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This is the published version of a paper published in New England Journal of Medicine.
Citation for the original published paper (version of record):
Chinot, O., Wick, W., Mason, W., Henriksson, R., Saran, F. et al. (2014)
Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.
New England Journal of Medicine, 370(8): 709-722
http://dx.doi.org/10.1056/NEJMoa1308345
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The
new england journal
of
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n engl j med 370;8 nejm.org february 20, 2014
709
original article
Bevacizumab plus Radiotherapy–Temozolomide
for Newly Diagnosed Glioblastoma
Olivier L. Chinot, M.D., Wolfgang Wick, M.D., Warren Mason, M.D.,
Roger Henriksson, M.D., Frank Saran, M.D., Ryo Nishikawa, M.D.,
Antoine F. Carpentier, M.D., Ph.D., Khe Hoang-Xuan, M.D., Ph.D.,
Petr Kavan, M.D., Ph.D., Dana Cernea, Ph.D., Alba A. Brandes, M.D.,
Magalie Hilton, M.Sc., Lauren Abrey, M.D., and Timothy Cloughesy, M.D.
From Aix-Marseille University, Assis-
tance Publique–Hôpitaux de Marseille,
Service de Neuro-Oncologie, Centre
Hospitaliere Universitaire Timone, Mar-
seille (O.L.C.), UFR de Santé, Médecine
et Biologie Humaine, Bobigny (A.F.C.),
and Assistance Publique–Hôpitaux de
Paris (AP–HP), Hôpital Avicenne, Ser-
vice de Neurologie, Université Paris 13
(A.F.C.), and AP–HP, Université Pierre-
et-Marie-Curie, Group Hospitalier Pitié-
Salpêtrière (K.H.-X.), Paris — all in
France; University Hospital of Heidel-
berg, Department of Neurooncology,
and German Cancer Consortium, German
Cancer Research Center, Heidelberg, Ger-
many (W.W.); Princess Margaret Hospital,
Toronto (W.M.), and McGill University,
Montreal (P.K.) — both in Canada; Re-
gional Cancer Center, Stockholm Gotland,
Karolinska, Stockholm, and the Depart-
ment of Radiation Sciences and Oncolo-
gy, Umeå University, Umeå — both in
Sweden (R.H.); the Royal Marsden Na-
tional Health Service Foundation Trust,
Sutton, Surrey, United Kingdom (F.S.); Sai-
tama Medical University, Saitama, Japan
(R.N.); Oncology Institute “Ion Chiricuta,”
Cluj-Napoca, Romania (D.C.); Medical
Oncology Department, Azienda Unità
Sanitaria Locale, Bologna, Italy (A.A.B.);
F. Hoffmann–La Roche, Basel, Switzer-
land (M.H., L.A.); and University of Cali-
fornia, Los Angeles, Los Angeles (T.C.).
Address reprint requests to Dr. Chinot at
Aix-Marseille University, AP-HM, Service
de Neuro-Oncologie, CHU Timone, 264,
Rue Saint Pierre, 13005 Marseille, France,
or at olivier.chinot@ap-hm.fr.
N Engl J Med 2014;370:709-22.
DOI: 10.1056/NEJMoa1308345
Copyright © 2014 Massachusetts Medical Society.
ABSTRACT
Background
Standard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolo-
mide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab
to radiotherapy–temozolomide for the treatment of newly diagnosed glioblastoma.
Methods
We randomly assigned patients with supratentorial glioblastoma to receive intrave-
nous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo,
plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide
(75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day
treatment break, maintenance bevacizumab (10 mg per kilogram intravenously
every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per
day for 5 days), was continued for six 4-week cycles, followed by bevacizumab
monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the
disease progressed or unacceptable toxic effects developed. The coprimary end
points were investigator-assessed progression-free survival and overall survival.
Results
A total of 458 patients were assigned to the bevacizumab group, and 463 patients to
the placebo group. The median progression-free survival was longer in the bevaci-
zumab group than in the placebo group (10.6 months vs. 6.2 months; stratified
hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74;
P<0.001). The benefit with respect to progression-free survival was observed across
subgroups. Overall survival did not differ significantly between groups (stratified
hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P = 0.10). The respective overall sur-
vival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P = 0.049)
and 33.9% and 30.1% at 2 years (P = 0.24). Baseline health-related quality of life and
performance status were maintained longer in the bevacizumab group, and the gluco-
corticoid requirement was lower. More patients in the bevacizumab group than in the
placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or
higher adverse events often associated with bevacizumab (32.5% vs. 15.8%).
Conclusions
The addition of bevacizumab to radiotherapy–temozolomide did not improve survival
in patients with glioblastoma. Improved progression-free survival and maintenance
of baseline quality of life and performance status were observed with bevacizumab;
however, the rate of adverse events was higher with bevacizumab than with placebo.
(Funded by F. Hoffmann–La Roche; ClinicalTrials.gov number, NCT00943826.)
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new england journal
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n engl j med 370;8 nejm.org february 20, 2014
710
T
umor progression in glioblastoma,
the most common primary brain can-
cer,
1,2
is associated with deterioration in
neurocognitive function,
3,4
decreased functional
independence,
5
and a progressive decrease in
health-related quality of life.
6,7
After surgical
resection, the standard of care for patients with
newly diagnosed glioblastoma and a good Karnof-
sky performance score (≥70, on a scale of 0 to 100,
with higher numbers indicating better function-
ing) is concurrent radiotherapy and temozolo-
mide, followed by adjuvant temozolomide.
8-11
The
prognosis remains poor; no further improvements
in outcomes have been doc umented since the in-
troduction of radiotherapy–temozolomide therapy
in 2005.
Glioblastomas are characterized by overex-
pression of vascular endothelial growth factor
A (VEGF-A), a key regulator of tumor-associated
angiogenesis,
12-15
and these tumors are highly
vascularized.
16
The results of phase 1/2 studies sup-
port a role for the anti–VEGF-A molecule bevaciz-
umab in recurrent and newly diagnosed glioblas-
toma.
17-22
We report the results of a phase 3 trial
of bevacizumab plus radiotherapy–temozolomide
as compared with placebo plus radiotherapy–
temozolomide in patients with newly diagnosed
glioblastoma.
Methods
Study Oversight
The Avastin in Glioblastoma (AVAglio) study
(BO21990) was a randomized, double-blind, pla-
cebo-controlled trial sponsored by F. Hoffmann–
La Roche and designed by the AVAglio steering
committee (see the Supplementary Appendix, avail-
able with the full text of this article at NEJM
.org) and the sponsor. We conducted the study
at 120 sites in 23 countries. The steering com-
mittee provided oversight of the overall scientific
integrity of the study. The protocol (available at
NEJM.org) was approved by the applicable inde-
pendent ethics committees and institutional re-
view boards. Real-time monitoring of safety
events was overseen by an independent data and
safety monitoring board. The study adhered to
the principles of the Declaration of Helsinki and
the Guidelines for Good Clinical Practice. All the
authors signed confidentiality agreements with
the sponsor regarding the data. The data were
collected by the sponsor and were analyzed by an
author employed by the sponsor, who vouches for
the accuracy of the data. Medical writing assis-
tance was provided by Gardiner–Caldwell Com-
munications and paid for by the sponsor. All the
authors vouch for the adherence of the study to
the protocol and made the decision to submit the
manuscript for publication.
Patients
Patients 18 years of age or older with newly diag-
nosed, histologically confirmed, supratentorial
glioblastoma were eligible for participation in
the study. Additional inclusion criteria were a
World Health Organization (WHO) performance
status of 2 or lower (on a scale of 0 to 5, with
higher numbers indicating decreasing perfor-
mance); the use of stable or decreasing glucocorti-
coid doses within the 5 days before randomization;
adequate healing of craniotomy or cranial-biopsy
site; adequate hematologic, hepatic, and renal
function; and acceptable blood coagulation levels.
Investigators submitted available tumor tissue
blocks for pathological central review and analy-
sis of status with respect to O-6-methylguanine–
DNA methyltransferase (MGMT). Treatment had
to be initiated between 29 and 48 days after the
most recent surgery. Patients were excluded if they
had evidence of recent symptomatic intracranial
hemorrhage on magnetic resonance imaging
(MRI), prior chemotherapy or immunotherapy
for glioblastoma or low-grade astrocytoma, prior
radiotherapy to the brain, a history of intracra-
nial abscess within 6 months before randomiza-
tion, or a serious nonhealing wound. All patients
were required to give written informed consent
before enrollment.
Randomization and Treatment
Patients were randomly assigned, in a 1:1 ratio,
to bevacizumab or placebo. Randomization was
performed centrally with the use of an interactive
voice-response system, with stratification accord-
ing to study region (Western Europe, Eastern Eu-
rope, Asia, United States, or other) and recursive
partitioning analysis class (III, IV, or V).
23
(There
are six recursive partitioning analysis classes, of
which classes III, IV, V, and VI are used to catego-
rize glioblastoma, with higher numbers repre-
senting a worse prognosis. Class VI patients were
considered too frail to participate in this study.)
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Bevacizumab plus Radiotherapy–Temozolomide for Glioblastoma
n engl j med 370;8 nejm.org february 20, 2014
711
The study sponsor, study investigators, and pa-
tients were unaware of the study-group assign-
ments. Unblinding of the assignments was al-
lowed at any time for safety reasons or at the
time of disease progression if deemed necessary
by the investigator.
After undergoing surgical resection or biopsy,
patients received concurrent radiotherapy (60 Gy
administered as 2-Gy fractions 5 days per week)
and oral temozolomide (75 mg per square meter
of body-surface area per day for a maximum of
49 days), in combination with intravenous beva-
cizumab (10 mg per kilogram of body weight) or
placebo every 2 weeks. The last concurrent doses
of temozolomide and bevacizumab or placebo
were administered on the day of the last dose of
radiotherapy. The concurrent-therapy phase was
followed by a 28-day treatment break.
In the maintenance phase, patients received
temozolomide (150 mg per square meter per day
on days 1 to 5 during the first cycle and 200 mg
per square meter per day during subsequent cy-
cles if unacceptable toxic effects did not devel-
op
24
) plus intravenous bevacizumab (10 mg per
kilogram) or placebo every 2 weeks, for six
4-week cycles. In the monotherapy phase, intra-
venous bevacizumab (15 mg per kilogram) or
placebo was continued every 3 weeks until the
disease progressed or unacceptable toxic effects
developed.
Assessments
The determination of progression was based on
imaging assessment (MRI), clinical assessment,
and glucocorticoid use
25
(Table S1 in the Supple-
mentary Appendix). Radiographic criteria were
adapted to address specific concerns related to
the effect of antiangiogenic therapy on imaging.
Specifically, assessment of nonenhancing tumor
components was included, and a specific algorithm
was used to assess pseudoprogression.
25
These ad-
aptations are consistent with current international
consensus guidelines.
26
Assessments were carried
out at baseline; 28 days after completion of the con-
current-therapy phase; during cycles 2, 4, and 6 of
the maintenance phase; every 9 weeks throughout
the monotherapy phase; and at the time of disease
progression. Pseudoprogression was assessed at the
end of the treatment break with the use of a strict
algorithm,
26
and confirmatory imaging was per-
formed after two cycles of maintenance therapy.
In addition to investigator-assessed progres-
sion, radiologists at an independent review facil-
ity analyzed all MRI scans. The independent
reviewers were unaware of the study-group as-
signments, with read-only access to previous
reviews until the final imaging data set was re-
viewed; at completion of the study, a review of
the entire scan series verified the time of pro-
gression on MRI. In a final independent review,
the determination of progression was calculated
with the use of a prespecified algorithm that
combined the assessment of the scans by the
independent reviewer with the investigator’s
neurologic evaluation and assessment of gluco-
corticoid use.
Quality of life was measured with the use of
the validated core quality-of-life questionnaire
(QLQ-C30) and a quality-of-life questionnaire
specifically for patients with brain tumors
(BN20) of the European Organization for Re-
search and Treatment of Cancer.
27-29
Patients
completed the questionnaires without assis-
tance. Five scales were prespecified for the
primary analysis of deterioration-free survival:
global health status, physical functioning, social
functioning, motor dysfunction, and communi-
cation deficit. An additional 21 nonprespecified
scales were assessed in exploratory analyses.
The score on the Mini–Mental State Examination
(MMSE, on which scores range from 0 to 30, with
higher scores indicating better cognitive func-
tion) was used to assess neurocognitive function
(see Section 4 in the Supplementary Appendix).
These assessments were performed at each dis-
ease-assessment time point (before the clinical
evaluation). The Karnofsky performance status
was graded by the treating physician. Adverse
events were assessed throughout the study, ac-
cording to National Cancer Institute Common
Terminology Criteria, version 3.0.
30
Statistical Analysis
The coprimary end points were investigator-
assessed progression-free survival and overall sur-
vival. The overall 0.05 level of significance was
split asymmetrically between the two coprimary
end points, with 0.01 allocated to progression-
free survival and 0.04 to overall survival. For the
analysis of progression-free survival, assuming me-
dian durations of 9.1 months in the group receiv-
ing bevacizumab plus radiotherapy–temozolomide
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712
921 Patients underwent randomization
458 Were assigned to bevacizumab+RT–TMZ
452 Received treatment
6 Did not receive treatment
2 Had violations of entry criteria
1 Withdrew consent
1 Had adverse event before treatment
2 Had administrative or other reason
463 Were assigned to placebo+RT–TMZ
459 Received treatment
4 Did not receive treatment
1 Had violation of entry criteria
1 Had adverse event before treatment
1 Had progression prior to treatment
1 Had administrative or other reason
22 Were withdrawn from RT
16 Had adverse events or intercurrent
illness
3 Declined treatment or did not
adhere to protocol
1 Withdrew consent
1 Had administrative or other reason
1 Had protocol violation
21 Were withdrawn from RT
7 Had disease progression
8 Had adverse events or intercurrent
illness
2 Declined treatment or did not
adhere to protocol
4 Withdrew consent
150 Were withdrawn from TMZ
59 Had disease progression
65 Had adverse events or intercurrent
illness
8 Declined treatment or did not
adhere to protocol
5 Withdrew consent
7 Died
5 Had administrative or other reason
1 Had insufficient therapeutic response
280 Were withdrawn from TMZ
196 Had disease progression
52 Had adverse events or intercurrent
illness
11 Declined treatment or did not
adhere to protocol
9 Withdrew consent
7 Died
3 Had administrative or other reason
1 Had insufficient therapeutic response
1 Was lost to follow-up
425 Were withdrawn from bevacizumab
261 Had disease progression
112 Had adverse events or intercurrent
illness
17 Declined treatment or did not
adhere to protocol
7 Withdrew consent
10 Died
15 Had administrative or other reason
1 Had insufficient therapeutic response
2 Were lost to follow-up
438 Were withdrawn from placebo
346 Had disease progression
46 Had adverse events or intercurrent
illness
11 Declined treatment or did not
adhere to protocol
14 Withdrew consent
10 Died
8 Had administrative or other reason
1 Had insufficient therapeutic response
2 Were lost to follow-up
6 Patients were withdrawn from the study
during disease assessment
6 Withdrew consent
19 Patients were withdrawn from the study
during disease assessment
11 Withdrew consent
8 Had unknown reason
11 Patients were withdrawn from the study
during survival follow-up
11 Withdrew consent
20 Patients were withdrawn from the study
during survival follow-up
16 Withdrew consent
4 Were lost to follow-up
458 Were included in the intention-to-treat
population
465 Were included in the safety population
463 Were included in the intention-to-treat
population
446 Were included in the safety population
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