SPINAL RADIOSURGERY

DELAYED RADIATION-INDUCED MYELOPATHY

AFTER SPINAL RADIOSURGERY

Iris C. Gibbs, M.D.
Department of Radiation Oncology,
Stanford University Medical Center,
Stanford, California
Chirag Patil, M.D.
Department of Neurosurgery,
Stanford University Medical Center,
Stanford, California
Peter C. Gerszten, M.D.
Departments of Neurological Surgery
and Radiation Oncology,
University of Pittsburgh School of Medicine
University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania
John R. Adler, Jr., M.D.
Department of Neurosurgery,
Stanford University Medical Center,
Stanford, California
Steven A. Burton, M.D.
Department of Radiation Oncology,
University of Pittsburgh School of Medicine,
University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania
Reprint requests:
Iris C. Gibbs, M.D.,
Department of Radiation Oncology,
Stanford University Medical Center,
875 Blake Wilbur Drive,
Stanford, CA 94305-5847.
Email: iris.gibbs@stanford.edu
OBJECTIVE: Spinal cord injury is arguably the most feared complication in radiotherapy
and has historically limited the aggressiveness of spinal tumor treatment. We report a
case series of 6 patients treated with radiosurgery who developed delayed myelopathy.
METHODS: Between 1996 and 2005, 1075 patients with benign or malignant spinal
tumors were treated by CyberKnife (Accuray, Inc., Sunnyvale, CA) robotic radiosurgery at
Stanford University Medical Center and the University of Pittsburgh Medical Center.
Patients were followed prospectively with clinical and radiographic assessments at
1- to 6-month intervals. A retrospective review identified patients who developed delayed
radiation-induced myelopathy. Six patients (5 women, 1 man) with a mean age of 48
years (range, 25–61 years) developed delayed myelopathy at a mean of 6.3 months (range,
2–9 months) after spinal radiosurgery. Three tumors were metastatic; 3 were benign. The
metastases were in the upper to midthoracic spine, whereas the benign tumors were par-
tially in the cervical region. Three cases involved previous radiation therapy.
RESULTS: Dose volume histograms were generated for target and critical structures.
Clinical and dosimetric factors were analyzed for factors predictive of spinal cord injury.
Specific dosimetric factors contributing to this complication could not be identified,
but one-half of the patients with myelopathy received spinal cord biological equiva-
lent doses exceeding 8 Gy.
CONCLUSION: Delayed myelopathy after radiosurgery is uncommon with the dose
schedules used in this case series. Radiation injury to the spinal cord occurred over a
spectrum of dose parameters that prevented identification of specific dosimetric fac-
tors contributing to this complication. Primarily, biological equivalent dose estimates
were not usable for defining spinal cord tolerance to hypofractionated dose schedules.
We recommend limiting the volume of spinal cord treated above an 8-Gy equivalent
dose, because half of the complications occurred beyond this level.
KEY WORDS: Myelopathy, Radiation complications, Radiosurgery
Neurosurgery 64:A67–A72, 2009 DOI: 10.1227/01.NEU.0000341628.98141.B6 www.neurosurgery-online.com

S
Received, June 2, 2008. ince the classic reports of cervical spinal
Accepted, November 6, 2008. cord radiation myelopathy by Ahlbom (1)
in 1941 and Boden (3) in 1948, radiation-
Copyright © 2009 by the
Congress of Neurological Surgeons
induced myelopathy has been a feared com-
plication of conventional radiotherapy (13).
Animal studies and clinical modeling derived
from observational data provide the basis
for our current understanding of the factors
affecting the spinal cord’s tolerance to radia-
tion. The most important of these appear to
be the radiation dose schedule, which includes
dose per fraction, total dose, and interfraction
ABBREVIATIONS: BED, biological equivalent dose;
MRI, magnetic resonance imaging
interval. It is widely accepted that the thera-
peutic index of radiotherapy limits the radia-
tion dose near the spinal cord to such an
extent that the control of many tumors is
compromised. With advances in technology,
especially the development of image-guided
radiosurgery, the ability to deliver a more
aggressive radiation dose adjacent to the spine
is now feasible. Nevertheless, the tolerance of
the spinal cord to such single or hypofraction-
ated radiation schedules is uncertain and may
well differ markedly from conventional radia-
tion therapy precedents. Combining 2 of the
largest CyberKnife (Accuray, Inc., Sunnyvale,
CA) spinal radiosurgery series, we report 6

NEUROSURGERY VOLUME 64 | NUMBER 2 | FEBRUARY 2009 SUPPLEMENT | A67

GIBBS ET AL.
cases of radiation-induced myelopathy among more than 1000
patients treated with the CyberKnife for benign and metasta-
tic spinal tumors.
PATIENTS AND METHODS
Between 1996 and 2005, 1075 patients with benign or metastatic
spinal tumors were enrolled prospectively onto Institutional Review
Board-approved registry protocols and treated with CyberKnife radio-
surgery at either Stanford University or the University of Pittsburgh.
Patients with spinal instability, target tumors involving more than
2 vertebral levels, or spinal cord compression causing acute neurolog-
ical deterioration were excluded from enrollment. The overall cohort of
1075 patients included 156 patients with benign extramedullary tumors
and 919 patients with metastatic tumors. Of the metastatic tumors, the
primary histologies were predominantly renal cell carcinoma (142
patients), breast cancer (134 patients), lung cancer (129 patients),
melanoma (49 patients), gastrointestinal adenocarcinoma (57 patients),
sarcoma (42 patients), and prostate (40 patients). A database of clinical
and dosimetric factors was collected and used to identify patients who
developed treatment-related spinal cord injury.
Pretreatment setup and immobilization of cervical lesions used a sim-
ple, nonrigid Aquaplast face mask (WFR/Aquaplast Corp., Wyckoff,
NJ). In the lumbothoracosacral region, a vacuum foam cradle was used.
Treatment plans were generated using thin-section (1.25-mm slice thick-
ness) contrast computed tomographic scans through the anatomic region
of interest. As most metastatic vertebral body tumors were clearly visi-
ble by computed tomography, magnetic resonance imaging (MRI) with
image fusion was used when necessary to define the extent of benign
extramedullary tumors. In general, for treatment planning purposes,
small metastatic tumors involving less than 25% of the vertebral body
were contoured with an approximately 2- to 3-mm margin; all other ver-
tebral body tumors encompassed the entire vertebra. Until 2004, spinal
targeting in the lower cervical, thoracic, and lumbar spine required the
preradiosurgical percutaneous insertion of either stainless steel bone
screws (Stanford University Medical Center) or subperiosteal gold seeds
(University of Pittsburgh Medical Center), which served as localizing
fiducials. Treatment simulation techniques were similar at the 2 institu-
tions and have been described previously (4, 6). In 2004, the availability
of fiducial-less Xsight (Accuray, Inc.) hierarchical mesh tracking obviated
the need for metallic markers; with this system, the imaging system cor-
relates images of bony anatomy rather than implanted fiducials.
On the basis of institutional preference, radiosurgery was generally
administered in a single fraction at the University of Pittsburgh,
whereas patients were treated in 2 to 5 sessions at Stanford University,
depending on the tumor size or proximity to the spinal cord. A detailed
description of the treatment planning used at both institutions has pre-
viously been published (6). For all patients, the total dose prescription
varied between 12.5 and 25 Gy (12.5–20 Gy in 1 fraction, 18 to 22 Gy in
2 fractions, 18 to 24 Gy in 3 fractions, 14 to 24 Gy in 4 fractions, or 25
Gy in 5 fractions). The majority of patients (112 benign, 803 metastatic)
were treated with a single fraction; 90 (22 benign, 68 metastatic) were
treated in 2 fractions; and 70 (22 benign, 48 metastatic) were treated in
3 to 5 fractions. Care was taken to limit the maximum dose to the
spinal cord or cauda equina to less than 8 to 10 Gy while aiming to
optimize the coverage of the target lesion to at least 90%. However, this
constraint was relaxed when the volume of spinal cord receiving
greater than this dose was estimated to be only a few voxels.
Dose volume histograms were generated for the target lesion and
critical structures including the spinal cord. Conformality, homogene-
ity, and coverage indices were calculated and recorded using conven-
A68 | VOLUME 64 | NUMBER 2 | FEBRUARY 2009 SUPPLEMENT
tional measures (12, 16). Radiosurgery was performed as an outpatient
procedure lasting 30 to 60 minutes. Subsequently, patients with
metastatic lesions were followed both clinically and radiographically at
1- to 3-month intervals, and patients with benign lesions were followed
at 6-month intervals. Late complications were scored according to the
Common Toxicity Criteria, Versions 2.0 and 3.0 (17, 19).
The dose volume effects on the spinal cord were analyzed for all
patients in this series. Because of the variety of radiation schedules,
each was converted to biological equivalent doses (BED3) using the
following formula, with an assumed α/β ratio of 3 for spinal cord (7):
冢 冣
d
BED  nd 1 
α/β
To determine which factors were predictive of spinal cord injury, mul-
tiple clinical and dosimetric factors including sex, age, histology, present-
ing symptoms, previous radiotherapy, anatomic level, prescribed dose,
dose per fraction, tumor volume, and spinal cord dose were analyzed.
RESULTS
The tumor volumes in all patients ranged from 0.025 to 685
mL. More than 55% of metastatic patients were previously irra-
diated. Although care was taken to limit the volume of spinal
cord receiving 8 Gy or higher, the maximum spinal cord dose
ranged from 3.6 to 29.9 Gy. In all but 2 patients treated in single
fractions, the volume of spinal cord treated to a dose of more
than 8 Gy was less than 1 mL. The average spinal cord volume
treated to 8 Gy equivalent dose or more was also less than 1 mL.
Our review identified 6 patients who developed radiation-
induced delayed spinal cord myelopathy. The mean time to
onset was 6.3 months (range, 2–10 months). Four patients were
treated at Stanford University Medical Center and 2 at the
University of Pittsburgh Medical Center. The characteristics of
the 6 patients who developed radiation-induced myelopathy
after spinal radiosurgery are shown in Tables 1 and 2. The mean
age of the 5 women and 1 man was 48 years (range, 25–61
years). Three of the 6 spinal tumors were metastases, and 3 were
benign tumors (meningioma, schwannoma, and neurofibroma).
The three metastatic tumors were located entirely in the upper
to midthoracic spine, whereas all 3 benign tumors were located
predominantly in the cervical and cervicothoracic region. With
regard to clinical symptoms of myelopathy, 5 of the 6 patients
had motor and sensory deficits, 3 had bowel and bladder symp-
toms, and 4 had significant pain (Table 3).
Myelopathic symptoms were initially managed by corticos-
teroids in all patients. Some patients also received a combina-
tion of vitamin E and pentoxifylline (Trental; Sanofi-Aventis,
Bridgewater, NJ), hyberbaric oxygen, gabapentin (Neurontin;
Pfizer, New York), and/or physical therapy. After an initial
worsening, 3 of the 6 patients had improvement in their myelo-
pathic symptoms after treatment, 2 reached a plateau, and 1
patient progressed to paraplegia. All 3 patients who showed
clinical improvement had complete radiographic resolution of
their spinal cord edema on MRI. The earliest radiographic find-
ings were edema within the spinal cord, signified by hyperin-
tensity on the T2-weighted MRI sequence above and below the
region of injury. In most patients, clinical symptoms shortly
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 SPINAL MYELOPATHY AFTER RADIOSURGERY

TABLE 1. Patient characteristics and tumor location

Onset of Previous radiation
Patient Age (y)/ Previous Previous
Tumor type Location myelopathy and interval
no. sex surgery chemotherapy
(mo) between courses (mo)
1 59/F Renal cell carcinoma T6 9 No No Yes
2 55/F Breast cancer T5 6 Yes (80.8) No Yes
3 59/F Breast cancer T1 4 Yes (70.0) Yes Yes
4 29/F Meningioma C7–T2 9 No Yes No
5 61/F Schwannoma C6 2 No Yes No
6 25/M Neurofibroma C–C7 5 No No No

TABLE 2. Tumor and radiosurgery treatment plan characteristicsa

Treatment Total Maximum Maximum Volume of cord
Patient No. of
Tumor type Location volume prescription dose to spinal spinal cord receiving  BED3
no. 3 treatments
(cm ) dose (Gy) cord (Gy) BED3 (Gy) (8 Gy) (cm3)
1 Renal cell T6 vertebral body 13.7 25 2 26.2 140.6 3.4
carcinoma and spinal canal
2 Breast cancer T5 vertebral body 10.5 20 2 19.2 80.6 2.6
3 Breast cancer T1 posterior elements 18.9 21 2 13.9 46.1 0.3
4 Meningioma Right C7–T2 spinal 7.6 24 3 29.9 129.2 4.0
canal
5 Schwannoma Right C6 spinal canal 4.5 20 1 8.5 32.6 0.1
6 Neurofibroma Right C7 spinal canal 1.2 20 1 10 43.3 0.2

a
BED3 (8 Gy)  biological equivalent dose of 8 Gy in 1 fraction  29 Gy.

preceded or were coincident with these findings. Within 6 to 8

months, an area of contrast enhancement at the level of injury A B
developed. By 12 to 18 months from onset, a region of myelo-
malacia was seen within the spinal cord at the area of injury.
Figure 1 shows these characteristic radiographic findings of
radiation- induced myelopathy. Two of the patients had
received irradiation before radiosurgery at doses of 50.4 and
39.6 Gy in 1.8-Gy fractions, at 70 and 81 months, respectively.
The estimated maximum spinal cord doses in these previous
courses were 25.2 and 40 Gy, respectively. Also of interest is that
2 of the 6 patients who developed these injuries received an
antiangiogenic or epidermal growth factor inhibitor-targeted
therapy within 2 months of developing clinical myelopathy.
One patient died of systemic disease progression 17 months FIGURE 1. Characteristic radio- C
after treatment and 7 months after the onset of myelopathy. Of graphic findings of delayed radia-
note, the treated lesion in this patient appeared radiographi- tion- induced myelopathy. A,
cally stable at the last follow-up examination. spinal cord edema at the onset of
symptoms (brackets) and vertebral
An analysis of the cohort of myelopathic patients shows that
level of the T1 spinous process ini-
the mean prescribed dose to the tumor margin was 21.6 Gy. tially treated (arrow). B, spinal
The mean treatment volume was 9.4 mL. The mean maximum cord enhancement (brackets) at 6
BED3 for the spinal cord dose was 78.7 Gy (range, 32.6–140.3 Gy; to 8 months after onset. C, myelo-
standard deviation, 46.4 Gy) (Table 2). Three of the 6 patients malacia (brackets) 12 to 18 months
received a maximum spinal cord dose of less than the average after onset of symptoms.
dose received among all patients. One patient received a dose

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GIBBS ET AL.

TABLE 3. Myelopathy symptoms and response to treatment

Bowel or Neurological
Patient Sensory Motor Mortality
Pain bladder Treatments status after Current disability
no. symptoms weakness status
symptoms intervention
1 Yes No Yes Yes Corticosteroids, vitamin Stable Walker-dependent Dead
E, pentoxifylline, ambulation
hyperbaric oxygen,
physical therapy
2 Yes Yes Yes Yes Corticosteroids, vitamin Progressive Progression to Alive
E, pentoxifylline, myelopathy T4 paraplegia
hyperbaric oxygen,
physical therapy
3 Yes Yes Yes Yes Corticosteroids, Improved Walker-dependent Alive
physical therapy, ambulation
gabapentin
4 No Yes Yes No Physical therapy, Stable Intermittent Alive
corticoteroids use of cane

5 No Yes No No Corticosteroids, vitamin Improved Mild left lower- Alive

E, pentoxifylline extremity
numbness
6 Yes Yes Yes No Corticosteroids, Improved Gradual Alive
gabapentin, vitamin E, improvement in
pentoxifylline, numbness,
hyperbaric oxygen, weakness, and
physical therapy ambulation

above 1 standard deviation, and another received a maximum
dose nearly 2 standard deviations of the mean within this
cohort. Among these 6 patients, the mean volume of the spinal
cord receiving the biological equivalent of 8 Gy in 1 fraction (i.e.,
BED3  29 Gy) was 1.77 mL (range, 0.1–4.0 mL; standard devi-
ation, 1.77 mL). Three of the myelopathic patients had a spinal
cord volume of more than 1 mL treated above this dose level.
Owing to the low incidence of myelopathy among our
patients, logistic regression failed to show age, sex, primary
site, anatomic location, anatomic level, previous treatment, total
dose, dose per fraction, maximum dose, maximum spinal cord
dose, and tumor volume as predictive of spinal injury.
DISCUSSION
Although multiple publications now describe the technique
for and outcome from spinal radiosurgery, the complication of
radiation-induced myelopathy has never been analyzed and
characterized in detail. In this study, we report 6 patients treated
with spinal stereotactic radiosurgery who developed delayed
radiation-induced myelopathy. Similar to radiation therapy-
induced spinal cord injury, the pathogenesis of myelopathy after
radiosurgery is likely to be multifactorial, with no single target
cell and no single pathway. Injury is likely mediated by damage
to both white matter tracts and the local vasculature. This asser-
tion is supported by the pathological observation of demyelina-
tion, necrosis, increased vascularity, telangiectasis, hyaline
degeneration, vasculitis, fibrin exudation, thrombosis, and
edema in cases of spinal cord injury from radiation (16). By
virtue of lying within a vascular watershed region, the lower
cervical and upper thoracic spinal cord have a more tenuous
blood supply and may be more susceptible to radiation injury.
Early symptoms of spinal cord radiation damage include sen-
sory deficit, clumsiness, leg weakness, and Lhermitte’s syndrome.
These symptoms occur within weeks of therapy and are often
reversible. However, delayed radiation-induced myelopathy typ-
ically occurs more than 6 months after irradiation and is charac-
terized by more profound weakness, numbness, spasticity, pares-
thesias, pain, and hyper-reflexia. In the current series, the latency
between radiosurgery and the onset of spinal cord symptoms
averaged 6.3 months and is similar to what has been described
for delayed myelopathy after conventional radiotherapy.
Because the presentation of radiation myelopathy mirrors
myelopathy from other causes, alternative etiologies (such as
tumor progression) must be excluded. MRI is of greatest help
in distinguishing between these etiologies. For each patient
reported here, the initial radiographic sign of radiation injury
was an intramedullary increase in signal intensity on T2-
weighted MRI sequences, which is thought to correlate with
spinal cord edema.

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Data from numerous studies shape our current understand-
ing of the radiation dose tolerance for the spinal cord. Current
estimates are that 45 Gy in 22 to 25 fractions yields an incidence
of myelopathy of less than 0.2%. It is also suggested that a 5%
incidence rate of radiation myelopathy lies between 57 and 61
Gy (2). Marcus and Million (10) have demonstrated that con-
ventionally fractionated 45 Gy is on the flat part of the dose-
response curve such that any decrease in dose leads to a mini-
mal decrement in the incidence of myelopathy.
Unlike conventional radiotherapy, during which a full dose
is delivered to both the spine and the spinal cord, the Cyber-
Knife can deliver higher-dose hypofractionated radiation to the
target region while relatively sparing the adjacent spinal cord.
Thus, only portions of the spinal cord, rather than the entire
spinal cord, were subjected to the prescription dose at the tar-
geted spinal level. This reinforces the concept that there may be
a partial volume effect, which has also been suggested using
other LINAC-based radiosurgery techniques (14). The spinal
cord dose limit using conventional radiotherapy fractions of 1.8
to 2 Gy and a total dose of 45 Gy is generally observed. This
dose corresponds to a BED3 equal to 76 Gy. Even though the
BED formula predicts this rather high spinal cord dose limit of
76 Gy, our fear of possible catastrophic spinal cord injury led us
to observe a more conservative limit. Thus, we observed a
single-session spinal cord dose limit of 8 to 10 Gy, or the equiv-
alent of a BED3 of 29 Gy, if multifractions were delivered. On
the basis of clinical experience with other neural structures
such as the optic chiasm and optic nerve, this dose limit is
widely believed to be safe.
In an ad hoc and nonrandomized fashion, this constraint
was gradually relaxed over the course of our several years of
experience. With respect to the maximal spinal cord BED3, 3
of the 6 injured patients in this series were, in hindsight, clear
outliers and regretfully treated with much larger than aver-
age doses. However, inexplicably, spinal injury occurred in
the remaining 3 patients, even though only a small volume of
spinal cord received the equivalent of 8 Gy in a single frac-
tion and virtually no portion was treated to more than 10 Gy.
Although genetic mutations were not tested in this study, it
is possible that potential predisposing genetic factors may
have been present that could explain these toxicities. For
example, it has been suggested that germ line alterations in
genes such as transforming growth factor β 1(TGβ1) and
ataxia telangiectasia (ATM) may predict radiation-induced
late effects (18).
Animal studies support the notion of a dose volume, i.e.,
dose length, radiation effect in spinal cord (9). Available clin-
ical data after radiation therapy, however, fail to support
such a phenomenon. This fact may be attributable to the rel-
atively large volume (or length) of spinal cord irradiated in
conventional radiotherapy. Nevertheless, in a summary of
dose volume effects, Emami et al. (5) determined that when
one-third or the entire spinal cord was irradiated, the spinal
cord radiation tolerance varied narrowly between 50 and 47
Gy, respectively. Despite the lack of evidence supporting
a significant dose volume effect for the spinal cord, we
NEUROSURGERY
SPINAL MYELOPATHY AFTER RADIOSURGERY
attempted to minimize the amount of spinal cord treated
above a BED of 29 Gy.
In assessing the risk of radiation-induced myelopathy, other
factors to consider are the effects of re-irradiation and systemic
therapy. Particularly among patients treated for metastatic
tumors, more than one- half of our current patients have
received such previous irradiation. In the current series, the 2
previously irradiated patients had been treated more than 6
years before undergoing radiosurgery. In a recent review of 40
re-irradiated patients, myelopathy did not occur when BED2
for either course was 102 Gy or less (which approximates a
BED3 of 85 Gy) or when the interval between courses was more
than 2 months (11). In contrast, the 2 previously irradiated
patients in the present series who developed spinal complica-
tions had received a BED3 of only 46 and 81 Gy, and the inter-
val between courses of radiation was 70 to 80 months.
Because some chemotherapy agents can potentiate the effects
of radiation, we are cautious about concurrent chemotherapy.
In the past few years, targeted antibody and antireceptor ther-
apies have emerged. Two of the patients in this series had
received vascular endothelial growth factor and epidermal
growth factor receptor inhibitors within 3 months of the onset
of myelopathy. These same patients were also among the more
aggressively treated dose volume outliers. Therefore, the extent
to which dose volume effects versus radiosensitization by these
agents contributed to myelopathy remains unknown.
Given the experience presented here with more than 1000
patients, among whom 6 (0.6%) developed injury, we conclude
that radiation-induced myelopathy is an uncommon complica-
tion of spinal radiosurgery and that the key variables underly-
ing this phenomenon remain, at best, partially elucidated.
Similar to other efforts to understand the risks of myelopathy
using hypofractionated dose strategies, we were unable to
define clear factors (8). Although we attempted to use radiobi-
ological estimates of the BED to guide us, it is unlikely that
these formulae will ultimately prove to be useful in establish-
ing the limits of spinal cord tolerance to hypofractionated radi-
ation courses.
Delayed myelopathy after radiosurgery is uncommon with
the dose schedules used in this case series. Specific dosimetric
factors contributing to this complication could not be identified
in this small series. BED estimates did not clearly predict spinal
cord tolerance to hypofractionated dose schedules. We recom-
mend limiting the volume of spinal cord treated above an 8-Gy
equivalent dose, because half of the complications occurred
beyond this level.
CONCLUSION
Hypofractionated radiosurgery is safe. On the basis of the
data presented here, we suggest that caution be used when
considering radiosurgery plans that expose more than approx-
imately 1 cm3 of the spinal cord to a 8-Gy or higher dose equiv-
alent. With a better understanding and future refinements in
radiosurgical technique, it may be possible to reduce the risk of
this dreaded complication.
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GIBBS ET AL.

Disclosures
Iris C. Gibbs, M.D., is a member of the Clinical Advisory Board of Accuray,
Inc., the manufacturer of CyberKnife. John R. Adler, Jr., M.D., is a stockholder of
Accuray, Inc. The other authors have no personal financial or institutional inter-
est in any of the drugs, materials, or devices described in this article.
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IN-TRAINING LIAISONS
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by a commitment to excellence in education and by a dedication to research and scientific knowledge.

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they relate to journal content and perspective.

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Issues attendant to in-training matters should be conveyed to:
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Department of Neurosurgery Department of Neurosurgery Department of Neurological Surgery Department of Neurological Surgery
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A72 | VOLUME 64 | NUMBER 2 | FEBRUARY 2009 SUPPLEMENT www.neurosurgery-online.com