Radiation Myelopathy

260 Pages·2022·5.071 MB·English

by  Timothy Schultheiss

Radiation
Myelopathy
Timothy Schultheiss
123
Radiation Myelopathy
Timothy Schultheiss
Radiation Myelopathy
Timothy Schultheiss
Department of Radiation Oncology
City Of Hope National Medical Centre
Duarte, CA, USA
ISBN 978-3-030-94657-9 ISBN 978-3-030-94658-6 (eBook)
https://doi.org/10.1007/978-3-030-94658-6
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Preface
Radiation myelopathy is a terrifying complication of cancer therapy. It can lead to
quadriplegia and death. As with traumatic spinal cord injuries, it is not uncommon
for victims of this progressively debilitating injury to take their own lives.
It is no surprise then that hundreds of research papers have been devoted to pre-
senting the clinical data available and to describing experimental results. Experiments
in the spinal cord’s response to radiation have been performed in virtually every
animal model used in radiation studies. These experiments include not only the dose
response, but also many aspects of fractionation effects, volume effects, retreat-
ment, dose-response modification, and of course the pathogenesis of injury. The
radiation injury is rarely equivocal, and therefore the endpoint of both the experi-
ments and the clinical outcome is rarely in doubt.
Because the spinal cord is small and has a simple geometry, it is ideal for describ-
ing radiation responses using biomathematical models. Generally the dosimetry is
simple and the dose is uniform. In clinical studies, the dose to the spinal cord can
usually be well described by a single dose without the need to resort to a dose-
volume histogram.
With the possible exception of the skin, the spinal cord is the organ most studied
in the radiation literature. Unlike the skin, the spinal cord’s response is nearly
always easily dichotomized—myelopathy has or has not occurred. Thus the radia-
tion response of the spinal cord has been a favorite subject of study, not only because
of the crucial knowledge that may be gained regarding the clinical complication, but
also because it can serve as a testing ground for all biomathematical models of
radiation response. If a model cannot be successfully deployed in this area, there is
little hope it can describe the results of any other radiation complication.
The purpose of this book is to coalesce in a single volume most of the clinical
dose-response data and the experience with the numerous experimental studies.
Frankly, some experimental and clinical studies do not seem to fit well with the
totality of knowledge in this area. By compiling this information, it may be possible
to identify those outliers as one would identify outlying data points.
Reflecting the literature, the most extensively covered topic in this book is the
rodent model of radiation myelopathy. The rat has been the proving ground for
every class of radiation myelopathy experiment.
Like much of the medical literature, publications in this field have a broad range
in the quality of the study design, execution, and analysis, and the overwhelming
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majority of study conclusions have not been critically assessed by the target con-
sumers of radiation oncology literature. Accordingly, much of the experimental lit-
erature that is discussed here has been subjected to re-analysis in an effort to
determine to what degree the conclusions are supported by the data. The findings
are mixed. In the early literature, results of the data analysis were commonly
reported without providing the reader with any direct exposure to the raw data in
either table or graphical form. Being given values or graphs of D without even
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seeing the dose-response curve fitted to the data leaves the reader without any basis
for assessing whether the data and the model agree. In fact, it was also common to
use so few animals per dose group that either one or zero data points had responses
between 0% and 100%. This issue is addressed in considerable detail.
As this field of study matured, certain mathematical models used to describe the
radiation response have become standardized and accepted as being useful, and pos-
sibly accurate. However, it has been somewhat unusual for these models to be
assessed for their ability to describe the data, that is, goodness-of-fit tests are not the
standard. One objective of this book is to re-analyze data from seminal works to
determine the degree to which our beliefs are supported by the data. In some cases,
this re-analysis broadens or clarifies the current understanding of the subject. This
exercise also discloses areas where specific information is missing. The areas of
volume effects and retreatment have received particular attention in this work.
This book also contains original work that has not been previously published. A
new proposal to describe the final step in the pathogenesis that leads to white matter
necrosis is offered. A composite dose-response function for both the cervical and
thoracic spinal cord levels is presented, with the new component being the thoracic
cord’s dose response. A new model of retreatment is put forward that does not
equate expression of damage and dose. The last chapter is a presentation of a multi-
species dose-response model that has only been published in abstract form.
Although we know a great deal about radiation myelopathy and how to avoid it,
the most important aspect of this injury has remained elusive—how to treat it. Some
progress has been made and many now believe that the elements of the pathogenesis
are sufficiently well understood to make logical attempts in its prevention and
treatment.
The clinical occurrence of RM frequently leads to civil cases of malpractice and
sometimes product liability where machines fail to perform as anticipated. This area
is briefly addressed in the Appendix.
I would like to acknowledge the mentorship of Colin G. Orton, who introduced
me to medical physics and Lester J. Peters whose guidance in clinical research and
academic medicine was indispensable. Finally, the daily collaborations with
L. Clifton Stephens grew to be the most important experience in my research career.
In the writing of this book, I have been fortunate to enjoy the enduring patience of
my wife, Ginamarie.
Duarte, CA, USA Timothy Schultheiss
Contents
1 History and the Search for the Tolerance Dose . . . . . . . . . . . . . . . . . . . 1
1.1 Early Clinical Reports: How We Arrived at the
45-Gy Tolerance Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 The Advent of New Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.3 Hypofractionation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.4 The Spaghetti Plot: Not Culinary Intrigue,
But Rather a Watershed in Radiobiology . . . . . . . . . . . . . . . . . . . . . . 6
1.5 Pathogenesis and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2 Pathology and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1 Some Spinal Cord Anatomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.2 Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.3.1 Cervical and Thoracic Levels. . . . . . . . . . . . . . . . . . . . . . . . . 19
2.3.2 Lumbar Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.3.3 Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.3.4 BNCT Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.3.5 Roles of Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.4 Traumatic Injury, Inflammation, and Covid-19 . . . . . . . . . . . . . . . . . 31
2.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3 Statistics of Dose Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.1 Experimental Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.2 Experimental Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.2.1 Separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
3.2.2 More on Extreme Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.3 Analyzing Dose-Response Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.3.1 The Dose-Response Function . . . . . . . . . . . . . . . . . . . . . . . . 43
3.3.2 Collinearity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3.4 Fitting Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.4.1 Maximum Likelihood Estimation . . . . . . . . . . . . . . . . . . . . . 47
3.4.2 Model Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
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3.4.3 Degrees of Freedom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.4.4 Confidence Intervals and Joint Confidence Regions . . . . . . . 53
3.4.5 Examination of Residuals . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
3.5 Factors Other than Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
3.5.1 Odds Ratio and Dose Modifying Factor . . . . . . . . . . . . . . . . 57
3.5.2 Exact Interval for Proportion: Graphical Presentation
of the Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4 Radiation Myelopathy in Conventional Treatments . . . . . . . . . . . . . . . 61
4.1 Relevant Aspects of Anatomy of the Spinal Cord by Level . . . . . . . . 61
4.2 Appearance of Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.3 Dose Response by Level of Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
4.4 Dose Limits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
4.5 Radiation Myelopathy in Stereotactic Radiosurgery . . . . . . . . . . . . . 80
4.6 Other Altered Fractionation Schedules . . . . . . . . . . . . . . . . . . . . . . . 93
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
5 Experimental Studies on Rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
5.1 Mouse Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
5.2 Rat Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
5.3 Dose Modifying Factors (DMF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
5.4 Fractionation Studies in the Rat Up to 1990 . . . . . . . . . . . . . . . . . . . 106
5.4.1 Transition from the Power-Law Model to the LQ Model . . . 107
5.4.2 Studies from van der Kogel . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.4.3 The Fe-Plot. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
5.4.4 Altered Fractionation and Top-Up Experiments . . . . . . . . . . 114
5.4.5 Additional Ang Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
5.5 Dose Response After 1990 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
5.6 Relative Biological Effectiveness (RBE) . . . . . . . . . . . . . . . . . . . . . . 126
5.6.1 Neutrons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
5.6.2 Leith et al. Charged Particles . . . . . . . . . . . . . . . . . . . . . . . . . 129
5.6.3 Carbon Ions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
5.6.4 Protons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
5.7 In Closing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
6 Volume Effect Studies in Rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
7 Long-Term Repair and Retreatment, Treatment of Immature
Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
7.1 Retreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
7.1.1 The Dose-Repaired/Recovered Model . . . . . . . . . . . . . . . . . . 165
7.1.2 The Volume-Repaired Model of Retreatment Response . . . . 178
7.1.3 Human Retreatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
7.2 RM in Immature Humans and Animals . . . . . . . . . . . . . . . . . . . . . . . 183
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Contents ix
8 Experimental Studies on Large Animals . . . . . . . . . . . . . . . . . . . . . . . . 191
8.1 Rhesus Monkeys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
8.2 Pigs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
8.3 Beagles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
8.4 Fractionation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
9 Multispecies Dose-Response Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
9.1 Biostatistical Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
9.2 The Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
9.3 Results of Large Animal Data Analysis . . . . . . . . . . . . . . . . . . . . . . . 209
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Epilogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
Appendix: Medico-Legal Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
About the Author
Timothy Schultheiss Radiation myelopathy has been the primary research area

for Timothy Schultheiss for 40 years, but he has numerous publications on the radia-
tion dose response of many organs in addition to the spinal cord. His research con-
tributions have been acknowledged by the awarding of Fellowships in the American
College of Radiology, the American Association of Medical Physicists, and the
American Society for Radiation Oncology. He is currently Professor Emeritus at
City of Hope National Medical Center after having retired as Director of Radiation
Physics. Before that he served in the same capacity at Fox Chase Cancer Center.
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