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Cancer Biology & Therapy
ISSN: 1538-4047 (Print) 1555-8576 (Online) Journal homepage: http://www.tandfonline.com/loi/kcbt20
Potential novel role of bevacizumab in
glioblastoma and cervical cancer
Andrew K L Goey & William D Figg
To cite this article: Andrew K L Goey & William D Figg (2014) Potential novel role of
bevacizumab in glioblastoma and cervical cancer, Cancer Biology & Therapy, 15:10, 1296-1298,
DOI: 10.4161/cbt.29926
To link to this article: http://dx.doi.org/10.4161/cbt.29926
Published online: 21 Jul 2014.
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©2014 Landes Bioscience. Do not distribute.
Cancer Biology & Therapy 15:10, 1296–1298; October 2014; © 2014 Landes Bioscience
JOURNAL CLUB
1296 Cancer Biology & Therapy Volume 15 Issue 10
JOURNAL CLUB
The VEGF-A binding monoclonal
antibody bevacizumab is a widely
prescribed angiogenesis inhibitor and
indicated for many types of cancer. As
shown by three randomized phase 3 trials
recently published in the New England
Journal of Medicine, novel indications for
this drug are still being explored. In the
RTOG 0825 and AVAglio trials the effect
of bevacizumab addition to standard
therapy in newly diagnosed glioblas-
toma (radiotherapy plus temozolomide)
was investigated, while in GOG 240 the
combination of platinum-based chemo-
therapy plus bevacizumab was explored
in advanced cervical cancer.
In RTOG 0825, addition of beva-
cizumab to standard therapy did not
result in survival benefit, and moreover,
quality of life was more deteriorated in
the bevacizumab arm. In AVAglio, how-
ever, progression-free survival (PFS)
was significantly increased in the beva-
cizumab group and these patients also
experienced a longer deterioration-free
survival. These conflicting results do
not fully support the incorporation of
bevacizumab in the first-line treatment
of glioblastoma. In contrast, in GOG
240 the bevacizumab group (including
paclitaxel plus topotecan or paclitaxel)
experienced a signif icant longer PFS and
overall survival, and quality of life was
not negatively affected in these patients.
Thus, these results favor the use of beva-
cizumab in the treatment of advanced
cervical cancer.
Targeted therapy against vascular
endothelial growth factor A (VEGF-A)
is a widely used strategy to inhibit angio-
genesis of many tumors. To this purpose,
the application of VEGF-A binding agents
(bevacizumab, aflibercept), antibodies
blocking the VEGF receptor 2 (ramuci-
rumab) a nd antiangiogenic tyrosine kinase
inhibitors (e.g., sunitinib, sorafenib, pazo-
panib, axitinib) is expanding.
Since its introduction in 2004 as the
first angiogenesis inhibitor in the USA,
bevacizumab has been approved for a wide
range of cancer types including metastatic
colorectal cancer, non-squamous non-
small cell lung cancer, metastatic renal cell
carcinoma, and recurrent glioblastoma.
Two randomized, placebo-controlled,
double-blinded, phase 3 trials recently
published in the New England Journal
of Medicine (NEJM )1,2 investigated the
potential role of bevacizumab in newly
diagnosed glioblastoma. Glioblastoma
is the most lethal primary brain tumor
in humans with a five-year survival rate
of only 3 percent. Targeting VEGF-A in
glioblastoma is appealing because VEGF-
A-overexpression and angiogenesis are
prominent features of this type of cancer.3
Current standard therapy in newly diag-
nosed glioblastoma consists of temozolo-
mide in combination with radiotherapy
followed by maintenance temozolomide
that results in a median overall survival of
only approximately 15 mo.4 Thus, there is
a high demand for novel, more effective
treatment options.
RTOG 0825 and AVAglio
In the Radiation Therapy Oncology
Group (RTOG) 0825 trial by Gilbert
et al.,1 patients with newly diagnosed
glioblastoma underwent radiotherapy for
6 wk (5 d/week × 2 Gy), while receiving
daily temozolomide (75 mg/m2, oral)
until completion of radiotherapy. At week
Potential novel role of bevacizumab in glioblastoma and cervical cancer
Andrew K L Goey and William D Figg*
Clinical Pharmacolog y Program; National Ca ncer Institute; Bethesda, MD USA
Keywords: bevacizumab (Avastin),
angiogenesis, VEGF-A, glioblastoma,
cervical cancer
*Correspondence to: William D Figg;
Email: wdfigg@helix.nih.gov
Submitted: 07/03/2014
Accepted: 07/13/2014
Published Online: 07/21/2014
http://dx.doi.org/10.4161/cbt.29926
Comment on: Gilbert MR, Dignam JJ, Armstrong
TS, Wefel JS, Blumenthal DT, Vogelbaum MA,
Colman H, Chakravarti A, Pugh S, Won M, etal. A
randomized trial of bevacizumab for newly diag-
nosed glioblastoma. N Engl J Med 2014; 370:699-
708; PMID:24552317; http://dx.doi.org/10.1056/
NE J Moa130 8573
and
Chinot OL, Wick W, Mason W, Henriksson R,
Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan
K, Kavan P, Cernea D, etal. Bevacizumab plus
radiotherapy-temozolomide for newly diag-
nosed glioblastoma. N Engl J Med 2014; 370:709-
22; PMID:24552318; http://dx.doi.org/10.1056/
NEJMoa1308345
and
Tewari KS, Sill MW, Long HJ 3rd, Penson RT,
Huang H, Ramondetta LM, Landrum LM, Oaknin
A, Reid TJ, Leitao MM, etal. Improved survival
with bevacizumab in advanced cervical cancer.
N Engl J Med 2014; 370:734-43; PMID:24552320;
http://dx.doi.org/10.1056/NEJMoa1309748
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©2014 Landes Bioscience. Do not distribute.
www.landesbioscience.com Cancer Biology & Therapy 1297
4 of radiotherapy, patients were random-
ized for treatment with bevacizumab (10
mg/kg every 2 wk, IV, n = 320) or pla-
cebo (n = 317). Administration of bevaci-
zumab or placebo continued until disease
progression, severe treatment-related tox-
icities, or completion of adjuvant therapy.
Four weeks after completion of radio-
therapy, patients underwent maintenance
therapy with temozolomide (150 mg/m2
for 5 consecutive days of a 28-d cycle,
6–12 cycles). Overall survival (OS) and
progression-free survival (PFS) were the
primary endpoints.
In this trial, addition of bevacizumab
did not significantly improve OS, which
was 15.7 mo in the bevacizumab and 16.1
mo in the placebo group (hazard ratio for
death in bevacizumab group: 1.13, P =
0.21). Also PFS did not differ significantly
between the bevacizumab and placebo
group, which was 10.7 and 7.3 mo, respec-
tively. Hazard ratio for PFS was 0.79, P =
0.007 (α = 0.004).
The lack of survival benefit was accom-
panied with a higher incidence of grade
3 or higher serious adverse events (e.g.,
hypertension, fatigue, neutropenia) in
the bevacizumab group compared with
placebo. Quality of life of patients in the
bevacizumab arm was also more deterio-
rated due to worsening of neurocognitive
and motoric function, and activity- and
mood-related symptoms.
In the Avastin in Glioblastoma
(AVAglio) study, Chinot et al. also stud-
ied the effect of bevacizumab addition
to radiotherapy and temozolomide in
newly diagnosed glioblastoma.2 During
the initial 6-wk phase of this study, treat-
ment consisted of radiotherapy (5 d/week
× 2 Gy, maximum 60 Gy), temozolo-
mide (75 mg/m2, oral) and bevacizumab
(10 mg/kg every 2 wk, IV) or placebo.
After a 28-d break, maintenance therapy
(four 6-wk cycles) started with temozolo-
mide (150 mg/m2/day for 5 d in cycle 1,
200 mg/m2/d in subsequent cycles) plus
bevacizumab (10 mg/kg) or placebo every
2 wk, for six 4-wk cycles. In the subsequent
monotherapy phase, bevacizumab (15 mg/
kg) or placebo was administered every
3 wk until disease progression or devel-
opment of unacceptable toxicities. Four
hundred and fifty-eight patients were ran-
domized to the bevacizumab group, while
463 patients received placebo. Similar to
the RTOG 0825 study, OS and PFS were
the primary endpoints in this trial.
The median PFS was 10.6 mo in the
bevacizumab group and 6.2 mo in the pla-
cebo group (P < 0.001, α = 0.01). Median
OS, however, did not differ significantly
between these groups: 16.8 (bevacizumab)
vs. 16.7 mo (placebo, P = 0.10 ).
Grade 3 or higher adverse events (e.g.,
thromboembolic events, bleeding, gas-
trointestinal perforation) occurred more
often in the bevacizumab group than in
the placebo group (66.8% vs. 51.3%).
In contrast to the RTOG 0825 study,
quality of life (i.e., deterioration-free
survival) and performance status were
maintained signif icantly longer in the bev-
acizumab arm in AVAglio. Furthermore,
the need to use glucocorticoids was lower
among patients receiving bevacizumab
than those who were receiving placebo.
In summary, in the RTOG 0825 and
the AVAglio study addition of bevaci-
zumab to temozolomide plus radiother-
apy increased PFS with 3.4 and 4.4 mo,
respectively. Compared with the statisti-
cally non-significant improvement in PFS
of 3.4 mo in the RTOG 0825 study, the
significant 4.4-mo-improvement of PFS in
the AVAglio study was likely attributable
to a higher α level in AVAglio (α = 0.01
and 0.004 in AVAglio and RTOG 0825,
respectively). No significant effects on OS
were observed in either trial. However,
results regarding quality of life were con-
flicting: bevacizumab-treated patients in
the RTOG 0825 experienced deteriorated
quality of life, while the quality of life
in the AVAglio study was not negatively
affected in the bevacizumab group.
Significant PFS Improvement
Often Not Accompanied by
Significant Effects on OS
The results of the RTOG 0825 and
the AVAglio study are consistent with
previous findings that bevacizumab sig-
nificantly improves PFS, but fails to have
a significant impact on OS. This discon-
cordance has been reported in patients
with non-small cell lung cancer,5-8 meta-
static renal cell carcinoma,9-1 2 and ovarian
cancer.13 The lack of significant effects
on OS may be caused by the use of addi-
tional chemotherapy (including crossover
to bevacizumab) in the control group
after disease progression. For example,
in the RTOG 0825 study almost 50%
of the patients with progressive disease
in the placebo group started with beva-
cizumab. As such, the survival benefit of
the bevacizumab arm could be mitigated.
The median OS of 16.1–16.7 mo in the
control group (temozolomide plus radio-
therapy) in RTOG 0825 and AVAglio was
approximately 1.5 mo longer than previ-
ously reported in the pre-bevacizumab
era.4 PFS, which is not affected by patient
crossover or subsequent therapies,14 rather
than OS would be more accurate to esti-
mate the eff icacy of bevacizumab.
Compared with newly diagnosed glio-
blastoma, bevacizumab treatment appears
to be more effective in other tumors.
For example, in patients with metastatic
colorectal cancer both OS and PFS were
significantly increased in the bevaci-
zumab-treated groups.15 Also patients
with advanced cervical cancer could ben-
efit by adding bevacizumab to their che-
motherapy regimen. While early-stage
and locally advanced cervical cancer is
curable, patients with recurrent or meta-
static cervical cancer have limited treat-
ment options. Tewari et al. investigated
the incorporation of bevacizumab and
the use of nonplatinum combination che-
motherapy in the treatment of advanced
cervical cancer.16 In their phase 3, ran-
domized trial (GOG 240), published
in the New England Journal of Medicine,
425 patients were randomized into four
groups. Group 1 (control) received cispla-
tin (50 mg/m2) and paclitaxel (135 or 175
mg/m2). In group 2 topotecan (0.75 mg/
m2 on days 1–3) and paclitaxel (175 mg/
m2, day 1) were administered. In group 3
and 4 bevacizumab (15 mg/kg on day 1)
was added to the treatments in group 1
and 2, respectively.
Results show that PFS of cisplatin-
treated patients (groups 1 and 3) was sig-
nificantly higher compared with patients
who received topotecan (7.6 vs. 5.7 mo,
P = 0.008). The difference in OS was not
significant.
Addition of bevacizumab (groups 3 +
4 vs. groups 1 + 2) increased OS (17.0 vs
13.3 mo, P = 0.004), PFS (8.2 vs. 5.9 mo,
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©2014 Landes Bioscience. Do not distribute.
1298 Cancer Biology & Therapy Volume 15 Issue 10
P = 0.002), and response rate (48% vs.
36%, P = 0.008).
The use of bevacizumab was signifi-
cantly associated with an increased inci-
dence of grade 2 or higher hypertension
(25 vs. 2%), grade 3 or higher thrombo-
embolic events (8% vs. 1%), and grade 3
or higher gastrointestinal fistulas (3% vs.
0%). However, these increased incidences
of toxicities did not significantly affect
quality of life. These f indings support the
addition of bevacizumab to cisplatin and
paclitaxel in metastatic or advanced cervi-
cal cancer.
In conclusion, based on the modest
effects of bevacizumab in newly diagnosed
glioblastoma in the RTOG 0825 and the
AVAglio study (significant PFS prolon-
gation, non-significant effect on OS,
potential decrease of quality of life due to
bevacizumab-related toxicities), bevazi-
cumab should not be added to standard
chemotherapeutic regimens for this type
of cancer. In contrast, the GOG 240 study
results indicate that addition of bevaci-
zumab to platinum-based chemotherapy
in patients with advanced cervical cancer
is recommended.
Disclosure of Potential Conflicts of Interest
No potential conf licts of interest were
disclosed.
Disclaimer
The content of this publication does
not necessarily reflect the views or poli-
cies of the Department of Health and
Human Services, nor does mention of
trade names, commercial products, or
organization imply endorsement by the
US government. The views in this manu-
script are those of the authors and may not
necessarily reflect NIH policy. No official
endorsement is intended nor should be
inferred.
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