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Title: Radiotherapy plus concomitant and adjuvant temozolomide for
glioblastoma.
Authors: Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B,
Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U,
Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D,
Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation
for Research and Treatment of Cancer Brain Tumor and Radiotherapy
Groups., National Cancer Institute of Canada Clinical Trials Group.
Journal: The New England journal of medicine
Year: 2005 Mar 10
Volume: 352
Issue: 10
Pages: 987-96
DOI: 10.1056/NEJMoa043330
n engl j med
352;10
www.nejm.org march
10, 2005
The
new england journal
of
medicine
987
original article
Radiotherapy plus Concomitant
and Adjuvant Temozolomide for Glioblastoma
Roger Stupp, M.D., Warren P. Mason, M.D., Martin J. van den Bent, M.D.,
Michael Weller, M.D., Barbara Fisher, M.D., Martin J.B. Taphoorn, M.D.,
Karl Belanger, M.D., Alba A. Brandes, M.D., Christine Marosi, M.D.,
Ulrich Bogdahn, M.D., Jürgen Curschmann, M.D., Robert C. Janzer, M.D.,
Samuel K. Ludwin, M.D.,Thierry Gorlia, M.Sc., Anouk Allgeier, Ph.D.,
Denis Lacombe, M.D., J. Gregory Cairncross, M.D., Elizabeth Eisenhauer, M.D.,
and René O. Mirimanoff, M.D., for the European Organisation for Research
and Treatment of Cancer Brain Tumor and Radiotherapy Groups and the National
Cancer Institute of Canada Clinical Trials Group*
From the Centre Hospitalier Universitaire
Vaudois, Lausanne, Switzerland (R.S.,
R-C.J., R.O.M.); Princess Margaret Hospital,
Toronto (W.P.M.); Daniel den Hoed Oncol-
ogy Center–Erasmus University Medical
Center Rotterdam, Rotterdam, the Neth-
erlands (M.J.B.); the University of Tübin-
gen Medical School, Tübingen, Germany
(M.W.); the University of Western Ontario,
London, Ont., Canada (B.F.); the Universi-
ty Medical Center, Utrecht, the Netherlands
(M.J.B.T.); Hôpital Notre Dame du Centre
Hospitalier Universitaire, Montreal (K.B.);
Azienda-Ospedale Università, Padova, Italy
(A.A.B.); Medical University of Vienna, Vi-
enna (C.M.); Universitätskliniken, Regens-
burg, Germany (U.B.); Inselspital, Bern,
Switzerland (J.C.); Queen’s University,
Kingston, Ont., Canada (S.K.L.); the Euro-
pean Organisation for Research and Treat-
ment of Cancer Data Center, Brussels (T.G.,
A.A., D.L.); the University of Calgary, Cal-
gary, Alta., Canada (J.G.C.); and the Nation-
al Cancer Institute of Canada Clinical Trials
Group, Kingston, Ont., Canada (E.E.). Ad-
dress reprint requests to Dr. Stupp at the
Multidisciplinary Oncology Center, Centre
Hospitalier Universitaire Vaudois, 46, rue
du Bugnon, CH-1011 Lausanne, Switzer-
land, or at roger.stupp@chuv.hospvd.ch.
*Participating institutions and investiga-
tors are listed in the Appendix.
N Engl J Med 2005;352:987-96.
Copyright © 2005 Massachusetts Medical Society.
background
Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal.
The current standard of care for newly diagnosed glioblastoma is surgical resection to
the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radio-
therapy alone with radiotherapy plus temozolomide, given concomitantly with and after
radiotherapy, in terms of efficacy and safety.
methods
Patients with newly diagnosed, histologically confirmed glioblastoma were randomly
assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of
2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus contin-
uous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days
per week from the first to the last day of radiotherapy), followed by six cycles of adju-
vant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day
cycle). The primary end point was overall survival.
results
A total of 573 patients from 85 centers underwent randomization. The median age was
56 years, and 84 percent of patients had undergone debulking surgery. At a median fol-
low-up of 28 months, the median survival was 14.6 months with radiotherapy plus
temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio
for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence
interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was
26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy
alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3
or 4 hematologic toxic effects in 7 percent of patients.
conclusions
The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma result-
ed in a clinically meaningful and statistically significant survival benefit with minimal
additional toxicity.
abstract
The New England Journal of Medicine
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Copyright © 2005 Massachusetts Medical Society. All rights reserved.
n engl j med
352;10
www.nejm.org march
10
,
2005
The
new england journal
of
medicine
988
lioblastoma is the most frequent
primary malignant brain tumor in adults.
Median survival is generally less than one
year from the time of diagnosis, and even in the
most favorable situations, most patients die within
two years.
1-3
Standard therapy consists of surgical
resection to the extent that is safely feasible, fol-
lowed by radiotherapy; in the United States, adju-
vant carmustine, a nitrosourea drug, is commonly
prescribed.
4,5
Cooperative-group trials have inves-
tigated the addition of various chemotherapeutic
regimens to radiotherapy,
6-9
but no randomized
phase 3 trial of nitrosourea-based adjuvant chemo-
therapy has demonstrated a significant survival ben-
efit as compared with radiotherapy alone, although
there were more long-term survivors in the chemo-
therapy groups in some studies.
10
A meta-analysis
based on 12 randomized trials suggested a small
survival benefit of chemotherapy, as compared
with radiotherapy alone (a 5 percent increase in
survival at two years, from 15 percent to 20 per-
cent).
11
The meta-analysis included 37 percent of
patients with prognostically more favorable, lower-
grade gliomas.
Temozolomide, an oral alkylating agent, has
demonstrated antitumor activity as a single agent
in the treatment of recurrent glioma.
12-14
The ap-
proved conventional schedule is a daily dose of 150
to 200 mg per square meter of body-surface area for
5 days of every 28-day cycle. Daily therapy at a dose
of 75 mg per square meter for up to seven weeks is
safe; this level of exposure to temozolomide
15
de-
pletes the DNA-repair enzyme O
6
-methylguanine-
DNA methyltransferase (MGMT).
16
This effect may
be important because low levels of MGMT in tumor
tissue are associated with longer survival among pa-
tients with glioblastoma who are receiving nitroso-
urea-based adjuvant chemotherapy.
17,18
A pilot phase 2 trial demonstrated the feasibility
of the concomitant administration of temozolo-
mide with fractionated radiotherapy, followed by up
to six cycles of adjuvant temozolomide, and suggest-
ed that this treatment had promising clinical activ-
ity (two-year survival rate, 31 percent).
19
The Euro-
pean Organisation for Research and Treatment of
Cancer (EORTC) Brain Tumor and Radiotherapy
Groups and the National Cancer Institute of Canada
(NCIC) Clinical Trials Group therefore initiated a
randomized, multicenter, phase 3 trial to compare
this regimen with radiotherapy alone in patients
with newly diagnosed glioblastoma.
patients
Patients 18 to 70 years of age with newly diagnosed
and histologically confirmed glioblastoma (World
Health Organization [WHO] grade IV astrocytoma)
were eligible for the study. Eligible patients had a
WHO performance status of 2 or less and adequate
hematologic, renal, and hepatic function (absolute
neutrophil count, ≥1500 per cubic millimeter; plate-
let count, ≥100,000 per cubic millimeter; serum cre-
atinine level, ≤1.5 times the upper limit of normal
in the laboratory where it was measured; total se-
rum bilirubin level, ≤1.5 times the upper limit of
normal; and liver-function values, <3 times the up-
per limit of normal for the laboratory). Patients who
were receiving corticosteroids had to receive a stable
or decreasing dose for at least 14 days before ran-
domization. All patients provided written informed
consent, and the study was approved by the ethics
committees of the participating centers.
study design and treatment
Within six weeks after the histologic diagnosis of
glioblastoma, we randomly assigned eligible pa-
tients to receive standard focal radiotherapy alone
(the control group) or standard radiotherapy plus
concomitant daily temozolomide, followed by adju-
vant temozolomide. Randomization was performed
at the EORTC Data Center, and patients were strat-
ified according to WHO performance status, wheth-
er or not they had previously undergone debulking
surgery, and the treatment center.
20
The assigned
treatment had to begin within one week after ran-
domization.
Radiotherapy consisted of fractionated focal ir-
radiation at a dose of 2 Gy per fraction given once
daily five days per week (Monday through Friday)
over a period of six weeks, for a total dose of 60 Gy.
Radiotherapy was delivered to the gross tumor vol-
ume with a 2-to-3-cm margin for the clinical target
volume. Radiotherapy was planned with dedicated
computed tomography (CT) and three-dimensional
planning systems; conformal radiotherapy was de-
livered with linear accelerators with nominal energy
of 6 MV or more, and quality assurance was per-
formed by means of individual case reviews.
21
Concomitant chemotherapy consisted of tem-
ozolomide (marketed as Temodal in Europe and
Canada and Temodar in the United States; Scher-
ing-Plough) at a dose of 75 mg per square meter per
g
methods
The New England Journal of Medicine
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Copyright © 2005 Massachusetts Medical Society. All rights reserved.
n engl j med
352;10
www.nejm.org march
10, 2005
radiotherapy with or without temozolomide for glioblastoma
989
day, given 7 days per week from the first day of ra-
diotherapy until the last day of radiotherapy, but for
no longer than 49 days. After a 4-week break, pa-
tients were then to receive up to six cycles of adju-
vant temozolomide according to the standard 5-day
schedule every 28 days. The dose was 150 mg per
square meter for the first cycle and was increased to
200 mg per square meter beginning with the second
cycle, so long as there were no hematologic toxic ef-
fects. Because continuous daily temozolomide can
cause lymphocytopenia, with a possible increased
risk of opportunistic infections, patients in the ra-
diotherapy-plus-temozolomide group were to re-
ceive prophylaxis against
Pneumocystis carinii
pneu-
monia, consisting of either inhaled pentamidine
or oral trimethoprim–sulfamethoxazole,
22
during
concomitant treatment with radiotherapy plus tem-
ozolomide. Antiemetic prophylaxis with metoclo-
pramide or a 5-hydroxytryptamine
3
antagonist was
recommended before the initial doses of concomi-
tant temozolomide and was required during the ad-
juvant five-day courses of temozolomide.
surveillance and follow-up
The baseline examination included CT or magnetic
resonance imaging (MRI), full blood counts and
blood chemistry tests, and a physical examination
that included the Mini–Mental State Examination
(MMSE) and a quality-of-life questionnaire. During
radiotherapy (with or without temozolomide), pa-
tients were to be seen every week. Twenty-one to 28
days after the completion of radiotherapy and every
3 months thereafter, patients underwent a compre-
hensive evaluation, including administration of the
MMSE and the quality-of-life questionnaire and
radiologic assessment of the tumor. During adju-
vant temozolomide therapy, patients underwent a
monthly clinical evaluation and a comprehensive
evaluation at the end of cycles 3 and 6. Tumor pro-
gression was defined according to the modified
WHO criteria as an increase in tumor size by 25 per-
cent, the appearance of new lesions, or an increased
need for corticosteroids.
23
When there was tumor
progression or after two years of follow-up, patients
were treated at the investigator’s discretion, and the
type of second-line therapy was recorded. Toxic ef-
fects were graded according to the National Cancer
Institute Common Toxicity Criteria, version 2.0,
with a score of 1 indicating mild adverse effects, a
score of 2 moderate adverse effects, a score of 3 se-
vere adverse effects, and a score of 4 life-threatening
adverse effects.
statistical analysis
The primary end point was overall survival; second-
ary end points were progression-free survival, safety,
and the quality of life. Overall survival and pro-
gression-free survival were analyzed by the Kaplan–
Meier method, with use of two-sided log-rank
statistics. This study had 80 percent power at a sig-
nificance level of 0.05 to detect a 33 percent in-
crease in median survival (hazard ratio for death,
0.75), assuming that 382 deaths occurred. All analy-
ses were conducted on an intention-to-treat basis.
The Cox proportional-hazards model was fitted to
adjust for stratification factors and other confound-
ing variables. Toxic effects are reported separately
for the radiotherapy period, defined as extending
from day 1 of radiotherapy until 28 days after the
last day of radiotherapy, or until the first day of ad-
juvant temozolomide therapy. The adjuvant-therapy
period was defined as extending from the first day
of adjuvant temozolomide therapy until 35 days
after day 1 of the last cycle of temozolomide. Find-
ings with respect to the quality of life are not re-
ported here.
organization of the trial
The concept of the trial was developed by Dr. Stupp
in collaboration with the EORTC Data Center, the
EORTC Brain Tumor and Radiotherapy Groups,
and the NCIC Clinical Trials Group, represented by
Drs. Cairncross and Eisenhauer. The radiotherapy
design and quality assurance were supervised by
Dr. Mirimanoff. The trial was sponsored by the
EORTC Brain Tumor and Radiotherapy Groups
(trial 22981/26981) in Europe and the NCIC Clini-
cal Trials Group (trial CE.3) in Canada. The trial was
supported by an unrestricted educational grant
from Schering-Plough, which also provided the
study drug; however, Schering-Plough was not in-
volved in trial design or analysis. All data were col-
lected by the EORTC and NCIC data centers and re-
viewed by Drs. Stupp and Mirimanoff. The analysis
was performed by the EORTC statistician, Mr. Gor-
lia. Histologic specimens were reviewed centrally
(according to the revised WHO classification sys-
tem
24
) by a panel of three neuropathologists in Eu-
rope (Robert C. Janzer in Lausanne, Switzerland
[chair]; Peter Wesseling in Nijmegen, the Nether-
lands; and Karima Mohktari in Paris) and a single
neuropathologist in Canada (Samuel Ludwin, King-
ston, Ont.). The article was written by Dr. Stupp with
support from a medical writer and coauthors; all au-
thors reviewed the manuscript.
The New England Journal of Medicine
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n engl j med
352;10
www.nejm.org march
10
,
2005
The
new england journal
of
medicine
990
patients
From August 2000 until March 2002, 573 patients
from 85 institutions in 15 countries were randomly
assigned to receive radiotherapy (286 patients) or
radiotherapy plus temozolomide (287 patients).
Nearly 50 percent of the patients were enrolled at
17 institutions. The characteristics of the patients
in the two groups were well balanced at baseline
(Table 1). The median age was 56 years, and 84 per-
cent of patients had undergone debulking surgery.
Slightly more patients in the radiotherapy group
than in the radiotherapy-plus-temozolomide group
were receiving corticosteroids at the time of ran-
domization (75 percent vs. 67 percent). Histologic
slides were submitted for 85 percent of patients,
and central pathological review confirmed the diag-
nosis of glioblastoma in 93 percent of the reviewed
cases; 3 percent had anaplastic astrocytoma or oli-
goastrocytoma (WHO grade III), and in 1 percent
submitted material was insufficient for a definitive
diagnosis.
disposition of patients and delivery
of treatment
The median time from diagnosis to the start of ther-
apy was 5 weeks (range, 2.0 to 12.9) in the radio-
therapy group and 5 weeks (range, 1.7 to 10.7) in
the radiotherapy-plus-temozolomide group. Table 2
summarizes the details of treatment. Unplanned
interruptions in radiotherapy were usually brief
(median, four days) and interruptions due to the
toxicity of therapy occurred in only 3 percent of the
radiotherapy group and 4 percent of the radiother-
apy-plus-temozolomide group. The other reasons
were mainly administrative (e.g., holidays, radio-
therapy equipment maintenance, or technical prob-
lems). One patient randomly assigned to radiother-
apy alone received radiotherapy plus temozolomide.
Among the 287 patients who were assigned to re-
ceive concomitant radiotherapy plus temozolo-
mide, 85 percent completed both radiotherapy and
temozolomide as planned. Thirty-seven patients
(13 percent) prematurely discontinued temozolo-
mide because of toxic effects (in 14 patients), dis-
ease progression (in 11), or other reasons (in 12).
After radiotherapy, 223 patients in the radio-
therapy-plus-temozolomide group (78 percent)
started adjuvant temozolomide and received a me-
dian of 3 cycles (range, 0 to 7); 47 percent of pa-
tients completed 6 cycles. The main reason for not
results
* This characteristic was used as a stratification factor at the time of random-
ization.
† A performance status of 0 denotes asymptomatic, 1 symptomatic and fully
ambulatory, and 2 symptomatic and in bed less than 50 percent of the day.
‡ The maximum score on the Mini–Mental State Examination (MMSE) is 30,
and scores above 26 are considered to indicate normal mental status.
§ Anaplastic astrocytoma included oligoastrocytoma.
Table 1. Demographic Characteristics of the Patients at Baseline.
Characteristic
Radiotherapy
(N=286)
Radiotherapy
plus Temozolo-
mide (N=287)
Age — yr
Median 57 56
Range 23–71 19–70
Age — no. (%)*
<50 yr 81 (28) 90 (31)
≥50 yr 205 (72) 197 (69)
Sex — no. (%)
Male 175 (61) 185 (64)
Female 111 (39) 102 (36)
WHO performance status — no. (%)*†
0 110 (38) 113 (39)
1 141 (49) 136 (47)
2 35 (12) 38 (13)
Extent of surgery — no. (%)*
Biopsy 45 (16) 48 (17)
Debulking 241 (84) 239 (83)
Complete resection 113 (40) 113 (39)
Partial resection 128 (45) 126 (44)
Time from diagnosis to radiotherapy — wk
Median 5 5
Range 2.0–12.9 1.7–10.7
Baseline MMSE score — no. (%)‡
30 91 (32) 100 (35)
27–29 97 (34) 96 (33)
≤26 86 (30) 81 (28)
Data missing 12 (4) 10 (3)
Corticosteroid therapy — no. (%)
Yes 215 (75) 193 (67)
No 70 (24) 94 (33)
Data missing 1 (<1) 0
Slides available for pathological review
— no. (%)
246 (86) 239 (83)
Findings on pathological review — no. (%)
Glioblastoma 229 (93) 221 (92)
Anaplastic astrocytoma§ 9 (4) 7 (3)
Inconclusive material 3 (1) 3 (1)
Other 5 (2) 8 (3)
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