Journal of Radiation Oncology

, Volume 7, Issue 4, pp 293–305 | Cite as

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

  • Jinyu XueEmail author
  • Bahman Emami
  • Jimm Grimm
  • Gregory J. Kubicek
  • Sucha O. Asbell
  • Rachelle Lanciano
  • James S. Welsh
  • Luke Peng
  • Harry Quon
  • Wolfram Laub
  • Chengcheng Gui
  • Nicholas Spoleti
  • Indra J. Das
  • Howard Warren Goldman
  • Kristin J. Redmond
  • Lawrence R. Kleinberg
  • Luther W. Brady
Original Research



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.


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.


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.


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.


Radiosurgery Radiotherapy Fractionation Toxicities Biologically effective dose Outcomes 



Adverse event


Biologically effective dose


Central nervous system


Gross tumor volume


High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic


Linear quadratic


Maximum likelihood estimate


N-fraction equivalent dose


Normal tissue complication probability


Quantitative Analysis of Normal Tissue Effects in the Clinic


Radiation therapy


Radiation therapy oncology group


Stereotactic ablative body radiotherapy


Stereotactic body radiation therapy


Single fraction equivalent dose


Stereotactic radiosurgery


Whole brain radiation therapy


Compliance with ethical standards


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.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jinyu Xue
    • 1
    Email author
  • Bahman Emami
    • 2
  • Jimm Grimm
    • 3
  • Gregory J. Kubicek
    • 4
  • Sucha O. Asbell
    • 4
  • Rachelle Lanciano
    • 5
  • James S. Welsh
    • 2
  • Luke Peng
    • 3
  • Harry Quon
    • 3
  • Wolfram Laub
    • 3
  • Chengcheng Gui
    • 3
  • Nicholas Spoleti
    • 3
  • Indra J. Das
    • 1
  • Howard Warren Goldman
    • 6
  • Kristin J. Redmond
    • 3
  • Lawrence R. Kleinberg
    • 3
  • Luther W. Brady
    • 5
  1. 1.Department of Radiation OncologyNYU Langone Medical CenterNew YorkUSA
  2. 2.Department of Radiation OncologyLoyola University Medical CenterMaywoodUSA
  3. 3.Department Radiation Oncology and Mol. Rad. SciencesJohns Hopkins University HospitalBaltimoreUSA
  4. 4.Department of Radiation OncologyMD Anderson Cancer Center at CooperCamdenUSA
  5. 5.Philadelphia CyberKnife, Crozer-Keystone Health SystemHavertownUSA
  6. 6.Department of Neurological SurgeryCooper University HospitalCamdenUSA

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