that combines either cisplatin (CDDP) or carboplatin, administered intracerebrally (i.c.) by means of convection-enhanced delivery (CED) or osmotic pumps, in combination with either synchrotron or conventional X-irradiation.
F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Approximately 14 days later, either CDDP or carboplatin was administered i.c. by CED, followed 24 h later by radiotherapy using either a synchrotron or, subsequently, megavoltage linear accelerators (LINAC).
CDDP was administered at a dose of 3 µg in 5 µL, followed 24 h later with an irradiation dose of 15 Gy or carboplatin at a dose of 20 µg in 10 µL, followed 24 h later with 3 fractions of 8 Gy each, at the source at the European Synchrotron Radiation Facility (ESRF). This resulted in a median survival time (MeST) > 180 days with 33% long term survivors (LTS) for CDDP and a MeST > 60 days with 8 to 22% LTS, for carboplatin. Subsequently it became apparent that comparable survival data could be obtained with megavoltage X-irradiation using a LINAC source. The best survival data were obtained with a dose of 72 µg of carboplatin administered by means of Alzet® osmotic pumps over 7 days. This resulted in a MeST of > 180 days, with 55% LTS. Histopathologic examination of all the brains of the surviving rats revealed no residual tumor cells or evidence of significant radiation related effects.
The results obtained using this combination therapy has, to the best of our knowledge, yielded the most promising survival data ever reported using the F98 glioma model.
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Blood–brain barrier disruption
Dexamethasone, mannitol, furosemide
Dose reduction index
DNA double strand breaks
European synchrotron radiation facility
- F98EGFR :
F98 glioma cells transfected with the human gene encoding EGFR
Inductively coupled plasma-optical emission spectroscopy
Percent increase in life span
Linear energy transfer
Long term survivors
Median survival time
Magnetic resonance imaging
13 Mer B-cell epitope
16 Mer HER-1 epitope
Stereotactic synchrotron radiotherapy
- Vd :
Volume of distribution
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We thank Michael Weldon, Nilendu Gupta, and John C. Grecula for their help in carrying out radiation studies for the Barth Laboratory, W. Hans Meisen, Balveen Kaur, Pravin Kaumaya and Robert Lee for their assistance in carrying out studies relating to molecular targeting, Gong Wu for preparation of bioconjugates and Delisa Watkins and David Carpenter for their assistance in the preparation of this manuscript. We thank the ESRF for their technical support and for providing beam time and special thanks to Thierry Brochard, Christian Nemoz and Dominique Dallery. Finally, we thank Marie-Claude Biston, Jean-François Adam, Anne-Marie Charvet, Caroline Boudou and François Estève, for their help in carrying out radiation studies in Grenoble.
Support for studies, carried out by Barth and his co-workers, has been provided by the Musella Foundation, Voices against Brain Cancer, The Ohio State University Department of Pathology and the Kevin J. Mullin Memorial Fund for Brain Tumor Research. Those carried out by Elleaume and her research team were supported by the University Grenoble Alpes, INSERM, the Auvergne Rhône Alpes region and the Labex Primes (ANR-11-LABX-0063).
Conflict of interest
The authors declare that they have no competing interests.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All animal studies performed by Hélène Elleaume’s team were performed in compliance with the European Directive 2010/63/EU. The protocols were submitted to the ESRF ethical committee reference number ETHAX N°113. Animal studies carried out by Rolf Barth and his research team were in accordance with the Guide for the Care and the Use of Laboratory Animals (National Academy press, Washington DC, 1996) and the protocols were approved by the Institutional Laboratory Care and Use Committee of The Ohio State University.
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Elleaume, H., Barth, R.F., Rousseau, J. et al. Radiation therapy combined with intracerebral convection-enhanced delivery of cisplatin or carboplatin for treatment of the F98 rat glioma. J Neurooncol 149, 193–208 (2020). https://doi.org/10.1007/s11060-020-03600-x
- F98 glioma
- Convection-enhanced delivery
- Radiation therapy
- Brain tumors
- Synchrotron radiation