Immediate post-radiotherapy changes in malignant glioma can mimic tumor progression.

Abstract

To determine the frequency of progressive MRI lesions shortly after radiotherapy for glioma with spontaneous improvement or stabilization, the authors studied a cohort of patients treated within two prospective phase III trials with radiotherapy only. In 9 out of 32 patients, the first post-radiotherapy MRI showed progressive enhancement. In 3 of these 9 the MRI improved or stabilized for 6 months without additional treatment. The authors conclude that patients with progressive lesions within 3 months after radiotherapy should not be eligible for phase II trials on recurrent glioma.

Full text

Page 1

2004;63;535-537
Neurology
den Bent
M. C.Y. de Wit, H. G. de Bruin, W. Eijkenboom, P. A.E. Sillevis Smitt and M. J. van

progression
Immediate post-radiotherapy changes in malignant glioma can mimic tumor
This information is current as of September 11, 2008
http://www.neurology.org/cgi/content/full/63/3/535
located on the World Wide Web at:
The online version of this article, along with updated information and services, is
All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
since 1951, it is now a weekly with 48 issues per year. Copyright © 2004 by AAN Enterprises, Inc.
® is the official journal of the American Academy of Neurology. Published continuously
Neurology
by on September 11, 2008 www.neurology.org Downloaded from

Page 2

Brief Communications
Immediate post-radiotherapy changes in
malignant glioma can mimic tumor
progression
M.C.Y. de Wit, MD; H.G. de Bruin, MD; W. Eijkenboom, MD; P.A.E. Sillevis Smitt, MD, PhD; and
M.J. van den Bent, MD, PhD
Abstract—To determine the frequency of progressive MRI lesions shortly after radiotherapy for glioma with spontaneous
improvement or stabilization, the authors studied a cohort of patients treated within two prospective phase III trials with
radiotherapy only. In 9 out of 32 patients, the first post-radiotherapy MRI showed progressive enhancement. In 3 of these
9 the MRI improved or stabilized for 6 months without additional treatment. The authors conclude that patients with
progressive lesions within 3 months after radiotherapy should not be eligible for phase II trials on recurrent glioma.
NEUROLOGY 2004;63:535–537
Most phase II and phase III trials on recurrent ana-
plastic glioma require radiologic evidence of progres-
sion as a mandatory inclusion criterion. As a rule,
this requires either an increase in area of gadolinium
uptake on MRI or the appearance of new lesions.
This is unspecific, as radiation therapy induced le-
sions may mimic recurrent tumor.1,2Due to inherent
risks and invasiveness of a stereotactic biopsy, it is
generally considered unethical to include mandatory
repeat tumor biopsies in protocols on recurrent high
grade glioma. Most protocols deal with this in part
by avoiding patients with an increased risk of radio-
necrosis by precluding patients treated with high
dose radiotherapy, stereotactic radiosurgery, or in-
terstitial radiotherapy.3
In the last years we observed several patients
with radiologic deterioration on MRI shortly after
the end of radiotherapy, which proved to be a tran-
sient phenomenon even when no further treatment
was initiated. Some articles mention the possibility
of early post-radiotherapy changes, but virtually no
data on this phenomenon are available.4,5Moreover,
many phase II studies on recurrent glioma still ac-
cept patients with progressive lesions within the
first 3 months after radiotherapy. Cases similar to
the index patient described below led us to investi-
gate the clinical relevance of this phenomenon by
reviewing a cohort of patients included in prospec-
tive phase III trials on newly diagnosed glioma
treated with radiotherapy only and for whom strict
follow-up at three monthly intervals was available.
Index case.
presented with seizures and underwent a gross total
resection of a right frontal anaplastic astrocytoma,
followed by radiation therapy (64 Gy). A brain MRI
made immediately following radiotherapy (figure, A
and B) was unchanged compared to the pre-
radiotherapy scan, showing the resection cavity but
no gadolinium uptake. Two months after the comple-
tion of radiotherapy he developed headache, drowsi-
ness, and nausea. Repeat MRI (figure, C and D)
showed a new area of gadolinium uptake and edema.
Dexamethasone resulted in a complete disappear-
ance of all signs and symptoms; no other treatment
was given. Dexamethasone was then discontinued.
Follow-up MRI at 12 months after the end of radio-
therapy (figure, E and F) showed a complete resolu-
tion of the gadolinium uptake and edema.
A previously healthy 47-year-old man
Patients and methods.
tients included in our center in EORTC studies 25951 and 26981.
Both studies addressed the value of adjuvant chemotherapy in
high-grade glioma (EORTC 26951: PCV-chemotherapy; EORTC
26981: temozolomide); both had a control arm with radiation ther-
apy only. At our center, all eligible patients were routinely asked
For this study, we reviewed all pa-
See Commentary, page 407
From the Departments of Neuro-oncology/Neurology (Drs. de Wit, Sillevis Smitt, and van den Bent), Radiology (Dr. de Bruin), and Radiotherapy (Dr.
Eijkenboom), Daniel den Hoed Cancer Center/Erasmus Medical Center, Rotterdam, The Netherlands.
Received December 4, 2003. Accepted in final form April 13, 2004.
Address correspondence and reprint requests to Dr. M.J. van den Bent, Department of Neuro-oncology/Neurology, Daniel den Hoed Cancer Center/Erasmus
Medical Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands; e-mail: m.vandenbent@erasmusmc.nl
Copyright © 2004 by AAN Enterprises, Inc.
by on September 11, 2008
535
www.neurology.orgDownloaded from

Page 3

to participate, to which the majority consented. Only patients
randomized to the control arms were used for the present study.
All pre- and post-radiotherapy brain MRI up to and including
the MRIs made after 12 months were reviewed by two indepen-
dent observers: a radiologist (H.G.d.B.) and a neuro-oncologist
(M.J.v.d.B.). The timing of MRIs was prescribed by the EORTC
protocol and is shown for patients with progression on the first
post-radiotherapy MRI in the table. The evaluation was primarily
based on T1-weighted pre- and postcontrast MR images. Mac-
donald’s criteria were used to assess the response to radiothera-
Figure. (A through F) Index case: T1-weighted images after gadolinium administration. (A, B) Immediately following
the end of radiotherapy showing the post-resection cavity; (C, D) 2 months after radiation therapy at the time of clinical
signs and symptoms showing a new area of gadolinium uptake and edema causing a slight midline shift; (E, F) 1 year
after the end of radiotherapy: resolution of edema and enhancement.
Table Description of demographics, interval between pre-RT MRI and start RT, interval between end of RT and first post-RT MRI,
dexamethasone dosage on the day of pre- and post-RT MRI, and outcome in the nine patients with an increasing lesion at the time of the
first follow-up MRI scan after radiotherapy
Patients with progression at first post-RT MRI
MRI interval/DXM
dose, mgr
MRI changes compared to
prior MRI
Survival,
mo No.Age, y SexHistology SurgeryRT Pre-RT Post-RTPost-RTAt 3 moAt 6 mo
1 36M AOAPartial resection59 Gy12/42/4.5 PD PR SD33?
2 33FAODTotal resection 59 Gy0/430/2 PD PRPR11.5
3 55F GBMPartial resection60 Gy0/1618/24 PDSDSD16.5
4 46F GBMBiopsy 25 Gy*9/2.57/16 PDDied 1.5
5 53M GBMBiopsy60 Gy2/1628/24 PDDied3
6 63M GBMPartial resection60 Gy12/435/3 PDPDDied7.4
7 40M AODPartial resection59 Gy2/424/8 PDPDDied6
8 53M GBMTotal resection46 Gy*32/40/24 PDDied 1.1
9 53F AOABiopsy59 Gy33/416/2 PDPDND11.7
* Radiotherapy prematurely discontinued.
RT ? radiotherapy, either 59 Gy in 33 fractions or 60 Gy in 30 fractions; DXM ? dexamethasone; pre-RT ? interval between pre-RT
MRI and start RT; post-RT ? interval between end of RT and first post RT MRI; PD ? progressive lesion; PR ? decreasing lesion;
SD ? stable lesion. Survival is measured in months from the first day of radiotherapy. GBM ? glioblastoma multiforme; AOA ? ana-
plastic oligoastrocytoma; AOD ? anaplastic oligodendroglioma; ND ? not done.
536
NEUROLOGY 63
August (1 of 2) 2004
by on September 11, 2008 www.neurology.orgDownloaded from

Page 4

py.6In case of disagreement on progressive lesions the scans were
jointly re-evaluated. Patients showing radiologic deterioration at
the first MRI following radiotherapy were examined more closely,
and information was collected on radiation dose, timing of the
MRI in relation to the start and end of radiotherapy, clinical
performance, dexamethasone dose, histology, and survival.
Results.
studies by our center; 32 had been randomized in the con-
trol arm. Mean age was 49 years, and 22 were men. One
patient was lost to follow-up during radiation therapy. In
nine patients the first follow-up scan after radiotherapy
showed progression as compared to the pre-radiotherapy
imaging (see the table). Six of these nine patients devel-
oped further progression at further follow-up or died
within a year, but two showed subsequent improvement
and one stabilized for 6 months without additional treat-
ment (Patients 1–3). Both reviewers identified these three
patients as progressive at the first post-radiotherapy MRI.
In one case the radiologic progression was accompanied by
clinical deterioration, which then stabilized (Patient 3).
The individual charts were checked for other explanations
of remission, but none were found. In particular, no new
treatments had been initiated and changes in dexametha-
sone dose could not explain the observed changes.
Seventy-three patients were included in these
Discussion.
treated with radiotherapy only, in three of the nine
patients with a progressive lesion at the first tumor
evaluation after radiotherapy further follow-up
showed that the progressive enhancement was not
due to tumor progression. In two patients, the le-
sions decreased to a PR during follow-up, whereas
the third patient remained stable for 6 months. Both
decrease and absence of progression for 6 months
have been considered endpoints in recent phase II
studies on recurrent high grade glioma.7With a tra-
ditional two-step statistical design used for phase II
studies in GBM aiming at a response rate of at least
25% these three out of nine patients would have
sufficed to initiate the second step and might have
lead to a false positive result of the study.8The three
patients with transient increased gadolinium en-
hancement also had a much longer survival than the
remaining six patients with a progressive lesion on
the first post-radiotherapy MRI. Others have ob-
served apparent tumor progression on radiologic ex-
amination followed by spontaneous remission, but
the frequency of this occurrence has remained un-
clear. An article on 51 patients from the pre-MRI era
using neurologic examination, brain CTs, and radio-
nucleotide scans noted in 25 patients clear deteriora-
tion in any of the three tests within the first 18
weeks.4Seven of those 25 showed subsequent im-
provement without any change in therapy, but all
patients were treated with adjuvant chemotherapy,
which may have contributed to the observed im-
provement. It is clear though from our series and
from other studies that immediate progression after
radiotherapy in general heralds a poor outcome.9
Five of the other six patients with progressive lesion
From this cohort of 32 trial patients
at the end of radiotherapy died within 8 months from
the start of radiotherapy.
The intermediate and late sequelae of radiother-
apy to the brain have been well documented.10The
characteristic difference between the early somno-
lence syndrome and the patients described in this
report is the focal increase in gadolinium enhance-
ment, with or without focal signs and symptoms. The
explanation of this early post-radiotherapy deteriora-
tion may be manifold, including tumor progression
during the first part of radiotherapy and subsequent
response, and radiation-induced vascular changes.
The classic article on the WHO-based response
criteria for glioma mentions the possibility of early
post-radiotherapy changes without further details.6
The authors advised not to start investigational
treatments within the 2 months following conven-
tional radiotherapy. The protocols according to which
the patients of this cohort were treated required a
first post radiotherapy MRI within 4 weeks after the
end of radiotherapy. However, the index case (which
was not included in any of the EORTC protocols)
shows that such transient increase in size may occur
well after these first 4 weeks.
Because the value of metabolic imaging like PET
in this situation is unclear, the most prudent ap-
proach to this methodologic problem is to exclude
patients with progression within the first 3 months
of radiotherapy from trials on recurrent glioma, un-
less histologic proof of the recurrence is obtained.
This is already current practice in some cooperative
groups (NABTT, NCCTG, EORTC). Our data show
that this should be the rule for all phase II studies
on recurrent glioma after radiotherapy. For the indi-
vidual patient an increase in gadolinium enhance-
ment is most likely to represent tumor progression,
and they should be managed accordingly, but prefer-
ably outside clinical trials.
References
1. Kumar AJ, Leeds NE, Fuller GN, et al. Malignant gliomas: MR imaging
spectrum of radiation therapy- and chemotherapy-induced necrosis of
the brain after treatment. Radiology 2000;217:377–384.
2. Norris AM, Carrington BM, Slevin NJ. Late radiation change in the
CNS: MR imaging following gadolinium enhancement. Clin Radiol
1997;52:356–362.
3. Bakardjiev AI, Barnes PD, Goumnerova LC, et al. Magnetic resonance
imaging changes after stereotactic radiation therapy for childhood low
grade astrocytoma. Cancer 1996;78:864–873.
4. Hoffman WF, Levin VA, Wilson CB. Evaluation of malignant glioma
patients during the postirradiation period. J Neurosurg 1979;50:624–
628.
5. Cascino TL, Kimmel DW, Dinapoli RP, O’Neill BP, Scheithauer B.
Report of four cases with a resolving syndrome which otherwise simu-
lates recurrent brain tumor. Neurology 1988;38(suppl 1):306. Abstract.
6. Macdonald DR, Cascino TL, Schold SC, Cairncross JG. Response crite-
ria for phase II studies of supratentorial malignant glioma. J Clin Oncol
1990;8:1277–1280.
7. Yung WKA, Albright RE, Olson J, et al. A phase II study of temozolo-
mide vs. procarbazine in patients with glioblastoma multiforme at first
relapse. Br J Cancer 2000;83:588–593.
8. Simon R. Optimal two-stage designs for phase II clinical trials. Control
Clin Trials 1989;10:1–10.
9. Gaspar LE, Fisher BJ, Macdonald DR, et al. Malignant glioma—timing
of response to radiation therapy. Int J Radiation Oncol Biol Phys 1993;
25:877–879.
10. Jennings MT. Neurological complications of radiotherapy. In: Wiley
RG, ed. Neurological complications of cancer. New York: Marcel Dek-
ker, 1995;219–240.
August (1 of 2) 2004
NEUROLOGY 63
537
by on September 11, 2008 www.neurology.orgDownloaded from

Page 5

2004;63;535-537
Neurology
den Bent
M. C.Y. de Wit, H. G. de Bruin, W. Eijkenboom, P. A.E. Sillevis Smitt and M. J. van

progression
Immediate post-radiotherapy changes in malignant glioma can mimic tumor
This information is current as of September 11, 2008

& Services
Updated Information
http://www.neurology.org/cgi/content/full/63/3/535
including high-resolution figures, can be found at:

Related Articles
http://www.neurology.org/cgi/content/full/63/3/407
A related article has been published:

Subspecialty Collections
http://www.neurology.org/cgi/collection/radiation_therapytumor

Radiation therapy-tumor
http://www.neurology.org/cgi/collection/primary_brain_tumor

brain tumor
Primary
http://www.neurology.org/cgi/collection/all_oncology

All Oncology
http://www.neurology.org/cgi/collection/mri

MRI
following collection(s):
This article, along with others on similar topics, appears in the

Permissions & Licensing
http://www.neurology.org/misc/Permissions.shtml
or in its entirety can be found online at:
Information about reproducing this article in parts (figures, tables)

Reprints
http://www.neurology.org/misc/reprints.shtml
Information about ordering reprints can be found online:
by on September 11, 2008 www.neurology.org Downloaded from