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Analysis of a Surgical Series of 21 Cerebral Radiation Necroses
Journal Pre-proof Analysis of a surgical series of 21 cerebral radiation necroses Benito Campos, MD, Jan-Oliver Neumann, MD, Alexander Hubert, MD, Sebastian Adeberg, MD, Rami El Shafie, MD, Andreas von Deimling, MD, Martin Bendszus, MD, Jürgen Debus, MD, PhD, Denise Bernhardt, MD, Andreas Unterberg, MD PII:
S1878-8750(20)30267-9
DOI:
https://doi.org/10.1016/j.wneu.2020.02.005
Reference:
WNEU 14279
To appear in:
World Neurosurgery
Received Date: 24 November 2019 Revised Date:
31 January 2020
Accepted Date: 1 February 2020
Please cite this article as: Campos B, Neumann J-O, Hubert A, Adeberg S, El Shafie R, von Deimling A, Bendszus M, Debus J, Bernhardt D, Unterberg A, Analysis of a surgical series of 21 cerebral radiation necroses, World Neurosurgery (2020), doi: https://doi.org/10.1016/j.wneu.2020.02.005. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Analysis of a surgical series of 21 cerebral radiation necroses
1 2 3
Benito Campos MD1,*, Jan-Oliver Neumann MD1,*, Alexander Hubert MD 2, Sebastian
4
Adeberg MD3,4,5, Rami El Shafie MD3,4,5, Andreas von Deimling MD6,7, Martin
5
Bendszus MD2, Jürgen Debus MD, PhD3,4,5,8,9,10, Denise Bernhardt MD3,4,5,*, Andreas
6
Unterberg MD1,*
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
1
22
Disclosure of funding statement: This work was supported by Heidelberg
23
University’s Young Investigator Grant (DB, RES). The funding source(s) had no
24
involvement in the research and/or preparation of the article.
25
Conflict of Interest: The authors declare no conflict of interest.
Department of Neurosurgery, University Hospital Heidelberg, Germany Department of Neuroradiology, University Hospital Heidelberg, Germany 3 Department of Radiation Oncology, University Hospital Heidelberg, Germany 4 Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany 5 National Center for Tumor diseases (NCT), Heidelberg, Germany 6 Department of Neuropathology, Heidelberg University and 7 Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany 9 Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany. 10 German Cancer Consortium (DKTK), partner site Heidelberg, Germany *These authors contributed equally to this work 2
26 27
Corresponding author:
28 29 30 31 32 33 34
Priv.-Doz. Dr. Benito Campos Department of Neurosurgery University of Heidelberg INF 400, 69120 Heidelberg, Germany Tel.: +49 6221 564797, Fax.: +49 6221 56 33893 Email: [email protected]
35
Short title: Analysis of cerebral radiation necrosis
36
Keywords: edema, radionecrosis, radiosurgery
37
Abbreviation list: MRI, magnetic resonance imaging; CT, computed tomography;
38
PET, positron emission tomography 1
39
Abstract
40
Background: There is no standard approach to differentiate cerebral radiation
41
necrosis from tumor recurrence and no standard treatment pathway for symptomatic
42
lesions. In addition, reports on histology-proven radiation necrosis and the underlying
43
pathophysiology are scarce and highly relevant.
44
Methods: Our monocentric, retrospective analysis included n=21 histology-proven
45
cerebral radiation necroses. Our study focused on i) potential risk factors for the
46
development of radiation necrosis, ii) on radiological and histopathological features of
47
individual necroses and iii) on the suitability of previously published, MRI-based
48
methods to identify radiation necroses based on specific structural image features.
49
Results: Average time between radiation treatment and development of necrosis
50
was 4.68y (95% CI, 0.19y - 9.55y). Matching available MRI data sets with that of
51
patients suffering from tumor lesions, we compared specificity and sensitivity of 3
52
previously published methods to identify radionecrosis based on imaging criteria. In
53
our hands, none of these methods reached a sensitivity ≥ 70 %. Radionecrosis
54
presented with large edema and showed elevated levels of cell proliferation as
55
inferred by Ki-67 staining. Surgical removal of radiation necrosis proved to be a safe
56
approach with low permanent morbidity (<5%) and no mortality.
57
Conclusions: While the overall incidence of cerebral radiation necrosis is low, our
58
data suggest an increasing incidence over the last two decades, which is likely
59
associated with the use of stereotactic radiotherapy. There are no current imaging
60
standards to identify radiation necrosis on standard MRI with structural sequences.
61
Surgical removal of radiation necrosis is associated with low morbidity and mortality.
62
Running title: Analysis of cerebral radiation necrosis
63
Keywords: edema, radionecrosis, radiosurgery 2
64
Introduction
65
Cerebral radiation necrosis was first described in 19301 and 5 decades later little
66
more than hundred cases had been described in the literature2. While
67
symptomatic/rapidly progressing radiation necrosis is still a rare consequence of
68
brain tumor radiation therapy, its incidence will likely rise with the propagation of
69
stereotactic radio-oncology3.
70
Most authors concur that radiation necrosis is a delayed complication of
71
radiotherapy, which develops months or years after treatment. There is still no
72
consensus, however, on the exact definition of radiation necrosis. In some cases
73
radiation necrosis is defined as an irreversible process as opposed to a potentially
74
reversible radiation injury4, while other studies define radiation necrosis as a
75
radiation-associated lesion that is diagnosed histo-pathologically or post hoc, in case
76
the lesion resolves over time5. Since most studies rely on MRI imaging rather than
77
histo-pathological criteria for the diagnosis of radiation necrosis, incidences as high
78
as 24%-30% were reported in studies relying solely on imaging criteria6,7. In contrast,
79
reported incidences in studies at least partially employing some form of pathological
80
confirmation8,9 range between 2.5%-17%. It has become evident that the incidence of
81
radionecrosis will further depend on type and dose of radiation employed, the nature
82
of the underlying involved and the duration of the follow-up period4.
83
Reports on histology-proven radiation necrosis are scarce. One of the largest series
84
included 12 bona fide lesions9. In this study, pathophysiology of these lesions was
85
not further studied as was the case in another study with lower numbers of histology-
86
proven necroses10. One exception is a study including 4 histology-proven necroses,
87
which were further evaluated with a panel of immunohistochemical stains11. Thus,
88
reports on histology-proven necroses and their pathophysiology are much needed. 3
89
In addition, there is no imaging approach that can reliably differentiate radiation
90
necrosis from tumor recurrence. As a surrogate for radiation necrosis two studies
91
have used specific ratios between the lesion’s area on T1-weighted and T2-weighted
92
images9,10 and one study had used a specific ratio between the lesions’ area on T1-
93
weighted images and the area of the lesions’ edema on T2-weighted images.
94
However, some of these results could not be confirmed by others4 or have not yet
95
been validated in independent studies. Other studies have used specific patterns of
96
perfusion on MRI images, PET or MR spectroscopy as a proxy for radiation
97
necroses12–14. Again, many of these studies were based on small patient series and
98
have not yet been validated independently.
99
In our monocentric, retrospective analysis we study a sample of pathology-proven
100
cerebral radiation necroses, which were surgically resected between 2003 and 2018
101
(n=21). Our study focuses on i) potential risk factors for the development of radiation
102
necrosis, ii) on radiological and histopathological features of individual necroses and
103
iii) on the suitability of previously published, MRI-based methods to identify radiation
104
necroses based on specific structural image features.
105
4
106
Material & Methods
107
Study Design
108
All patients in this study were treated at the local Department of Neurosurgery.
109
Patients with previous intracranial tumor (e.g. patients, who had received stereotactic
110
radiotherapy for a presumed metastasis and now presented with radionecrosis at the
111
same location) were only included after a follow-up period of at least 2 years after
112
surgical removal of the lesion, if no tumor had recurred during that time frame and if
113
they were free of local recurrence at the end of the follow-up period (01/2020). With
114
these selection criteria, we aimed to exclude false-positives radiation necroses, e.g.
115
cases where tumor cells in tissue were missed due to low tumor/connective tissue
116
ratio or due to analysis of unrepresentative tissue sections. Swift local recurrence for
117
example, would automatically challenge radiation necrosis diagnosis and lead to
118
exclusion of the patient.
119
During the study period (2003-2018) we gathered 21 cases of bona fide, histo-
120
pathologically confirmed radiation necrosis and compiled clinical parameters from
121
medical records. Additionally, radiological findings, T1 and T2 weighted MRI imaging
122
sets, ICU-Records and histopathological reports were acquired. Information was
123
gathered according to the research proposals approved by the local Institutional
124
Review Board. The study was performed in accordance with the declaration of
125
Helsinki. Informed consent was obtained from all patients.
126
Using available MRI data sets of patients with radiation necrosis we compared
127
specificity and sensitivity of 3 previously published methods to identify radiation
128
necrosis based on imaging criteria: Authors of the first study had calculated the ratio
129
between the nodular lesion’s area on T2-weighted and T1-weighted images10. A
130
quotient of less than 0.3 was associated with radiation necrosis. Another study had 5
131
identified a so-called T1/T2 mismatch, i.e. stark differences in the appearance of the
132
lesion on T1-weighted and T2-weighted images, as a sensitive marker for radiation
133
necrosis9. The third study had used a specific ratio between the lesions’ area on T1-
134
weighted images and the area of the lesions’s edema on T2-weighted images15. A
135
quotient of edema/lesion of more than 10 was associated with radiation necrosis. In
136
our study we applied the first two methods as described by the authors and applied a
137
modified version of the third method (using the lesion’s area rather than its volume
138
and an adapted ratio threshold of 4.2).
139 140
Data analysis
141
All statistical analyses were done using GraphPad Prism version 8.0.0 for Mac,
142
GraphPad Software, La Jolla California USA, www.graphpad.com. A D'Agostino-
143
Pearson K2 normality test was performed to assess normal distribution of our data.
144
Where applicable and depending on normal distribution of data, a paired t test or a
145
Wilcoxon matched-pairs signed rank test was performed. For correlation of data sets,
146
the spearman correlation coefficient r was calculated (pertinent data showed no
147
normal distribution). A p-value of less than 0.05 indicated a statistically significant
148
difference.
149 150
6
151
Results
152
Patient characteristics
153
Indication for radiotherapy was brain metastasis for most patients (n=11), followed by
154
meningioma (n=3), glioma (n=3), sarcoma/carcinoma in the nasopharyngeal area
155
(n=2), and others (n=2). Patient characteristics are summarized in table 1.
156 157
Type of radiation therapy
158
Detailed data on radiation therapy was available for 18 patients, most of whom had
159
received stereotactic radiation. Specifically, 66% of patients had received a single
160
application of stereotactic radiation, either alone or combined with whole brain
161
radiation. Out of the remaining patients, four patients had been treated with a particle
162
therapy, either as a boost or alone. Two patients had received fractionated
163
radiotherapy alone (table 1).
164
Mean time interval between radiation treatment and development of necrosis was
165
4.68y (95% CI, -0.19y - 9.55y). In one case, radionecrosis developed as late as 46y
166
after radiotherapy. Mean time span between radiation treatment and development of
167
necrosis was 2.17y (95% CI, 0.38y - 3.96y) for stereotactic radiation as compared to
168
7.74y (95% CI, -3.89y - 19.4y) for the remainder patients (figure 1A, supplemental
169
table 1). The difference, however, was not significant (p=0.94).
170
Mean time span between radiation treatment and development of necrosis for
171
patients who received particle therapy was 0.79y (95% CI, 0.25y - 1.33y) as
172
compared to 5.65y (95% CI, -0.47y – 11.77y) for the remainder patients (figure 1B,
173
supplemental table 1). Yet, again, the difference was not significant (p=0.21).
7
174
There was an inverse correlation between total radiation dose and the time span
175
between radiation treatment and development of necrosis (Spearman correlation
176
coefficient = -0.52; p=0.03, figure 1C, supplemental table 1).
177
Radiation necroses were further grouped according to their spatial relationship to the
178
primary lesion and/or the radiation field. In two cases the primary tumor had been a
179
sarcoma/carcinoma in the nasopharyngeal area and radiation necroses presented
180
adjacent to the initial radiation field, i.e. in the ipsilateral temporal lobe. For the
181
remaining cases radiation plans were revised and matched to site of necrosis. As
182
expected, all radiation necroses developed within the radiation field.
183 184
Histology
185
Data on cell proliferation, inferred by KI-67 staining, was available in 17/21 cases.
186
KI-67 frequencies were notably increased compared to reported values for normal
187
brain16 and averaged 4.23% (95% CI, 1.73% - 6.74%) on tissue hotspots. In 7 cases
188
KI-67 frequencies reached 5% or more (table 1). KI-67 frequencies averaged 4.80%
189
(95% CI, 0.60% - 9.00%) on tissues treated with stereotactic radiation and were not
190
significantly different from those in the remaining tissues (p=0.87) nor did they
191
correlate with the total radiation does received (Spearman correlation coefficient=
192
0.01; p=0.99).
193 194
Surgical treatment and complications
195
One third of patients was referred to our department with progressive neurological
196
symptoms. The other patients presented with progressive lesions in their routine MRI
197
controls. Surgical removal of radiation necrosis was associated with low morbidity
198
and no mortality: Only two patients suffered neurological deterioration (table 1). 8
199
Specifically, one patient with a parietal lesion suffered a transient Gerstman
200
syndrome. The other patient, also with a lesion seated in the parietal lobe, suffered
201
an aggravation of a preexisting paresis.
202 203
MRI analysis
204
T2-weighted and T1-weighted, contrast-enhanced MRI images were available and
205
could be evaluated for all but one patient who had been imaged at a different institute
206
and whose images were not obtainable.
207
On MRI images, most radionecroses (n=16/20) presented with a hypointense core,
208
which presumably corresponded to the central necrosis, and with a thin outer ring of
209
contrast enhancement as well as a large edema on T2 weighted images
210
(figure 2D-F).
211
Using available MRI data sets of patients with radiation necrosis (n=20) and a
212
sample of patients with histologically proven tumor diagnosis (n=20) we compared
213
specificity and sensitivity of 3 previously published methods to identify radiation
214
necrosis based on imaging criteria. MRI data sets of tumor cases had been chosen
215
to match anatomical distribution of radiation necroses and included cases of glioma,
216
metastasis and lymphoma. As a surrogate for radiation necroses two studies had
217
used specific ratios between the lesion’s area on T1-weighted and T2-weighted
218
images10,17 and one study had used a specific ratio between the lesions’ volume on
219
T1-weighted images and the volume of the lesion’s edema on T2-weighted images15.
220
In our analysis, sensitivity of the three methods ranged between 50% and 65%, while
221
specificity varied between 83% and 94% (table 2).
9
222
Discussion
223
Incidence and risk factors of rapidly progressing cerebral radiation necrosis
224
Overall incidence of symptomatic and/or rapidly progressing cerebral radiation
225
necrosis was low in our study, especially considering the length of the observation
226
period (16 years).
227
However, the number of histology-proven radionecrosis increased steadily in the last
228
years of the observation period, i.e. more than 50% of the lesions were removed in
229
the last 4 years of a 16 year study period (figure 2D). In addition, most of our
230
patients with available data on radiotherapy had been treated with stereotactic
231
radiation. Since there were no major changes in neuropathological diagnosis or
232
surgical treatment during that time period, one possible explanation might be the
233
increasing use of stereotactic radiotherapy at our institution in recent years as well as
234
the implementation of particle radiotherapy since 2009. This would be in line with
235
previous reports identifying stereotactic radiotherapy and heavy ion radiotherapy as
236
risk factors for radiation necrosis3,4,9. Other risk factors that have been described in
237
previous studies include dose, fraction size, treatment duration, volume treated,
238
chemotherapy, previous radiation therapy, and male sex4.
239
Specifically, from May 2016 until September 2018, 590 patients received stereotactic
240
cyberknife radiotherapy at our institution, and so far, 2 patients (0.34%) developed
241
radiation necroses, which required neurosurgical treatment (personal observation).
242
While this number might seem low, it is probably an underestimation of the true
243
incidence, given that the observation period is too short, i.e. considering the average
244
time between stereotactic radiation treatment and development of radiation necrosis
245
of 2.17y in our study. Combined, data from our study and from independent
246
reports4,5, mitigate previous fears that use of stereotactic radiotherapy will yield 10
247
intolerable incidences of radionecroses3. Instead, our data suggest that the apparent
248
rise in the incidence of symptomatic/rapidly progressing radionecroses merely
249
reflects a shift from traditional radiation therapy (with lower risk of radionecrosis) to
250
an increased implementation of stereotactic radiotherapy. It is further likely, that this
251
increment will eventually level out slightly below the reported incidence of 7%4,5,
252
given that some of the lesions will resolve over time and thus, will not require
253
surgery.
254
It is noteworthy that patients, who were treated with heavy ion radiotherapy in our
255
study, developed radionecrosis after an average time of only 0.79 years as compared
256
to 5.56 years for the remainder patients. The same was true for patients, who were
257
treated with stereotactic radiotherapy (2.17 years) as compared to the remainder
258
patients (7.74 years). While differences in both cases were not significant, it might be
259
worth to reevaluate the potential clinical significance of these finding with a larger
260
sample size, particularly, given the inverse correlation between radiation dose and
261
time to radiation necrosis described in our results.
262 263
Proliferation rates of rapidly progressing cerebral radiation necrosis
264
Necroses in our study presented with features of malignant lesions, i.e. large edema
265
with associated mass effect as well as with increased proliferation. In one case KI-67
266
frequency was as high as 20% in hotspots. Such proliferation levels are typically
267
observed in malignant tumors like glioblastoma and brain metastases16. Yet, even
268
the average proliferation levels found in our radiation necroses (4.23%) are above
269
average levels found in malignant brain tumors, such as diffuse astrocytoma and are
270
comparable to proliferation rates found in anaplastic astrocytomas16,18. We were
271
unable to find any study analyzing Ki-67 proliferation rates in cerebral radiation 11
272
necrosis but our results should nevertheless challenge our current perception of
273
these lesions as slow-growing, “benign” and convey the image of an aggressive
274
tumor comprised of connective tissue or, figuratively speaking, of a malignant scar. It
275
is remarkable, that proliferation rates of the seemingly “benign” lesions reported in
276
our study, which predominantly consist of astrocytes and endothelial cells19, exceed
277
previously reported proliferation rates in some malignant brain tumors. This indicates
278
that some cerebral radiation necroses can be as fast-growing and potentially
279
dangerous due to their rapid expansion as some aggressive brain tumors. Our study
280
on Ki-67 should encourage future studies to better characterize fast-growing cells in
281
radiation necrosis and to analyze their potential as therapeutic targets.
282 283
Surgical removal of rapidly progressing cerebral radiation necrosis
284
Currently, there is no standard therapeutic approach for symptomatic/rapidly
285
progressing radionecrosis other than surgical removal and alleviation of edema with
286
steroids. Several therapeutic approaches have been suggested in the past, including
287
hyperbaric oxygen, heparin, warfarin and vitamin E (reviewed in4). Most evidence
288
has been derived from a few number of trials with bevacizumab, including two
289
randomized clinical studies including 14 and 112 patients20,21. Combined, these
290
studies suggest that bevacizumab can “close” the blood brain barrier, lead to a
291
decrease in edema and alleviate symptoms associated with mass effect more
292
effectively than steroids. Considering bevacizumab costs, the fact that it is not
293
approved for routine use in some countries and the fact that it alleviates symptoms
294
linked to edema but does not treat radionecrosis per se, surgery remains the
295
standard treatment for symptomatic and rapidly progressing lesions. This approach is
12
296
consistent with the tumor-like growth pattern of radionecroses and can be achieved
297
with low rates of morbidity as reported in our study.
298
Detection of cerebral radiation necrosis on MRI images
299
Finally, and as mentioned above, several imaging approaches have been studied in
300
terms of their sensitivity and specificity to detect radiation necrosis (reviewed in4).
301
Most of these studies were based on small sample sizes and have not been or could
302
not be validated in follow-up studies4. In addition, there was no uniform definition of
303
radiation necrosis among studies and some lacked histological confirmation of
304
presumed radiation necrosis. In our study, none of three previously reported image
305
surrogate markers for radiation necrosis reached a sensitivity ≥ 70%. Considering
306
these findings, we are tempted to conclude that differences between radionecroses
307
and progressive tumors are too subtle to extract single features that can reliably
308
differentiate between both entities. A recent study employed unsupervised machine
309
learning to extract subtle and unbiased image features from 43 MRI data sets and
310
could classify radionecroses and tumors with higher accuracy than two experienced
311
neuroradiologists22. Their findings were further validated in a small prospective data
312
set including 15 patients. While this approach seems promising to overcome
313
difficulties encountered by previous imaging studies, it will still be limited by the
314
number of bona fide radionecroses available to train machine learning algorithms.
13
315
Conclusion
316
Our data suggest an increasing incidence for radiation necrosis over the last two
317
decades, which is mainly associated with increased implementation of stereotactic
318
radiotherapy. Currently, there are no imaging standards to identify radiation necrosis.
319
Surgical removal of radiation necrosis is associated with low morbidity and mortality
320
and remains the standard of treatment for symptomatic and rapidly progressing
321
lesions.
322
14
323
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Leeman JE, Clump DA, Flickinger JC, Mintz AH, Burton SA, Heron DE. Extent
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Kano H, Kondziolka D, Lobato-Polo J, Zorro O, Flickinger JC, Lunsford LD.
Neurosurgery.
2010;66(3):486-491;
discussion
491-492.
Hara A, Hirayama H, Sakai N, Yamada H, Tanaka T, Mori H. Correlation
16
386
19.
Nonoguchi N, Miyatake S-I, Fukumoto M, et al. The distribution of vascular
387
endothelial growth factor-producing cells in clinical radiation necrosis of the brain:
388
pathological consideration of their potential roles. J Neurooncol. 2011;105(2):423-
389
431. doi:10.1007/s11060-011-0610-9
390
20.
391
trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int
392
J Radiat Oncol Biol Phys. 2011;79(5):1487-1495. doi:10.1016/j.ijrobp.2009.12.061
393
21.
394
induced Brain Necrosis in Nasopharyngeal Carcinoma Patients: A Randomized
395
Controlled Trial. International Journal of Radiation Oncology • Biology • Physics.
396
2018;101(5):1087-1095. doi:10.1016/j.ijrobp.2018.04.068
397
22.
398
Features to Distinguish Cerebral Radionecrosis from Recurrent Brain Tumors on
399
Multiparametric MRI: A Feasibility Study. American Journal of Neuroradiology.
400
2016;37(12):2231-2236. doi:10.3174/ajnr.A4931
Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled
Xu Y, Rong X, Hu W, et al. Bevacizumab Monotherapy Reduces Radiation-
Tiwari P, Prasanna P, Wolansky L, et al. Computer-Extracted Texture
401 402 403
17
404
Figure legends
405
Figure 1 (A) Graph showing time between radiation and development of necrosis
406
(mean and 95% CI values) for patients receiving stereotactic radiation vs. patients
407
receiving any other type of radiation treatment (RX=radiation). (B) Graph showing
408
time between radiation and development of necrosis (mean and 95% CI values) for
409
patients receiving heavy ion radiation vs. patients receiving any other type of
410
radiation treatment. (C) Correlation between the dose of radiation received (x-axis)
411
and the time between radiation and development of necrosis (y-axis).
412 413
Figure 2 (A-C) Representative appearance of radionecroses on MRI images. Most
414
radionecroses presented with a hypointense core, which presumably corresponded
415
to the central necrosis, and with a thin outer ring of contrast enhancement as well as
416
a large edema on T2 weighted images. Lesions were round and symmetric, ribbed or
417
diffuse: Image (A) is representative of round and symmetric lesions. The
418
corresponding patient was diagnosed with metastasis and subjected to stereotactic
419
radiation. Image (B) is representative of ribbed lesions. The patient suffered from
420
carcinoma in the nasopharyngeal area and was treated with whole brain radiation
421
and a heavy ion radiation boost. Image (C) is representative of diffuse lesions. Such
422
lesions grew adjacent to tumor resection cavities. In this particular case the patient
423
suffered from a malignant astrocytoma and was treated with fractionated
424
radiotherapy. (D) Absolute numbers of cases of radionecrosis between 2003 and
425
2017 at our department (total = 21 cases).
426
18
Table 1: Patient characteristics Gender
Age (years)
Initial diagnosis
Localization of radiation necrosis
Type of radiation treatment
Applied dose
Time between radiation and diagnosis of RN (in years) 9.17
MIB frequency in hotspots (in %)
Preoperative symptoms
Postoperative symptoms
F
53
AVM
occipital
20Gy
F
48
Cerebral metastasis
parietal
F
66
M
42
Meningeom a WHO III Meningeom a WHO II
temporoparietal cerebellar
M
47
Sarcoma
temporal
M
46
Glioblastom a
parietal
stereotactic radiotherapy WB + stereotactic radiotherapy UK (radiation not in-house) fractionated radiotherapy + heavy ion radiation boost fractionated radiotherapy + heavy ion radiation boost fractionated radiotherapy + heavy ion radiation boost
8
hemiparesis
40Gy + 15Gy
0.64
3
paresis
no new symptoms aggravated paresis
UK
5.74
1
hemineglect
50Gy + 18Gy
0.51
8
fatigue
50Gy+ 24Gy
1.09
7
progressive desease on MRI
no new symptoms
50 Gy + 18 Gy (boost)
0.49
5
progressive desease on MRI
no new symptoms
F
57
Cerebral metastasis
parietal
WB + stereotactic radiotherapy stereotactic radiotherapy WB + 3x stereotactic radiotherapy stereotactic radiotherapy
30 Gy WB + 20Gy 20 Gy
0.56
0
numbness
no new symptoms
M
56
F
52
temporoparietal frontotemporal
M
67
Cerebral metastasis Multiple cerebral metastasis Cerebral metastasis
0.68
2
seizure
30Gy WB + 20 Gy
1.38
3
headache
no new symptoms no new symptoms
20 Gy
3.39
UK
no new symptoms
temporal
stereotactic radiotherapy
20 Gy
1.42
5
Eosinophilic granuloma Adenoid cystic carcinoma
occipital
UK
46.32
UK
66 Gy + 54 Gy
1.08
UK
Anaplastic oligodendro glioma WHO III Anaplastic astrozytom a WHO III Cerebral metastasis
parietal
UK (radiation not in-house) fractionated radiotherapy + heavy ion radiation reirradiation UK (radiation not in-house)
progressive desease on MRI progressive desease on MRI progressive desease on MRI cranial nerve palsy
F
55
Cerebral metastasis
M
72
M
61
F
63
UK
13.78
UK
progressive desease on MRI
no new symptoms
F
47
fractionated proton radiotherapy stereotactic radiotherapy
54 Gy
0.65
1
20 Gy
4.47
5
Transient Gerstmann syndrome no new symptoms
50
Cerebral metastasis
parietal
stereotactic radiotherapy
25 Gy
UK
2
F
57
Cerebral metastasis
occipital
stereotactic radiotherapy
20Gy+25 Gy
0.79
20
F
50
Meningeom a WHO II
frontal
fractionated radiotherapy
60Gy
0.04
0
F
70
Cerebral metastasis
parietal
stereotactic radiotherapy
20Gy+25 Gy
1.34
0
F
50
Cerebral metastasis
temporal
hypofractionat ed stereotactic radiotherapy
27Gy (3x9 Gy)
0.03
2
progressive desease on MRI progressive desease on MRI progressive desease on MRI progressive desease on MRI progressive desease on MRI progressive desease on MRI progressive desease on MRI
F
68
M
parietal
temporal
parietal
frontal
no new symptoms no new symptoms
no new symptoms no new symptoms no new symptoms
no new symptoms no new symptoms no new symptoms no new symptoms no new symptoms
WB = whole brain irradiation, UK=unknown, AVM= arteriovenous malformation
Table 2: MRI characteristics of individual patients
sensitivity
specificity
T1/T2 < 0.3
50%
94%
T1-T2 mismatch
55%
89%
edema/T1 > 4.2
65%
83%
Type of image feature
Supplemental Table 1: (A) Assessment of associations between radiation type, radiation dose and development of radiation necrosis
Time between radiation and diagnosis of radio necrosis (in years) ALL patients ALL patients excluding heavy ion excluding STX ONLY heavy ion RX RX ONLY STX RX RX # of patients 4 16 Mean 0.79 5.65 Std. Deviation 0.34 11.49 Lower 95% CI of mean 0.25 Significant -0.47 correlation? (yes/no) Upper 95% CI of mean dose (Gy) 1.33 11.77 Total radiation p-value Mannvs. yes, inverse Whitney test P= 0.94 Time between radiation and correlation diagnosis of radio necrosis (in years)
ALL patients
11 2.17 2.67
9 7.74 15.13
20 4.68 10.40
0.38
p-value-3.89
-0.19
3.96
19.38
9.54
P= 0.21 Spearman correlation coefficient = -0.52; p=0.03
RX = radiotherapy. STX = stereotactic radiotherapy
(B) Assessment of correlations between radiation dose and development of radiation necrosis
Author contributions Benito Campos: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Supervision, Project administration, Resources, Writing – Original Draft, Writing - Review & Editing Jan-Oliver Neumann: Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Alexander Hubert: Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Sebastian Adeberg: Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Rami El Shafie: Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Andreas von Deimling: Supervision, Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Martin
Bendszus:
Supervision,
Methodology,
Validation,
Formal
analysis,
Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Jürgen Debus: Supervision, Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Denise Bernhardt: Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing
Andreas Unterberg: Supervision, Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing
1
Abbreviation list:
2
MRI, magnetic resonance imaging
3
CT, computed tomography
4
PET, positron emission tomography
5
1
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
On behalf of all authors. Benito Campos, M.D. 11/24/2019
S1878-8750(20)30267-9
DOI:
https://doi.org/10.1016/j.wneu.2020.02.005
Reference:
WNEU 14279
To appear in:
World Neurosurgery
Received Date: 24 November 2019 Revised Date:
31 January 2020
Accepted Date: 1 February 2020
Please cite this article as: Campos B, Neumann J-O, Hubert A, Adeberg S, El Shafie R, von Deimling A, Bendszus M, Debus J, Bernhardt D, Unterberg A, Analysis of a surgical series of 21 cerebral radiation necroses, World Neurosurgery (2020), doi: https://doi.org/10.1016/j.wneu.2020.02.005. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier Inc.
Analysis of a surgical series of 21 cerebral radiation necroses
1 2 3
Benito Campos MD1,*, Jan-Oliver Neumann MD1,*, Alexander Hubert MD 2, Sebastian
4
Adeberg MD3,4,5, Rami El Shafie MD3,4,5, Andreas von Deimling MD6,7, Martin
5
Bendszus MD2, Jürgen Debus MD, PhD3,4,5,8,9,10, Denise Bernhardt MD3,4,5,*, Andreas
6
Unterberg MD1,*
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
1
22
Disclosure of funding statement: This work was supported by Heidelberg
23
University’s Young Investigator Grant (DB, RES). The funding source(s) had no
24
involvement in the research and/or preparation of the article.
25
Conflict of Interest: The authors declare no conflict of interest.
Department of Neurosurgery, University Hospital Heidelberg, Germany Department of Neuroradiology, University Hospital Heidelberg, Germany 3 Department of Radiation Oncology, University Hospital Heidelberg, Germany 4 Heidelberg Institute of Radiation Oncology (HIRO), Heidelberg, Germany 5 National Center for Tumor diseases (NCT), Heidelberg, Germany 6 Department of Neuropathology, Heidelberg University and 7 Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany 9 Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany. 10 German Cancer Consortium (DKTK), partner site Heidelberg, Germany *These authors contributed equally to this work 2
26 27
Corresponding author:
28 29 30 31 32 33 34
Priv.-Doz. Dr. Benito Campos Department of Neurosurgery University of Heidelberg INF 400, 69120 Heidelberg, Germany Tel.: +49 6221 564797, Fax.: +49 6221 56 33893 Email: [email protected]
35
Short title: Analysis of cerebral radiation necrosis
36
Keywords: edema, radionecrosis, radiosurgery
37
Abbreviation list: MRI, magnetic resonance imaging; CT, computed tomography;
38
PET, positron emission tomography 1
39
Abstract
40
Background: There is no standard approach to differentiate cerebral radiation
41
necrosis from tumor recurrence and no standard treatment pathway for symptomatic
42
lesions. In addition, reports on histology-proven radiation necrosis and the underlying
43
pathophysiology are scarce and highly relevant.
44
Methods: Our monocentric, retrospective analysis included n=21 histology-proven
45
cerebral radiation necroses. Our study focused on i) potential risk factors for the
46
development of radiation necrosis, ii) on radiological and histopathological features of
47
individual necroses and iii) on the suitability of previously published, MRI-based
48
methods to identify radiation necroses based on specific structural image features.
49
Results: Average time between radiation treatment and development of necrosis
50
was 4.68y (95% CI, 0.19y - 9.55y). Matching available MRI data sets with that of
51
patients suffering from tumor lesions, we compared specificity and sensitivity of 3
52
previously published methods to identify radionecrosis based on imaging criteria. In
53
our hands, none of these methods reached a sensitivity ≥ 70 %. Radionecrosis
54
presented with large edema and showed elevated levels of cell proliferation as
55
inferred by Ki-67 staining. Surgical removal of radiation necrosis proved to be a safe
56
approach with low permanent morbidity (<5%) and no mortality.
57
Conclusions: While the overall incidence of cerebral radiation necrosis is low, our
58
data suggest an increasing incidence over the last two decades, which is likely
59
associated with the use of stereotactic radiotherapy. There are no current imaging
60
standards to identify radiation necrosis on standard MRI with structural sequences.
61
Surgical removal of radiation necrosis is associated with low morbidity and mortality.
62
Running title: Analysis of cerebral radiation necrosis
63
Keywords: edema, radionecrosis, radiosurgery 2
64
Introduction
65
Cerebral radiation necrosis was first described in 19301 and 5 decades later little
66
more than hundred cases had been described in the literature2. While
67
symptomatic/rapidly progressing radiation necrosis is still a rare consequence of
68
brain tumor radiation therapy, its incidence will likely rise with the propagation of
69
stereotactic radio-oncology3.
70
Most authors concur that radiation necrosis is a delayed complication of
71
radiotherapy, which develops months or years after treatment. There is still no
72
consensus, however, on the exact definition of radiation necrosis. In some cases
73
radiation necrosis is defined as an irreversible process as opposed to a potentially
74
reversible radiation injury4, while other studies define radiation necrosis as a
75
radiation-associated lesion that is diagnosed histo-pathologically or post hoc, in case
76
the lesion resolves over time5. Since most studies rely on MRI imaging rather than
77
histo-pathological criteria for the diagnosis of radiation necrosis, incidences as high
78
as 24%-30% were reported in studies relying solely on imaging criteria6,7. In contrast,
79
reported incidences in studies at least partially employing some form of pathological
80
confirmation8,9 range between 2.5%-17%. It has become evident that the incidence of
81
radionecrosis will further depend on type and dose of radiation employed, the nature
82
of the underlying involved and the duration of the follow-up period4.
83
Reports on histology-proven radiation necrosis are scarce. One of the largest series
84
included 12 bona fide lesions9. In this study, pathophysiology of these lesions was
85
not further studied as was the case in another study with lower numbers of histology-
86
proven necroses10. One exception is a study including 4 histology-proven necroses,
87
which were further evaluated with a panel of immunohistochemical stains11. Thus,
88
reports on histology-proven necroses and their pathophysiology are much needed. 3
89
In addition, there is no imaging approach that can reliably differentiate radiation
90
necrosis from tumor recurrence. As a surrogate for radiation necrosis two studies
91
have used specific ratios between the lesion’s area on T1-weighted and T2-weighted
92
images9,10 and one study had used a specific ratio between the lesions’ area on T1-
93
weighted images and the area of the lesions’ edema on T2-weighted images.
94
However, some of these results could not be confirmed by others4 or have not yet
95
been validated in independent studies. Other studies have used specific patterns of
96
perfusion on MRI images, PET or MR spectroscopy as a proxy for radiation
97
necroses12–14. Again, many of these studies were based on small patient series and
98
have not yet been validated independently.
99
In our monocentric, retrospective analysis we study a sample of pathology-proven
100
cerebral radiation necroses, which were surgically resected between 2003 and 2018
101
(n=21). Our study focuses on i) potential risk factors for the development of radiation
102
necrosis, ii) on radiological and histopathological features of individual necroses and
103
iii) on the suitability of previously published, MRI-based methods to identify radiation
104
necroses based on specific structural image features.
105
4
106
Material & Methods
107
Study Design
108
All patients in this study were treated at the local Department of Neurosurgery.
109
Patients with previous intracranial tumor (e.g. patients, who had received stereotactic
110
radiotherapy for a presumed metastasis and now presented with radionecrosis at the
111
same location) were only included after a follow-up period of at least 2 years after
112
surgical removal of the lesion, if no tumor had recurred during that time frame and if
113
they were free of local recurrence at the end of the follow-up period (01/2020). With
114
these selection criteria, we aimed to exclude false-positives radiation necroses, e.g.
115
cases where tumor cells in tissue were missed due to low tumor/connective tissue
116
ratio or due to analysis of unrepresentative tissue sections. Swift local recurrence for
117
example, would automatically challenge radiation necrosis diagnosis and lead to
118
exclusion of the patient.
119
During the study period (2003-2018) we gathered 21 cases of bona fide, histo-
120
pathologically confirmed radiation necrosis and compiled clinical parameters from
121
medical records. Additionally, radiological findings, T1 and T2 weighted MRI imaging
122
sets, ICU-Records and histopathological reports were acquired. Information was
123
gathered according to the research proposals approved by the local Institutional
124
Review Board. The study was performed in accordance with the declaration of
125
Helsinki. Informed consent was obtained from all patients.
126
Using available MRI data sets of patients with radiation necrosis we compared
127
specificity and sensitivity of 3 previously published methods to identify radiation
128
necrosis based on imaging criteria: Authors of the first study had calculated the ratio
129
between the nodular lesion’s area on T2-weighted and T1-weighted images10. A
130
quotient of less than 0.3 was associated with radiation necrosis. Another study had 5
131
identified a so-called T1/T2 mismatch, i.e. stark differences in the appearance of the
132
lesion on T1-weighted and T2-weighted images, as a sensitive marker for radiation
133
necrosis9. The third study had used a specific ratio between the lesions’ area on T1-
134
weighted images and the area of the lesions’s edema on T2-weighted images15. A
135
quotient of edema/lesion of more than 10 was associated with radiation necrosis. In
136
our study we applied the first two methods as described by the authors and applied a
137
modified version of the third method (using the lesion’s area rather than its volume
138
and an adapted ratio threshold of 4.2).
139 140
Data analysis
141
All statistical analyses were done using GraphPad Prism version 8.0.0 for Mac,
142
GraphPad Software, La Jolla California USA, www.graphpad.com. A D'Agostino-
143
Pearson K2 normality test was performed to assess normal distribution of our data.
144
Where applicable and depending on normal distribution of data, a paired t test or a
145
Wilcoxon matched-pairs signed rank test was performed. For correlation of data sets,
146
the spearman correlation coefficient r was calculated (pertinent data showed no
147
normal distribution). A p-value of less than 0.05 indicated a statistically significant
148
difference.
149 150
6
151
Results
152
Patient characteristics
153
Indication for radiotherapy was brain metastasis for most patients (n=11), followed by
154
meningioma (n=3), glioma (n=3), sarcoma/carcinoma in the nasopharyngeal area
155
(n=2), and others (n=2). Patient characteristics are summarized in table 1.
156 157
Type of radiation therapy
158
Detailed data on radiation therapy was available for 18 patients, most of whom had
159
received stereotactic radiation. Specifically, 66% of patients had received a single
160
application of stereotactic radiation, either alone or combined with whole brain
161
radiation. Out of the remaining patients, four patients had been treated with a particle
162
therapy, either as a boost or alone. Two patients had received fractionated
163
radiotherapy alone (table 1).
164
Mean time interval between radiation treatment and development of necrosis was
165
4.68y (95% CI, -0.19y - 9.55y). In one case, radionecrosis developed as late as 46y
166
after radiotherapy. Mean time span between radiation treatment and development of
167
necrosis was 2.17y (95% CI, 0.38y - 3.96y) for stereotactic radiation as compared to
168
7.74y (95% CI, -3.89y - 19.4y) for the remainder patients (figure 1A, supplemental
169
table 1). The difference, however, was not significant (p=0.94).
170
Mean time span between radiation treatment and development of necrosis for
171
patients who received particle therapy was 0.79y (95% CI, 0.25y - 1.33y) as
172
compared to 5.65y (95% CI, -0.47y – 11.77y) for the remainder patients (figure 1B,
173
supplemental table 1). Yet, again, the difference was not significant (p=0.21).
7
174
There was an inverse correlation between total radiation dose and the time span
175
between radiation treatment and development of necrosis (Spearman correlation
176
coefficient = -0.52; p=0.03, figure 1C, supplemental table 1).
177
Radiation necroses were further grouped according to their spatial relationship to the
178
primary lesion and/or the radiation field. In two cases the primary tumor had been a
179
sarcoma/carcinoma in the nasopharyngeal area and radiation necroses presented
180
adjacent to the initial radiation field, i.e. in the ipsilateral temporal lobe. For the
181
remaining cases radiation plans were revised and matched to site of necrosis. As
182
expected, all radiation necroses developed within the radiation field.
183 184
Histology
185
Data on cell proliferation, inferred by KI-67 staining, was available in 17/21 cases.
186
KI-67 frequencies were notably increased compared to reported values for normal
187
brain16 and averaged 4.23% (95% CI, 1.73% - 6.74%) on tissue hotspots. In 7 cases
188
KI-67 frequencies reached 5% or more (table 1). KI-67 frequencies averaged 4.80%
189
(95% CI, 0.60% - 9.00%) on tissues treated with stereotactic radiation and were not
190
significantly different from those in the remaining tissues (p=0.87) nor did they
191
correlate with the total radiation does received (Spearman correlation coefficient=
192
0.01; p=0.99).
193 194
Surgical treatment and complications
195
One third of patients was referred to our department with progressive neurological
196
symptoms. The other patients presented with progressive lesions in their routine MRI
197
controls. Surgical removal of radiation necrosis was associated with low morbidity
198
and no mortality: Only two patients suffered neurological deterioration (table 1). 8
199
Specifically, one patient with a parietal lesion suffered a transient Gerstman
200
syndrome. The other patient, also with a lesion seated in the parietal lobe, suffered
201
an aggravation of a preexisting paresis.
202 203
MRI analysis
204
T2-weighted and T1-weighted, contrast-enhanced MRI images were available and
205
could be evaluated for all but one patient who had been imaged at a different institute
206
and whose images were not obtainable.
207
On MRI images, most radionecroses (n=16/20) presented with a hypointense core,
208
which presumably corresponded to the central necrosis, and with a thin outer ring of
209
contrast enhancement as well as a large edema on T2 weighted images
210
(figure 2D-F).
211
Using available MRI data sets of patients with radiation necrosis (n=20) and a
212
sample of patients with histologically proven tumor diagnosis (n=20) we compared
213
specificity and sensitivity of 3 previously published methods to identify radiation
214
necrosis based on imaging criteria. MRI data sets of tumor cases had been chosen
215
to match anatomical distribution of radiation necroses and included cases of glioma,
216
metastasis and lymphoma. As a surrogate for radiation necroses two studies had
217
used specific ratios between the lesion’s area on T1-weighted and T2-weighted
218
images10,17 and one study had used a specific ratio between the lesions’ volume on
219
T1-weighted images and the volume of the lesion’s edema on T2-weighted images15.
220
In our analysis, sensitivity of the three methods ranged between 50% and 65%, while
221
specificity varied between 83% and 94% (table 2).
9
222
Discussion
223
Incidence and risk factors of rapidly progressing cerebral radiation necrosis
224
Overall incidence of symptomatic and/or rapidly progressing cerebral radiation
225
necrosis was low in our study, especially considering the length of the observation
226
period (16 years).
227
However, the number of histology-proven radionecrosis increased steadily in the last
228
years of the observation period, i.e. more than 50% of the lesions were removed in
229
the last 4 years of a 16 year study period (figure 2D). In addition, most of our
230
patients with available data on radiotherapy had been treated with stereotactic
231
radiation. Since there were no major changes in neuropathological diagnosis or
232
surgical treatment during that time period, one possible explanation might be the
233
increasing use of stereotactic radiotherapy at our institution in recent years as well as
234
the implementation of particle radiotherapy since 2009. This would be in line with
235
previous reports identifying stereotactic radiotherapy and heavy ion radiotherapy as
236
risk factors for radiation necrosis3,4,9. Other risk factors that have been described in
237
previous studies include dose, fraction size, treatment duration, volume treated,
238
chemotherapy, previous radiation therapy, and male sex4.
239
Specifically, from May 2016 until September 2018, 590 patients received stereotactic
240
cyberknife radiotherapy at our institution, and so far, 2 patients (0.34%) developed
241
radiation necroses, which required neurosurgical treatment (personal observation).
242
While this number might seem low, it is probably an underestimation of the true
243
incidence, given that the observation period is too short, i.e. considering the average
244
time between stereotactic radiation treatment and development of radiation necrosis
245
of 2.17y in our study. Combined, data from our study and from independent
246
reports4,5, mitigate previous fears that use of stereotactic radiotherapy will yield 10
247
intolerable incidences of radionecroses3. Instead, our data suggest that the apparent
248
rise in the incidence of symptomatic/rapidly progressing radionecroses merely
249
reflects a shift from traditional radiation therapy (with lower risk of radionecrosis) to
250
an increased implementation of stereotactic radiotherapy. It is further likely, that this
251
increment will eventually level out slightly below the reported incidence of 7%4,5,
252
given that some of the lesions will resolve over time and thus, will not require
253
surgery.
254
It is noteworthy that patients, who were treated with heavy ion radiotherapy in our
255
study, developed radionecrosis after an average time of only 0.79 years as compared
256
to 5.56 years for the remainder patients. The same was true for patients, who were
257
treated with stereotactic radiotherapy (2.17 years) as compared to the remainder
258
patients (7.74 years). While differences in both cases were not significant, it might be
259
worth to reevaluate the potential clinical significance of these finding with a larger
260
sample size, particularly, given the inverse correlation between radiation dose and
261
time to radiation necrosis described in our results.
262 263
Proliferation rates of rapidly progressing cerebral radiation necrosis
264
Necroses in our study presented with features of malignant lesions, i.e. large edema
265
with associated mass effect as well as with increased proliferation. In one case KI-67
266
frequency was as high as 20% in hotspots. Such proliferation levels are typically
267
observed in malignant tumors like glioblastoma and brain metastases16. Yet, even
268
the average proliferation levels found in our radiation necroses (4.23%) are above
269
average levels found in malignant brain tumors, such as diffuse astrocytoma and are
270
comparable to proliferation rates found in anaplastic astrocytomas16,18. We were
271
unable to find any study analyzing Ki-67 proliferation rates in cerebral radiation 11
272
necrosis but our results should nevertheless challenge our current perception of
273
these lesions as slow-growing, “benign” and convey the image of an aggressive
274
tumor comprised of connective tissue or, figuratively speaking, of a malignant scar. It
275
is remarkable, that proliferation rates of the seemingly “benign” lesions reported in
276
our study, which predominantly consist of astrocytes and endothelial cells19, exceed
277
previously reported proliferation rates in some malignant brain tumors. This indicates
278
that some cerebral radiation necroses can be as fast-growing and potentially
279
dangerous due to their rapid expansion as some aggressive brain tumors. Our study
280
on Ki-67 should encourage future studies to better characterize fast-growing cells in
281
radiation necrosis and to analyze their potential as therapeutic targets.
282 283
Surgical removal of rapidly progressing cerebral radiation necrosis
284
Currently, there is no standard therapeutic approach for symptomatic/rapidly
285
progressing radionecrosis other than surgical removal and alleviation of edema with
286
steroids. Several therapeutic approaches have been suggested in the past, including
287
hyperbaric oxygen, heparin, warfarin and vitamin E (reviewed in4). Most evidence
288
has been derived from a few number of trials with bevacizumab, including two
289
randomized clinical studies including 14 and 112 patients20,21. Combined, these
290
studies suggest that bevacizumab can “close” the blood brain barrier, lead to a
291
decrease in edema and alleviate symptoms associated with mass effect more
292
effectively than steroids. Considering bevacizumab costs, the fact that it is not
293
approved for routine use in some countries and the fact that it alleviates symptoms
294
linked to edema but does not treat radionecrosis per se, surgery remains the
295
standard treatment for symptomatic and rapidly progressing lesions. This approach is
12
296
consistent with the tumor-like growth pattern of radionecroses and can be achieved
297
with low rates of morbidity as reported in our study.
298
Detection of cerebral radiation necrosis on MRI images
299
Finally, and as mentioned above, several imaging approaches have been studied in
300
terms of their sensitivity and specificity to detect radiation necrosis (reviewed in4).
301
Most of these studies were based on small sample sizes and have not been or could
302
not be validated in follow-up studies4. In addition, there was no uniform definition of
303
radiation necrosis among studies and some lacked histological confirmation of
304
presumed radiation necrosis. In our study, none of three previously reported image
305
surrogate markers for radiation necrosis reached a sensitivity ≥ 70%. Considering
306
these findings, we are tempted to conclude that differences between radionecroses
307
and progressive tumors are too subtle to extract single features that can reliably
308
differentiate between both entities. A recent study employed unsupervised machine
309
learning to extract subtle and unbiased image features from 43 MRI data sets and
310
could classify radionecroses and tumors with higher accuracy than two experienced
311
neuroradiologists22. Their findings were further validated in a small prospective data
312
set including 15 patients. While this approach seems promising to overcome
313
difficulties encountered by previous imaging studies, it will still be limited by the
314
number of bona fide radionecroses available to train machine learning algorithms.
13
315
Conclusion
316
Our data suggest an increasing incidence for radiation necrosis over the last two
317
decades, which is mainly associated with increased implementation of stereotactic
318
radiotherapy. Currently, there are no imaging standards to identify radiation necrosis.
319
Surgical removal of radiation necrosis is associated with low morbidity and mortality
320
and remains the standard of treatment for symptomatic and rapidly progressing
321
lesions.
322
14
323
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401 402 403
17
404
Figure legends
405
Figure 1 (A) Graph showing time between radiation and development of necrosis
406
(mean and 95% CI values) for patients receiving stereotactic radiation vs. patients
407
receiving any other type of radiation treatment (RX=radiation). (B) Graph showing
408
time between radiation and development of necrosis (mean and 95% CI values) for
409
patients receiving heavy ion radiation vs. patients receiving any other type of
410
radiation treatment. (C) Correlation between the dose of radiation received (x-axis)
411
and the time between radiation and development of necrosis (y-axis).
412 413
Figure 2 (A-C) Representative appearance of radionecroses on MRI images. Most
414
radionecroses presented with a hypointense core, which presumably corresponded
415
to the central necrosis, and with a thin outer ring of contrast enhancement as well as
416
a large edema on T2 weighted images. Lesions were round and symmetric, ribbed or
417
diffuse: Image (A) is representative of round and symmetric lesions. The
418
corresponding patient was diagnosed with metastasis and subjected to stereotactic
419
radiation. Image (B) is representative of ribbed lesions. The patient suffered from
420
carcinoma in the nasopharyngeal area and was treated with whole brain radiation
421
and a heavy ion radiation boost. Image (C) is representative of diffuse lesions. Such
422
lesions grew adjacent to tumor resection cavities. In this particular case the patient
423
suffered from a malignant astrocytoma and was treated with fractionated
424
radiotherapy. (D) Absolute numbers of cases of radionecrosis between 2003 and
425
2017 at our department (total = 21 cases).
426
18
Table 1: Patient characteristics Gender
Age (years)
Initial diagnosis
Localization of radiation necrosis
Type of radiation treatment
Applied dose
Time between radiation and diagnosis of RN (in years) 9.17
MIB frequency in hotspots (in %)
Preoperative symptoms
Postoperative symptoms
F
53
AVM
occipital
20Gy
F
48
Cerebral metastasis
parietal
F
66
M
42
Meningeom a WHO III Meningeom a WHO II
temporoparietal cerebellar
M
47
Sarcoma
temporal
M
46
Glioblastom a
parietal
stereotactic radiotherapy WB + stereotactic radiotherapy UK (radiation not in-house) fractionated radiotherapy + heavy ion radiation boost fractionated radiotherapy + heavy ion radiation boost fractionated radiotherapy + heavy ion radiation boost
8
hemiparesis
40Gy + 15Gy
0.64
3
paresis
no new symptoms aggravated paresis
UK
5.74
1
hemineglect
50Gy + 18Gy
0.51
8
fatigue
50Gy+ 24Gy
1.09
7
progressive desease on MRI
no new symptoms
50 Gy + 18 Gy (boost)
0.49
5
progressive desease on MRI
no new symptoms
F
57
Cerebral metastasis
parietal
WB + stereotactic radiotherapy stereotactic radiotherapy WB + 3x stereotactic radiotherapy stereotactic radiotherapy
30 Gy WB + 20Gy 20 Gy
0.56
0
numbness
no new symptoms
M
56
F
52
temporoparietal frontotemporal
M
67
Cerebral metastasis Multiple cerebral metastasis Cerebral metastasis
0.68
2
seizure
30Gy WB + 20 Gy
1.38
3
headache
no new symptoms no new symptoms
20 Gy
3.39
UK
no new symptoms
temporal
stereotactic radiotherapy
20 Gy
1.42
5
Eosinophilic granuloma Adenoid cystic carcinoma
occipital
UK
46.32
UK
66 Gy + 54 Gy
1.08
UK
Anaplastic oligodendro glioma WHO III Anaplastic astrozytom a WHO III Cerebral metastasis
parietal
UK (radiation not in-house) fractionated radiotherapy + heavy ion radiation reirradiation UK (radiation not in-house)
progressive desease on MRI progressive desease on MRI progressive desease on MRI cranial nerve palsy
F
55
Cerebral metastasis
M
72
M
61
F
63
UK
13.78
UK
progressive desease on MRI
no new symptoms
F
47
fractionated proton radiotherapy stereotactic radiotherapy
54 Gy
0.65
1
20 Gy
4.47
5
Transient Gerstmann syndrome no new symptoms
50
Cerebral metastasis
parietal
stereotactic radiotherapy
25 Gy
UK
2
F
57
Cerebral metastasis
occipital
stereotactic radiotherapy
20Gy+25 Gy
0.79
20
F
50
Meningeom a WHO II
frontal
fractionated radiotherapy
60Gy
0.04
0
F
70
Cerebral metastasis
parietal
stereotactic radiotherapy
20Gy+25 Gy
1.34
0
F
50
Cerebral metastasis
temporal
hypofractionat ed stereotactic radiotherapy
27Gy (3x9 Gy)
0.03
2
progressive desease on MRI progressive desease on MRI progressive desease on MRI progressive desease on MRI progressive desease on MRI progressive desease on MRI progressive desease on MRI
F
68
M
parietal
temporal
parietal
frontal
no new symptoms no new symptoms
no new symptoms no new symptoms no new symptoms
no new symptoms no new symptoms no new symptoms no new symptoms no new symptoms
WB = whole brain irradiation, UK=unknown, AVM= arteriovenous malformation
Table 2: MRI characteristics of individual patients
sensitivity
specificity
T1/T2 < 0.3
50%
94%
T1-T2 mismatch
55%
89%
edema/T1 > 4.2
65%
83%
Type of image feature
Supplemental Table 1: (A) Assessment of associations between radiation type, radiation dose and development of radiation necrosis
Time between radiation and diagnosis of radio necrosis (in years) ALL patients ALL patients excluding heavy ion excluding STX ONLY heavy ion RX RX ONLY STX RX RX # of patients 4 16 Mean 0.79 5.65 Std. Deviation 0.34 11.49 Lower 95% CI of mean 0.25 Significant -0.47 correlation? (yes/no) Upper 95% CI of mean dose (Gy) 1.33 11.77 Total radiation p-value Mannvs. yes, inverse Whitney test P= 0.94 Time between radiation and correlation diagnosis of radio necrosis (in years)
ALL patients
11 2.17 2.67
9 7.74 15.13
20 4.68 10.40
0.38
p-value-3.89
-0.19
3.96
19.38
9.54
P= 0.21 Spearman correlation coefficient = -0.52; p=0.03
RX = radiotherapy. STX = stereotactic radiotherapy
(B) Assessment of correlations between radiation dose and development of radiation necrosis
Author contributions Benito Campos: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Supervision, Project administration, Resources, Writing – Original Draft, Writing - Review & Editing Jan-Oliver Neumann: Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Alexander Hubert: Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Sebastian Adeberg: Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Rami El Shafie: Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Andreas von Deimling: Supervision, Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Martin
Bendszus:
Supervision,
Methodology,
Validation,
Formal
analysis,
Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Jürgen Debus: Supervision, Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing Denise Bernhardt: Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing
Andreas Unterberg: Supervision, Methodology, Validation, Formal analysis, Investigation, Data Curation, Visualization, Writing – Original Draft, Writing - Review & Editing
1
Abbreviation list:
2
MRI, magnetic resonance imaging
3
CT, computed tomography
4
PET, positron emission tomography
5
1
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
On behalf of all authors. Benito Campos, M.D. 11/24/2019