REVIEW ARTICLE
Anti-VEGF for ROP and Pediatric Retinal Diseases
An-Lun Wu, MD,*† and Wei-Chi Wu, MD, PhD*†
Abstract: Vascular endothelial growth factor (VEGF) is an important
mediator of the pathological neovascularization and vascular permeabil-
ity of the eye. The increasing use of intravitreal therapies targeting VEGF
has revolutionized the treatment of pediatric vitreoretinal diseases. In
retinopathy of prematurity (ROP), the role of VEGF in pathogenesis has
been well recognized and the use of anti-VEGF treatment in phase 2 ROP
has demonstrated promising results, particularly in severe cases of poste-
rior disease. This has made VEGF an established target in the treatment
of pediatric retinal diseases known to have abnormal vascular activity.
However, questions remain about late systemic and neurodevelopmen-
tal effects after anti-VEGF therapy for children because intravitreal in-
jection of anti-VEGF may result in systemic circulation of anti-VEGF
agent and a corresponding suppression of systemic VEGF. We do not
currently know whether the short-term suppression of systemic VEGF
affects long-term neurodevelopmental outcomes because VEGF is a vital
supporting factor during neurodevelopment. This review article focuses
on the evidence for the use of anti-VEGF treatment in certain pediatric
ocular diseases, including ROP, Coats disease, and retinoblastoma. More
extensive and prospective studies are warranted to further elucidate the
role of anti-VEGF therapy in these diseases and illustrate how we can
optimally use these agents in pediatric patients.
Key Words: bevacizumab, Coats disease, pediatric retinal disease,
retinopathy of prematurity, retinoblastoma, ranibizumab, treatment,
vascular endothelial growth factor
(Asia-Pac J Ophthalmol 2018;7:145–151)
R etinopathy of prematurity (ROP) is a vasoproliferative disor-
der of the retina that is one of the major worldwide causes of
blindness in children.1‒4 Ablation of the avascular retina by either
cryotherapy or laser photocoagulation, as shown in the Cryother-
apy for Retinopathy of Prematurity (CRYO-ROP) study5 and the
Early Treatment for Retinopathy of Prematurity (ETROP) study,6
has been regarded as a useful and effective treatment for ROP.
Currently, the role of vascular endothelial growth factor (VEGF)
in the pathogenesis of ROP has been extensively studied and neo-
vascularization was found to be primarily driven by VEGF.7,8 The
understanding of the 2 discrete phases in the pathogenesis of ROP
help determine the timing of ROP treatment.9 Use of intravitreal
anti-VEGF agents has gradually gained popularity and has even
From the *Department of Ophthalmology, Chang Gung Memorial Hospital,
Taoyuan, Taiwan; and †Chang Gung University, College of Medicine,
Taoyuan, Taiwan.
Received for publication January 23, 2018; accepted March 20, 2018.
The authors have no funding or conflicts of interest to declare.
Reprints: Wei-Chi Wu, MD, PhD, Department of Ophthalmology, Chang Gung
Memorial Hospital, No. 5, Fu-Hsin Rd., Taoyuan, Taiwan 33375. E‑mail:
weichi666@gmail.com.
Copyright © 2018 by Asia Pacific Academy of Ophthalmology
ISSN: 2162-0989
DOI: 10.22608/APO.201837
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018
Copyright © 2018 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
been advocated by some ophthalmologists as first-line therapy
in treating aggressive posterior ROP (APROP) and zone I dis-
ease.9‒11 Additionally, anti-VEGF has been used in the treatment
of other pediatric retinal diseases known to have abnormal neo-
vascularization or vascular activity.12‒14 This article reviews the
use of anti-VEGF for the treatment of ROP, Coats disease, and
retinoblastoma (RB).
PATHOGENESIS OF ROP
The pathogenesis of ROP involves 2 discrete phases: a vaso-
obliterative phase and a vasoproliferative phase.15,16 Phase 1 oc-
curs from roughly from the postmenstrual age (PMA) of 22 to
30 weeks and involves relative hyperoxia and decreased VEGF
levels. Normal retinal vascular growth is retarded in phase 1. This
occurs as a consequence of exposure to a hyperoxic environment
due to extrauterine hyperoxia along with therapeutic oxygen de-
livery. Anti-VEGF drugs are contraindicated in this phase because
VEGF is not elevated.
Phase 2 occurs from roughly the PMA of 31 to 44 weeks; it
is now understood that this period has a high risk of ROP devel-
opment because increasing metabolic demands of the developing
neural retina can cause retinal hypoxia, inducing a rapid increase
in VEGF-promoting neovascularization, followed by tractional
retinal detachment.9,17 These findings have important implications
for employing anti-VEGF as a treatment strategy for ROP during
the vasoproliferative phase. Thus, understanding the VEGF ex-
pression in the 2 phases of ROP may help determine the timing of
ROP management. Intravitreal anti-VEGF injection not only acts
against the VEGF that has already been released but also prevents
the further release of VEGF if the normal vasculature continues
toward the peripheral retina. Accordingly, normal vascular devel-
opment is delayed with VEGF injection, which is why recurrenc-
es after treatment with anti-VEGF can happen very late.
TYPES OF ANTI-VEGF AND CLINICAL OUTCOMES
Anti-VEGF agents for ROP include bevacizumab (Avastin;
Genentech Inc, South San Francisco, CA), ranibizumab (Lucen-
tis; Genentech Inc, South San Francisco, CA), pegaptanib (Macu-
gen; Eyetech Inc, Cedar Knolls, NJ), and aflibercept (Eylea; Re-
generon Pharmaceuticals, Tarrytown, NY). Each of these agents
has different pharmacokinetic effects, molecular sizes, structures,
and half-lives.9,11,18‒21
Pegaptanib is a single strand nucleotide that binds specifi-
cally to VEGF165 and was the first VEGF inhibitor approved by
the United States Food and Drug Administration (FDA) for the
treatment of wet age-related macular degeneration (AMD) in De-
cember 2004.22,23 However, this drug is now rarely used in most
countries because it was proven to be less effective than the other
anti–pan-VEGF compounds.
Bevacizumab is a humanized murine antiangiogenic
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Wu and Wu
monoclonal antibody that was originally developed for the treat-
ment of metastatic colorectal cancer and has been used with good
results in treating many retinopathies. Currently, bevacizumab is
the most commonly studied intravitreal anti-VEGF therapy for
the treatment of severe ROP; it has thus far demonstrated promis-
ing results, particularly in severe cases of posterior disease.9,24‒27
Ranibizumab, a much smaller humanized monoclonal antibody
Fab fragment, was later used with the aim of being a safer treat-
ment option. Ranibizumab binds to all VEGF-A isoforms and has
demonstrated efficacy in the treatment of type 1 ROP.11 It is rap-
idly eliminated from the blood stream because of its shorter half-
life and thus has the potential of decreased systemic toxicity.28
Although ranibizumab has been included in an increasing number
of studies in recent years, the rate of ROP recurrence after its use
has varied somewhat among various studies.11,29
Aflibercept is a “VEGF trap”—a fusion protein that binds to
VEGF-A with high affinity. It was approved by the FDA for the
treatment of wet AMD in 2011 and it is the only antiangiogenic
therapy that inhibits VEGF-A and placental growth factor.30 In-
travitreal administration of aflibercept should have a more potent
and prolonged clinical action because of its high binding affinity
and estimated intraocular half-life.31,32 However, aflibercept has
not been well studied in the treatment of ROP.
Although none of these drugs have been approved to date for
intraocular use in children, many investigators have evaluated the
off-label use of these agents in infants with ROP. Bevacizumab
and ranibizumab are the more commonly used agents, whereas
the other 2 are less frequently used for treating ROP. Anti-VEGF
has been used to treat ROP patients with different indications.
These treatment indications are summarized in Table 1.
One randomized trial and a few large comparative and non-
comparative case series have demonstrated the efficacy of bevaci-
zumab with complete resolution and low recurrence rates.9,18,24,26,33
A prospective randomized multicenter trial by the BEAT-ROP
(Bevacizumab Eliminates the Angiogenic Threat of Retinopathy
of Prematurity) Cooperative Group assessed the efficacy of be-
vacizumab monotherapy in the treatment of premature patients
with stage 3 ROP in zone I or posterior zone II as compared with
conventional laser therapy.9 The primary outcome was defined as
recurrence of ROP that required retreatment before a PMA of 54
weeks. Recurrence that required treatment occurred in 4% (6/140
eyes) of the bevacizumab group and in 22% (32/146 eyes) of the
laser group. Analysis stratified by the zone of ROP showed that a
significant treatment effect was found for zone I ROP (P = 0.003)
but not for zone II disease (P = 0.27). The study concluded that
intravitreal bevacizumab monotherapy showed a significant treat-
ment benefit with bevacizumab over laser for zone I, stage 3 plus
ROP. However, because of a high percentage of Hispanic infants
in this study, there may be an issue with its generalizability to the
entire population. Our group has conducted several multicenter
studies in Taiwan using intravitreal injection of bevacizumab to
treat high-risk prethreshold ROP (type 1 ROP). These studies have
TABLE 1. Timing in the Use of Anti-VEGF to Treat ROP
Monotherapy in type 1 ROP (zone I any stage with plus; zone I stage 3 without plus; zone II stage 2–3 with plus)
Aggressive posterior ROP
Salvage therapy after failure in laser photocoagulation
Before surgical intervention for stage 4/5 ROP
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Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018
shown similar promising outcomes when using bevacizumab for
ROP in the Asian population.11,26,34
In the determination of risk factors for recurrent ROP after
anti-VEGF treatment, APROP, extended duration of hospitaliza-
tion, and lower birth weight were found to have the greatest sig-
nificance.35 The characteristics of recurrence always include the
return of plus disease and the return of intravitreal neovascular-
ization. Late retinal detachment can occur despite early regres-
sion. Recurrence can occur later even up to PMA of 69 weeks
after anti-VEGF therapy.36 Thus, infants treated with anti-VEGF
should be carefully watched in a prolonged follow-up because
of the possibility of late recurrence and the need for retreatment.
There are 2 specific locations prone to recurrent neovasculariza-
tion: at the original site of the ridge and extraretinal fibrovascu-
lar proliferative complex and at the advancing edge of retinal
vascularization.35,36 Laser or vitrectomy is a useful treatment for
recurrence, though this depends on the severity of the recurrent
ROP.37,38 Of note, treatment with anti-VEGF is not a once-and-
done therapy. There is also a risk of delayed and incomplete reti-
nal vascularization (particularly for zone I eyes), and the follow-
up period after managing acute ROP with anti-VEGF treatment is
significantly prolonged as compared with laser photocoagulation
therapy.39
Although bevacizumab was the most commonly used and
studied anti-VEGF agent in the treatment of ROP, ranibizumab
for ROP has been reported in an increasing number of studies
in recent years because of its shorter half-life and the potential
for decreased systemic toxicity, which is due to the lower sup-
pression of systemic VEGF. In previous comparative case series,
several authors found a higher rate of ROP recurrence in eyes
treated with ranibizumab as compared with bevacizumab.29,40‒43
However, Chen et al11 performed a comparative case series using
both bevacizumab and ranibizumab as the primary treatment for
type 1 ROP. The results showed similar efficacy in disease regres-
sion and recurrence between these 2 drugs.11 Additionally, there
were no significant differences in mean refractive errors at 1 year
of corrected age, though there was a higher chance of developing
high myopia in the bevacizumab treatment group. Thus, more data
is needed in the future to objectively assess the effects of ranibi-
zumab in ROP. After the completion of the ongoing RAnibizumab
Compared With Laser Therapy for the Treatment of INfants BOrn
Prematurely With Retinopathy of Prematurity (RAINBOW) study
(ClinicalTrials.gov identifier: NCT02375971), we may have bet-
ter and more objective data for ranibizumab used in the treatment
of ROP.
PERIOPERATIVE ANTI-VEGF USE IN ROP
The presence of vascular activity is one of the major risk
factors of surgical failure when operating on stage 4 or 5 ROP
with retinal detachment. Intravitreal injection of anti-VEGF 1
week before surgical intervention for ROP has been reported as
© 2018 Asia-Pacific Academy of Ophthalmology
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018
reducing neovascular activity,44,45 allowing surgeons to operate on
a vascularly inactive or “quiet eye” rather than on an active one.
This might contribute to better results in some of these cases, in-
cluding shorter surgery time, higher percentage of lens preserva-
tion, higher percentage of anatomical reattachment, and possibly
better vision outcomes.44 However, caution is necessary regarding
the possible adverse effects of anti-VEGF management. Acute
contraction of the proliferative membrane after an intravitreal
injection of anti-VEGF in advanced ROP has been reported.46,47
Therefore, it is especially important to inject an anti-VEGF drug
at the right time to maintain balance between the neovascular
regression and avoiding the development of fibrous tissue with
traction on the retina when a retinal detachment is already pres-
ent. Although the optimal administration time before surgery has
not yet been defined, 1 week after delivering the anti-VEGF drug
is the most common interval that offers improved outcome of the
subsequent vitrectomy.44,45
INJECTION TECHNIQUE AND TREATMENT DOSE
The injection technique in pediatric eyes is quite different
from that which is used in adult eyes. There are certain consider-
ations before performing anti-VEGF injection for pediatric eyes,
including the appropriate injection site, needle gauge, and injec-
tion angle.26 Surgeons need to be very familiar with the technique
before applying this treatment to avoid damaging either the lens
or the retina because the lens is disproportionately large in pre-
term babies, and newborns do not have a well-developed pars pla-
na. After aseptic procedures, we suggest that the injection should
be performed with a 30-gauge needle at the pars plicata, which
is typically 1 mm posterior to the limbus.26 The injection angle
begins almost perpendicular to the globe. After the needle has
passed the lens equator, the tip of the needle is slightly directed
toward the center of the eyeball. Postoperative topical antibiotics
can be used for a few days. Potential complications associated
with intravitreal injection, including cataract, endophthalmitis,
and retinal detachment, need to be monitored closely after anti-
VEGF injection.
There is no definite conclusion regarding the optimal dose
of any of the anti-VEGF medications for ROP.48,49 Most previ-
ous studies have used 0.625 mg/0.025 mL for bevacizumab and
0.25 mg/0.025 mL for ranibizumab, both half of the respective
adult dose, when applying this procedure. We still do not know
the long-term effects of suppressed VEGF systemically after anti-
VEGF use locally in the eyes of these premature patients because
these drugs may leak into systemic circulation.50,51 Case series
have reported that a lower dose of 0.375 mg bevacizumab was
effective in regression of retinal neovascularization in ROP.49
Moreover, a dose of bevacizumab as low as 0.031 mg was also
effective in a masked phase 1 dose de-escalation study.52 Con-
sequently, further investigations to test the most optimal drug
TABLE 2. Advantages of Anti-VEGF Over Laser in Treating ROP
Increased success rate for zone I disease or aggressive posterior ROP
Better for cases with media opacity, tunica vasculosa lentis, and rigid pupil
Easier for cases with unstable systemic conditions
Less likely to develop myopia or high myopia
Allows retinal vasculature to further vascularize toward the peripheral retina
© 2018 Asia-Pacific Academy of Ophthalmology
Copyright © 2018 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Anti-VEGF for ROP
dosage are warranted to provide proper guidance for dose selec-
tion in these patients.
ADVANTAGES OF ANTI-VEGF IN TREATING ROP
Laser photocoagulation does not affect the VEGF already
present in the vitreous fluid because the peripheral retina ablative
procedure destroys the peripheral retina and inhibits the produc-
tion of VEGF only in the unvascularized retina. However, anti-
VEGF agents are able to neutralize the VEGF in the vitreous fluid
directly; thus, they may have more rapid response than laser pho-
tocoagulation. Moreover, there are several potential advantages
of anti-VEGF treatment over laser photocoagulation, as summa-
rized in Table 2.9,53 First, anti-VEGF had a better success rate in
zone I ROP or APROP cases when compared with laser therapy.
Approximately 27% to 47% of posterior zone I cases continue to
progress to retinal detachment even with the timely application of
laser ablation in the peripheral retina.54,55 On the contrary, in our
prior study, none of the eyes with zone I ROP, which consisted of
10% with type 1 ROP, progressed to retinal detachment after re-
ceiving intravitreal bevacizumab injection.26 Several studies also
support the observation that posterior location of the disease has
a better prognosis when treated with anti-VEGF.9,24,33,56 Secondly,
most laser photocoagulation needs to be performed under general
anesthesia with intubation, which altogether is a time-consum-
ing procedure. On the contrary, the administration of anti-VEGF
is a much shorter procedure and therefore can be performed at
the bedside without the need for intubation. This is easier and
safer for cases with unstable systemic conditions. Additionally,
intravitreal injection of anti-VEGF may still be given in cases
with media opacity, presence of tunica vasculosa lentis, or poor
pupillary dilation. It would be difficult to apply laser photocoagu-
lation in these patients with hazy media and poor visualization
of the retina. Third, ROP treated with anti-VEGF is more likely
to remain emmetropic and less likely to develop myopia or high
myopia when compared with the laser treatment group.20,57 It is
possible that anti-VEGF agents preserve more peripheral retina,
retain more anterior segment growth factors, and allow the ante-
rior segment growth to proceed with flatter corneas, deeper ante-
rior segments, and thinner lenses.58 Finally, anti-VEGF injection
may allow retinal vasculature to further vascularize toward the
peripheral retina, leaving an increased area of viable retina and
reducing the possible permanent visual field defect in ablative
laser therapy. However, this hypothesis needs to be confirmed by
future study.
OCULAR AND SYSTEMIC COMPLICATIONS
Possible ocular complications related to anti-VEGF agents
include cataracts, endophthalmitis, vitreous hemorrhage, prereti-
nal hemorrhage, transient vascular sheathing, and retinal detach-
ment.34 Table 3 summarizes the possible complications associated
with anti-VEGF for ROP. Although ocular complication rates
in the literature were low,59 these complications could be quite
damaging to vision and therefore these infants should be closely
monitored for potential complications after intravitreal injection
of anti-VEGF. In a multicenter study in Taiwan, our data dem-
onstrated that vitreous or preretinal hemorrhage occurred in 8%
of eyes and transient venous sheathing in 4% of eyes, both of
which were noted as complications of intravitreal bevacizumab
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Wu and Wu
injection; however, vitreous or preretinal hemorrhage had later
resolved in all of the treated eyes, and sheathed vessels had re-
perfused during subsequent follow-up.34 Some serious adverse
events include retinal breaks, bilateral vascular attenuation with
subretinal perivascular exudates, and optic atrophy, which were
reported in a case series from India.60
Another concern from treatment-induced complications is
termed “ROP crunch,” which denotes fast progression to trac-
tional retinal detachment due to the constriction of proliferative
tissues if anti-VEGF injection was performed in the presence of
significant tractional force. This can cause a significant increase
of traction and funnel-shaped retinal detachment and results in
poor outcomes.46,47
Virtually all publications have warned of possible systemic
complications due to VEGF suppression after intravitreal injec-
tion of anti-VEGF in newborns. In an animal study, intravitreal
injections of bevacizumab at an early age could result in more
systemic bevacizumab exposure.61 Sato et al62 have found evi-
dence of depression of systemic VEGF levels in premature infants
for at least 2 weeks after the administration of either 1 or 0.5 mg
intravitreal bevacizumab injections in ROP patients. A study of
ours has further shown that VEGF levels were depressed for 2
months due to the leakage of bevacizumab into systemic circula-
tion in type 1 ROP patients who were treated with intravitreal
bevacizumab injections.51 In comparison with bevacizumab, ra-
nibizumab injection for ROP resulted in no or barely detected
suppression of systemic VEGF in a prospective study recently
published.50 Vascular endothelial growth factor plays an impor-
tant role in neurogenesis and organogenesis in preterm newborns,
and deprivation of serum VEGF may have long-term effects on
the development of the central nervous system and other systems.
A retrospective observational study has revealed that preterm in-
fants treated with bevacizumab had higher odds of severe neuro-
developmental disabilities as compared with the laser treatment
group.63 However, several limitations, including selection bias,
inconsistent treatment indication, coexisting confounding fac-
tors, and the retrospective nature of the study, render its conclu-
sions uncertain. In contrast, the study by Martínez-Castellanos et
al64 did not show any neurodevelopmental impact 5 years after
the use of intravitreal bevacizumab injections in ROP patients.
We also conducted a study on the neurodevelopmental outcome
2 years after laser and/or intravitreal injections of bevacizumab
for infants with ROP. There was no difference in neurodevel-
opment noted for those who received only bevacizumab versus
only laser treatment. However, those sicker infants who required
rescue therapy with laser or bevacizumab injection after initial,
TABLE 3. Possible Complications Associated With Anti-VEGF for ROP
Cataract
Endophthalmitis
Retinal tear
Retinal detachment
Transient vascular sheathing
Preretinal hemorrhage
Vitreous hemorrhage
Vascular attenuation with subretinal perivascular exudates
Acute contraction of the proliferative membrane
Neurodevelopmental delay
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Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018
unsuccessful treatment (who finally received both bevacizumab
and laser photocoagulation) showed higher detrimental neuro-
developmental outcomes.65 Although anti-VEGF treatments are
well tolerated in eyes, more research is needed to verify the long-
term safety regarding the neurodevelopment of these children af-
ter their use.
ANTI-VEGF IN COATS DISEASE
Coats disease is an idiopathic exudative retinopathy charac-
terized by idiopathic retinal telangiectasia and retinal exudation.
It is usually unilateral and occurs mostly in young males within
the first decade of life. It can cause severe visual loss as a result
of exudative retinal detachment.66,67
Some studies have proposed the pathogenesis and pathologi-
cal processes in Coats disease. The pathologic features of blood-
retinal barrier breakdown with abnormal endothelial permeability,
particularly the absence of endothelium and pericytes in aberrant
retinal blood vessels,68 could secondarily result in telangiectasis
and leakage of the retina.69 Further, some studies suggest that
there may be a genetic cause. It is hypothesized that people with
Coats disease may have a mutation in the NDP gene,70 which re-
sults in a deficiency of norrin, a protein thought to be important
for normal retinal vasculogenesis.71 Notably, investigators have
demonstrated that VEGF may play a major role in the pathogen-
esis of Coats disease. They found an increased level of VEGF in
eyes with Coats disease and a significant decrease in VEGF after
injection of intravitreal injection of anti-VEGF agents.72,73 The
ischemic drive in Coats disease may lead to high VEGF levels in
the ocular fluid, which may also contribute to the increased per-
meability of the telangiectatic blood vessels leading to lipoprotein
leakage and subsequent exudative retinal detachment. Thus, anti-
VEGF has been proposed in the treatment of Coats disease as an
adjuvant therapy.
There are case reports and small case series in the litera-
ture concerning the treatment of Coats disease with anti-VEGF
agents.13,74,75 Results of intravitreal injections of anti-VEGF
agents are variable. Although a favorable response in some pa-
tients could have significant improvement in best-corrected vi-
sual acuity, most patients maintained their visual acuity with or
without reduction of subretinal fluid and exudation. It is very
important to mention that risks exist in the use of bevacizumab
for patients with Coats disease. Intravitreal bevacizumab should
be used with caution in patients with Coats disease in addition to
standard therapy, such as laser photocoagulation or cryotherapy,
because such treatment can lead to the development of vitreoreti-
nal fibrosis and tractional retinal detachment.13 In summary, anti-
VEGF may reduce exudation or subretinal fluid in Coats disease
and has the potential to work as an adjuvant therapy for retinal
ablative procedures to provide better results.
ANTI-VEGF IN RB
Retinoblastoma is the most common primary malignant in-
traocular cancer in children. Fortunately, RB is a treatable cancer,
which is curable if it is diagnosed early enough. The priority of
RB treatment is to preserve the life of the child, then to preserve
vision, and then to minimize complications or adverse effects
of treatment.76 However, subretinal and vitreous seeding due to
late diagnosis make enucleation common for these patients and
© 2018 Asia-Pacific Academy of Ophthalmology
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 3, May/June 2018
multimodal therapy is frequently needed to improve the chances
of survival and the quality of life of these RB patients.77
Angiogenesis is required for tumor growth and expansion.
Significant elevation of VEGF levels in patients with RB has
been reported in previous studies.78‒80 Therefore, the anti-VEGF
strategy theoretically plays a role in treating RB patients. How-
ever, anti-VEGF is not part of standard treatment protocols cur-
rently. Preclinical studies have shown that VEGF neutralization
with bevacizumab could inhibit differentiation of RB cells by
blockade of the extracellular signal-regulated kinase pathway.81,82
Moreover, bevacizumab has been proven to affect the growth and
differentiation of RB cells in vitro.83 Because the angiogenesis
and tumor growth of RB are not suppressed completely by us-
ing bevacizumab monotherapy, a recent study further suggested
that a combination of carboplatin and bevacizumab resulted in
a greater antitumor effect in advanced human RB in both in vi-
tro and in vivo analysis.77 Although this therapeutic strategy may
play a role in the clinical management of retinoblastoma, more
studies and evidence are required to optimize anti-VEGF therapy
for RB patients.
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