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Clinical evidence for dose tolerance of the central nervous system in hypofractionated radiotherapy

  • Original Research
  • Published:
Journal of Radiation Oncology

Abstract

Background

Stereotactic radiosurgery (SRS), stereotactic body radiotherapy (SBRT), and stereotactic ablative body radiotherapy (SABR) are commonly used in the treatment of central nervous system (CNS) disease. This study has refined the radiation toxicity estimates for some normal tissues of the CNS based on review and analysis of the clinical evidence for single fraction radiosurgery, hypofractionated SBRT, and conventionally fractionated radiation therapy.

Methods

Published guidelines and protocols are reviewed. In the past, many normal tissue tolerances were compiled based on the experience of the investigators and publications in the literature. Some tolerances were determined by modeling or calculation using the existing biological formulas, in particular the linear quadratic (LQ) model. In the present study, the estimate of risk for each dose tolerance limit in some CNS tissues is provided exclusively with normal tissue complication probability (NTCP). The clinical outcomes are compared to understand the difference in biological effect between radiosurgery and radiotherapy.

Results

Normal tissue dose tolerances and the corresponding complication rates are provided for brainstem, optic nerves, cochlea, and spinal cord, including single fraction SRS, five-fraction SBRT, and conventional radiation therapy. Calculation of biologically effective dose (BED) or single fraction equivalent dose (SFED) alone using the LQ model conveys no consensus on the biological effect across different fractionations. Comparison of conventional radiation therapy to brain and spinal cord with single fraction equivalent dose leads to even conflicting clinical outcomes.

Conclusions

Effective differences between single fraction SRS and conventional radiotherapy need to be better understood. The existing biological model might not be valid to predict the radiosurgical outcomes based on conventionally fractionated radiotherapy. However, application of the statistical dose response models of clinical SRS and SBRT outcomes data to selected current dose tolerance guidelines into simple tables can be a clinically useful resource.

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Notes

  1. The Hindo et al. study [90] of parallel opposed whole brain fields during the era of Cobalt differs in many ways from the modern era of radiosurgery, especially in terms of patient selection, prognosis, dose distribution, and other factors. Perhaps the most relevant comparison is for brainstem, since the entire cross-section of brainstem was probably within ± 10% of a comparable physical dose of 10 Gy/1 fraction in the whole brain study, whereas for modern radiosurgery only a small volume of the critical structure is usually allowed to reach levels like 10 Gy in 1 fraction. We are not advocating 10 Gy in 1 fraction to a large volume, but we feel it is an interesting historical point of comparison.

Abbreviations

AE:

Adverse event

BED:

Biologically effective dose

CNS:

Central nervous system

GTV:

Gross tumor volume

HyTEC:

High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic

LQ:

Linear quadratic

MLE:

Maximum likelihood estimate

NfxED:

N-fraction equivalent dose

NTCP:

Normal tissue complication probability

QUANTEC:

Quantitative Analysis of Normal Tissue Effects in the Clinic

RT:

Radiation therapy

RTOG:

Radiation therapy oncology group

SABR:

Stereotactic ablative body radiotherapy

SBRT:

Stereotactic body radiation therapy

SFED:

Single fraction equivalent dose

SRS:

Stereotactic radiosurgery

WBRT:

Whole brain radiation therapy

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Author information

Authors and Affiliations

  1. Department of Radiation Oncology, NYU Langone Medical Center, New York, NY, 10016, USA

    Jinyu Xue & Indra J. Das

  2. Department of Radiation Oncology, Loyola University Medical Center, Maywood, IL, 60153, USA

    Bahman Emami & James S. Welsh

  3. Department Radiation Oncology and Mol. Rad. Sciences, Johns Hopkins University Hospital, Baltimore, MD, 21231, USA

    Jimm Grimm, Luke Peng, Harry Quon, Wolfram Laub, Chengcheng Gui, Nicholas Spoleti, Kristin J. Redmond & Lawrence R. Kleinberg

  4. Department of Radiation Oncology, MD Anderson Cancer Center at Cooper, Camden, NJ, 08103, USA

    Gregory J. Kubicek & Sucha O. Asbell

  5. Philadelphia CyberKnife, Crozer-Keystone Health System, Havertown, PA, 19083, USA

    Rachelle Lanciano & Luther W. Brady

  6. Department of Neurological Surgery, Cooper University Hospital, Camden, NJ, 08103, USA

    Howard Warren Goldman

Authors
  1. Jinyu Xue
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  2. Bahman Emami
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  3. Jimm Grimm
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  4. Gregory J. Kubicek
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  5. Sucha O. Asbell
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  6. Rachelle Lanciano
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  7. James S. Welsh
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  8. Luke Peng
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  9. Harry Quon
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  10. Wolfram Laub
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  11. Chengcheng Gui
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  12. Nicholas Spoleti
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  13. Indra J. Das
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  14. Howard Warren Goldman
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  15. Kristin J. Redmond
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  16. Lawrence R. Kleinberg
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  17. Luther W. Brady
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Corresponding author

Correspondence to Jinyu Xue.

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Funding

This work was partially supported by a grant from Accuray.

Conflict of interest

Dr. Kleinberg has received research grants from Novocure, Arbor, Accuray, has performed consulting for Novocure, Accuray, and is on the advisory board for Novocure. Dr. Redmond has received research funding from Elekta AB and Accuray, as well as travel expenses and honorarium for speaking for Accuray. Dr. Grimm developed and holds intellectual property rights to the DVH Evaluator software tool which is an FDA-cleared product in commercial use, and which has been used for this analysis; and has received research grants from Novocure and Accuray. All other authors declare that they have no relevant conflict of interest.

Ethical approval

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008.

Informed consent

Informed consent was not applicable due to the retrospective nature of brain dose tolerance study. All other data was from the published literature.

Additional information

In memory of Dr. Jack Fowler, DSc, PhD, MD (Hon), FIPEM, FInstP, FRCR, FACR, FASTRO, FAAPM

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Xue, J., Emami, B., Grimm, J. et al. Clinical evidence for dose tolerance of the central nervous system in hypofractionated radiotherapy. J Radiat Oncol 7, 293–305 (2018). https://doi.org/10.1007/s13566-018-0367-2

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  • DOI: https://doi.org/10.1007/s13566-018-0367-2

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