Download Intra-arterial Chemotherapy for Retinoblastoma

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Intra-arterial Chemotherapy for Retinoblastoma
Report No. 2, Treatment Complications
Carol L. Shields, MD; Carlos G. Bianciotto, MD; Pascal Jabbour, MD; Gregory C. Griffin, MD;
Aparna Ramasubramanian, MD; Robert Rosenwasser, MD; Jerry A. Shields, MD
Objective: To describe treatment complications following intra-arterial chemotherapy (IAC) for retinoblastoma.
Methods: A retrospective interventional series of ophthalmic artery cannulation for IAC injection (3 planned sessions at 1-month intervals) was undertaken. Thirty-eight
catheterizations of 17 eyes of 17 patients were performed
from September 2008 to September 2010. Fluoroscopy of
the ophthalmic artery was performed before and immediately after treatment. Heparin was given during the procedure and aspirin (40 mg) was given orally for 1 week. The
treatment complications were determined.
Results: Only 17 of 190 children were selected for treat-
ment with IAC during this period. Following successful ophthalmic artery cannulation in 16 cases, there was no evidence of metastasis, stroke, brain injury, or persistent
systemic toxic effects. Fluoroscopy demonstrated patent
ophthalmic artery immediately before and after IAC injection in each case. Following therapy, orbital and adnexal
findings at 1 month included eyelid edema (n=13), blepha-
W
Author Affiliations: Ocular
Oncology Service, Wills Eye
Institute (Drs C. L. Shields,
Bianciotto, Ramasubramanian,
and J. A. Shields), Division of
Neurovascular and
Endovascular Surgery,
Department of Neurological
Surgery (Drs Jabbour and
Rosenwasser), and Division of
Pediatric Hematology/Oncology,
Department of Pediatrics,
Nemours/Alfred I. duPont
Hospital for Children
(Dr Griffin), Thomas Jefferson
University, Philadelphia,
Pennsylvania.
roptosis (n=10), cilia loss (n=1), and orbital congestion
with temporary dysmotility (n=12). These findings resolved within 6 months in all cases. Following therapy, vascular findings included ophthalmic artery stenosis (permanent in 3 cases, temporary in 1 case), confirmed on
fluoroscopy in 3 cases. Concomitant central or branch retinal artery occlusion was noted (permanent in 2 cases, temporary in 1 case). Subtle retinal pigment epithelial mottling in 9 cases that slowly evolved to later-onset underlying
choroidal atrophy in 5 cases was noted.
Conclusions: Treatment with IAC for retinoblastoma can
lead to mild and severe short-term ocular complications, including eyelid edema as well as potentially blinding vascular obstruction. This procedure should be used
with caution.
Arch Ophthalmol. 2011;129(11):1407-1415.
Published online June 13, 2011.
doi:10.1001/archophthalmol.2011.151
ITH MOST NEW
therapies, there is
an initial enthusiasm for the developing alternative
treatment; later, the limitations, indications, and complications are more precisely defined.1 With regard to retinoblastoma therapies, the enthusiasm for external
beam radiotherapy was dampened when
intermediate-term dry eye, cataract, sunken
socket, and facial deformity were noted and
See also pages 1399,
1458, 1487, 1490, and 1492
nearly abandoned when long-term second
cancers were realized.2,3 With chemoreduction, the initial dramatic response of advanced retinoblastoma to the 3-drug regimen was extraordinarily impressive, until
it was realized later that subretinal and vitreous seed recurrence was a problem.4 Similarly with plaque radiotherapy, the prelimi-
ARCH OPHTHALMOL / VOL 129 (NO. 11), NOV 2011
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nary remarkable tumor control was
occasionally followed by ischemic retinopathy, hemorrhage, and vision loss.5
Intra-arterial chemotherapy (IAC) for
retinoblastoma has been heralded as a novel
method for precise delivery of a small dose
of chemotherapy into the ophthalmic artery, minimizing systemic chemotherapy
toxic effects.1,6 Infusion of IAC for retinoblastoma was previously explored in the
1950s by Reese et al7 and in the 1960s by
Kiribuchi.8 Reese and coworkers evaluated 31 children with retinoblastoma treated
with internal carotid artery chemotherapy
and radiotherapy and found this combination more effective than radiotherapy alone.
More recently, Japanese collaborators
improved the technique by entering the carotid region from a remote femoral artery
access.9 They delivered chemotherapy into
the internal carotid artery at the branch point
of the ophthalmic artery (without entering
the artery) by occluding further distal flow
in the internal carotid artery using balloon
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obstruction. They described the safety of this technique with
hundreds of cannulations and no sign of stroke, but detailed
data regarding tumor control and treatment complications
were lacking in their articles.9,10
Gobin and Abramson11 and Gobin et al12 in the United
States devised a refined approach with direct catheter entry into the proximal portion of the ophthalmic artery for
deliver of chemotherapy to the eye. With this approach,
Abramson et al13-15 provided initial observations of impressive tumor response, even in eyes with advanced retinoblastoma.Regardingtreatmentcomplications,theyobserved
that “the only adverse ophthalmic findings were occasional
transient lid edema, forehead hyperemia, and loss of nasal lashes.”15 However, other information (from the same
group of investigators) remarked on more serious complications including femoral artery occlusion for 1 week
and leukopenia in fewer than 10%, and they identified that
“there were 4/46 severe ocular complications which consisted of avascular retinopathies resulting in blindness.”12
Further investigation of published reports has revealed illustrations documenting outstanding tumor regression but
with visible complications of diffuse retinal pigment epithelial (RPE) alterations and choroidal ischemia.15
We have described our experience with somewhat impressive short-term control of retinoblastoma using IAC
in selected cases.16 Herein, we delineate the ocular and
systemic complications using this technique.
METHODS
Institutional review board permission was obtained for this ongoing prospective study on September 15, 2008. Inclusion criteria were the presence of viable unilateral or bilateral retinoblastoma in patients aged 4 months or older in whom the only other
options would be enucleation, external beam radiotherapy, or systemic chemoreduction. Patients were excluded if the retinoblastoma could be controlled with more conservative methods of cryotherapy, thermotherapy, or plaque radiotherapy. Patients and
parents were informed of the risks of ophthalmic artery cannulation, including brain or orbital hemorrhage, infection, and inflammation, visual loss, loss of the eye, anaphylaxis, stroke, and
death. Patients and parents were informed of the unknown risks
of systemic metastasis from retinoblastoma using this technique
and long-term ocular and systemic toxic effects. Exclusion criteria included opaque or hazy media that precluded visualization of the fundus, fresh or recurrent retinoblastoma that could
be amenable to other conservative therapies, and clinical evidence suggestive of retinoblastoma invasion into the optic nerve,
choroid, sclera, or orbit or distant metastasis.
The details of the technique of examination and follow-up are
described in a separate article.16 Each patient was examined initially in the office and then under anesthesia by one of us (C.L.S.)
with clinical evaluation and large fundus drawings, fundus photography, and fluorescein angiography of all tumors in each eye.
The IAC was performed under anticoagulation with intravenous
heparin (75 IU/kg) and has been described previously.16,17 Chemotherapy diluted in 30 mL of saline was delivered using a pulsatile, nonlaminated technique manually over 30 minutes. The
selected chemotherapy drug was melphalan (5 mg) in all cases
and additional carboplatin (30 mg) was used in cases 1 through
6 based on previously documented efficacy.18 Carboplatin was later
discontinued after observations of ophthalmic or retinal vascular attenuation as platinum-based drugs have been recognized to
have a sclerosing effect.19 A postinfusion arteriogram was taken
to confirm patency of the ophthalmic artery. Following catheter
withdrawal, oral aspirin (40 mg) was delivered for 2 weeks.
Follow-up ophthalmic examination was provided at 1 month,
and a second treatment with IAC was performed as necessary
and then repeated 1 month later if necessary. Thereafter, ophthalmic examination was provided every 2 to 3 months. Documentation was made in each case with large fundus drawing,
fundus photography with a Retcam camera (Massie Industries, Dublin, California), fluorescein angiography, and electroretinography.
All data were collected in a retrospective fashion. Each patient was evaluated for age at diagnosis (months), race (African American, Asian, Hispanic, white), sex (male, female), and
hereditary pattern (sporadic, familial). Before and following IAC,
each patient was assessed for metastatic disease, second cancer, pinealoblastoma, and damage to the central nervous system manifesting as neurological deficit or stroke. The orbit and
adnexa were evaluated for permanent or temporary eyelid edema,
blepharoptosis, forehead erythema, eyelash loss, and dysfunction of the extraocular muscles. The globe was assessed for patency of the vascular flow to the eye including the internal carotid artery, ophthalmic artery, central retinal artery, branch
retinal artery, retinal venous drainage, and choroidal vascular
bed. The fundus was evaluated for the status of the retina, RPE,
and optic nerve. New or preexisting neovascularization of the
iris with or without neovascular glaucoma was recorded.
RESULTS
Seventeen patients were included in this study on IAC for
retinoblastoma. The mean patient age at IAC was 20 months
(range, 4-74 months). Cannulation into the proximal region of the ophthalmic artery was possible in 16 patients.
In 1 patient, cannulation was not possible owing to internal carotid artery anomalous pattern with a 360° loop and
severe spasm during the procedure. This patient was subsequently treated with intravenous chemoreduction. A total
of 37 of 38 catheterizations of the ophthalmic artery were
successful for delivery of chemotherapy. All catheterizations were unilateral. The mean number of catheterizations per eye for control of retinoblastoma was 2.25 (median, 2; range, 1-4). Following IAC, complete response of
the main tumor was achieved in 14 cases (88%), partial response was found in 2 cases (12%), and no response was
observed in 0 cases.16 Globe classification, tumor features,
treatment parameters, and tumor control for this cohort
of 17 patients are detailed in a separate article.16
The systemic and ocular complications of IAC for retinoblastoma are listed in Table 1 and Table 2 (Figures 1,
2, 3, 4, and 5). No patients developed metastasis, second cancer, or pinealoblastoma during a mean of 13 months
of follow-up. No patients developed neurological defect,
internal carotid artery occlusion, femoral artery occlusion, or stroke. One patient with anomalous internal carotid artery had a spasm during cannulation and the procedure was discontinued. Transient cytopenia was present
in 6 cases with spontaneous recovery in all cases without
the need for transfusion.
Ophthalmic adverse effects included eyelid edema
(n = 13), blepharoptosis (n = 10), and cilia loss (n = 1)
(Figure 1). There were no cases of forehead erythema.
Congested orbit with temporary extraocular muscle dysfunction was found in 12 eyes. These external findings
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Table 1. Systemic and Brain Complications From Intra-arterial Chemotherapy for Retinoblastoma
Systemic
Patient No.
Brain
Metastasis
Second
Cancer
Pinealoblastoma
Transient
Cytopenia
Neurological
Defect
Internal
Carotid Artery
Stroke
MRI
Result
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
0
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
0
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
0
No
Mild
No
No
Mild
No
Mild
Mild
Mild
No
No
No
No
No
Mild
No
No
6
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
0
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Spasm a
No
No
No
1
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
0
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Total, No.
Abbreviations: MRI, magnetic resonance imaging; Nl, normal.
a Transient carotid spasm occurred, so the procedure was discontinued. The patient was treated successfully with intravenous chemoreduction.
Table 2. Ocular Complications From Intra-arterial Chemotherapy for Retinoblastoma
Globe
Orbit and Adnexa
Transient
Extraocular
Muscle Ophthalmic Retinal Retinal
Retina
Patient No. Eyelid Forehead Eyelashes Restriction
Artery
Artery Vein Detachment
1
2a
E, P
E, P
Nl
Nl
Nl
Nl
Mild
Mild
3
4
5
6
7
E, P
E
E, P
Nl
E
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Loss
8
9c
10
11
12
E
E, P
Nl
E, P
E, P
Nl
Nl
Nl
Nl
Nl
13
E, P
14
15
16
17
Total, No.
Nl
E, P
E, P
Nl
13
RPE
Mottling
Choroidal
Vascular
Atrophy
Optic
Nerve
Atrophy
NVI
NVG
Nl
VH, no
view
Nl
Nl
Nl
CRAO
BRAO
Nl
VH, no
view
Nl
Nl
Nl
NA
Nl
SRD
No
No
VH, no view
No
No
No
No
VH, no view VH, no view Yes, new Yes, new
Mod
Mild
Mild
Nl
Mild
Nl
VH, no
view b
Nl
Nl
Nl
Stenosis
Stenosis
No
No
No
No
SRD
No
No
Yes, diffuse
Yes, diffuse
No
No
No
No
Yes
No
No
No
No
No
No
No
No
No
No
No
Nl
Nl
Nl
Nl
Nl
Mod
Nl
Mild
Nl
Mild
Nl
Nl
Nl
Nl
Nl
Nl
Nl
Nl
BRAO
Nl
Nl
Nl
Nl
Nl
Nl
No
TRD
No
No
No
Yes, diffuse
Yes, focal
Yes, diffuse
Yes, diffuse
Yes but
extensive
subretinal
seeding
Yes, focal
No view
Yes, diffuse
Yes, diffuse
No
No
No view
Yes, diffuse
Yes, diffuse
No
No
No view
No
No
No
No
Yes, old
No
No
No
Nl
Nl
Nl
Nl
Nl
Nl
No
No
No
Nl
Nl
Nl
Nl
0
Nl
Nl
Nl
Nl
1
Nl
Mild
Mod
Mild
12
NA
Stenosis d
Nl
Nl
4
NA
BRAO d
Nl
Nl
5
NA
Nl
Nl
Nl
0
NA
No
No
No
3
Yes, focal but
previous
SRD
NA
Yes, focal
No
No
9
No
Yes, old
No
No
Yes but
total
SRD
No
NA
Yes, focal
No
No
5
NA
No
No
No
1
NA
No
No
No
3
NA
No
No
No
2
No
Abbreviations: BRAO, branch retinal artery obstruction; CRAO, central retinal artery obstruction; E, edema; Mod, moderate; NA, not applicable; Nl, normal;
NVG, neovascular glaucoma; NVI; neovascularization of the iris; P, ptosis; RPE, retinal pigment epithelium; SRD, serous retinal detachment; TRD, traction retinal
detachment; VH, vitreous hemorrhage.
a Vitreous hemorrhage was present at the initial visit and worsened following chemotherapy.
b An ophthalmic arteriogram showed stenosis of the artery, despite no view.
c The patient had NVI at the initial visit with progression to NVG following chemotherapy, leading to enucleation despite tumor control.
d Stenosis was found at month 1 and resolved by month 2.
resolved in every case by 2 months, but blepharoptosis
resolved more slowly over 4 to 6 months. In 1 case, the
dysmotility respected the distribution of the third cra-
nial nerve and persisted for 4 months. Occlusive vasculopathy was noted in the ophthalmic artery in 4 cases and
diagnosed by funduscopy in 3 of those cases. In 1 case,
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A
B
Figure 1. Eyelid findings following intra-arterial chemotherapy for retinoblastoma. A, Case 2, with eyelid edema 1 week after intra-arterial chemotherapy. B, Case
8, with no eyelid abnormality 1 year after intra-arterial chemotherapy.
A
B
C
D
Figure 2. Retinal pigment epithelial (RPE) alterations after intra-arterial chemotherapy (IAC) for retinoblastoma. A and B, Case 4. Peripheral retinoblastoma with
vitreous seeding was treated with IAC. Note the normal RPE at the nasal juxtapapillary region at the initial visit (A) and mild RPE alterations following 1 cycle of
IAC (B). C and D, Case 10. C, Recurrent retinoblastoma on the temporal margin of the regressed tumor (at the photograph’s edge) following chemoreduction was
treated with IAC. Note the unaffected RPE superior to the calcified mass at the time of the first IAC treatment (C) and then moderate RPE alterations with choroidal
atrophy 6 months later (D).
preexisting mild vitreous hemorrhage worsened following IAC and there was no view of the fundus. However,
on arteriography, the ophthalmic artery showed stenosis and further therapy was discontinued. Of those with
clinically visible ophthalmic artery occlusion, the main
fundus features included central retinal artery obstruc-
tion (n=1), multifocal branch retinal artery obstruction
(n=3), and evidence of choroidal atrophy (n=2). In 1 case,
the ophthalmic artery obstruction and related branch retinal artery obstruction resolved completely within 1 month.
In 1 case, the choroid was camouflaged by extensive confluent subretinal seeding.
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A
B
C
D
Figure 3. Evolution of retinal pigment epithelial alterations after intra-arterial chemotherapy for retinoblastoma in case 8. Macular retinoblastoma (A) was treated
with 1 cycle of IAC, with complete response at 1 month (B). Nasal retinal pigment epithelial alterations were barely visible at 1 month (C) but evolved to a broad,
subtle, linear retinal pigment epithelial atrophy at 11 months’ follow-up (D), despite no further chemotherapy.
There were no visible emboli in any artery on ophthalmoscopy or fluorescein angiography. On fluorescein angiography, the 3 cases of posttreatment central retinal artery obstruction and branch retinal artery obstruction
showed slow perfusion of the attenuated retinal arteries. Despite the poor flow, no iris neovascularization, neovascular glaucoma, or pain developed. One patient who
initially had mild vitreous hemorrhage (presumably from
pretreatment retinal neovascularization) eventually developed dense vitreous hemorrhage and neovascular glaucoma and required enucleation. Of the 5 eyes with iris
neovascularization before treatment, only 1 had persistent neovascularization after treatment (requiring enucleation) and the remainder showed resolution of neovascularization with tumor regression and resolution of the
retinal detachment.
Following IAC, attenuation of the choroidal vascular
bed was found in 5 cases. Of 13 patients followed up for
6 months or longer, choroidal atrophy was noted in 4 of
the 9 patients (44%) in whom a clear view of the choroid was obtained. This finding was noted in 1 of 3 patients followed up for less than 6 months. This finding
initially manifested as focal or diffuse RPE mottling with
gradual loss of the choriocapillaris and, in some cases,
the larger choroidal vessels. Following IAC, RPE mottling was detected in 9 eyes and with gradual progression over time (Figure 3 and Figure 5). In 3 eyes, there
was poor to no view of the RPE due to overlying vitreous hemorrhage or confluent subretinal seeds.
COMMENT
We have used IAC for longer than 2 years in the management of selected cases of retinoblastoma.16 We have
observed both complete response and less impressive partial response of retinoblastoma. We have used this therapy
for primary as well as recurrent retinoblastoma. In a separate article describing our 2-year experience with this
approach, we found 100% tumor control for primary retinoblastoma in group C and D eyes and 33% control
for group E eyes.16 However, we use this new therapy with
caution because of the potential for local ocular toxic
effects.
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A
B
C
D
Figure 4. Transient ophthalmic artery obstruction following intra-arterial chemotherapy for retinoblastoma in case 15. Macular retinoblastoma (A) with retinal
detachment showed enhancement on fluorescein angiography (B) and good peripheral retinal perfusion. Following 1 cycle of intra-arterial chemotherapy, there
was ophthalmic artery stenosis with poor retinal and choroidal perfusion clinically (C) and angiographically (D). Retinal perfusion improved to normal by
2 months’ follow-up and no further chemotherapy was delivered.
Several benefits of IAC should be highlighted, including the localized chemotherapy injection, few necessary
sessions (approximately 2 doses), 1-day delivery, and systemic tolerance. On the other hand, several concerns about
IAC should be realized, including the potential for vascular injury or toxic effects, end-organ ischemia, and fluoroscopic-related radiation exposure.
Following IAC, some mild and some severe shortterm effects should be anticipated. The mild short-term
effects included eyelid edema, blepharoptosis, and orbital congestion, sometimes with temporary dysmotility. These findings were common and typically resolved
within a few months, leaving minimal or no residua and
without need for surgical repair. In 1 case of dysmotility, the features were consistent with transient oculomotor (third nerve) palsy. This finding has been previously
observed in 3 of 7 patients (43%).20
The more serious short-term effects involved acute and
chronic vascular insult, particularly to the ophthalmic,
retinal, and choroidal vessels. Ophthalmic artery stenosis or obstruction manifested with pale optic nerve, reduced retinal blood flow, and patchy reduction in choroidal blood flow. In our series, occlusion or stenosis of
the ophthalmic artery was observed in 4 cases, with reso-
lution in 1 case by 1 month of follow-up. In 3 cases, the
stenosis was confirmed under fluoroscopy at attempted
catheterization for a repeated dose. No affected eyes developed neovascularization of the disc or retina, neovascular glaucoma, or pain or required enucleation for this
finding. The specific pathogenesis of the vascular insult
remains unknown, but it could be secondary to catheterrelated injury to the endothelium, chemotherapy toxic
effects on the vessel or specifically the endothelium, or
embolization from foreign body contamination or chemotherapy precipitation. There were no clinically visible emboli in any case. The prefluoroscopy and postfluoroscopy findings showed that the ophthalmic artery
was patent at the time of IAC in all cases, suggesting a
lack of catheter-related dissection, trauma, or embolism. The onset of ophthalmic and retinal arterial obstruction was often evident by the 1-month follow-up,
whereas the choroidal vascular atrophy generally took
several months to become apparent, showing slow progression. These findings might suggest chemotherapy
toxic effects.
This finding of ischemia has been previously recognized as a serious short-term risk of this therapy. Gobin
et al noted that 4 of 46 eyes (9%) had “severe ocular com-
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A
B
C
D
Figure 5. Nontransient ophthalmic artery obstruction following intra-arterial chemotherapy for retinoblastoma in case 6. Macular retinoblastoma (A) showed
complete response following 1 cycle of intra-arterial chemotherapy (B). However, the intact nasal retina before treatment (C) showed broad choroidal atrophy at
1 year following treatment (D).
plications which consisted of avascular retinopathies resulting in blindness.”12 We speculate that this finding
could be overlooked in some cases, particularly if fluorescein angiography is not used. We perform fluorescein angiography at each session to confirm ocular blood
flow. Occasionally, the retinal vessels appear intact clinically and the attenuation is detected only by fluorescein
angiography. We encourage all centers using IAC to carefully study the ocular blood flow using fluorescein angiography. In comparison, our experience with intravenous chemoreduction in more than 500 children has
revealed no similar incident of postchemotherapy ophthalmic, retinal, or choroidal ischemia.
In contrast to the abrupt finding of ophthalmic or retinal vascular obstruction, the choroidal ischemic process manifested more slowly, with patchy focal areas of
subtle RPE alterations that gradually evolved over several months into RPE atrophy, then choriocapillaris and
occasionally large choroidal vessel atrophy. The features of choroidal atrophy were mild in most cases. It is
recognized that the presence of serous retinal detachment or even a large tumor base could lead to chronic
underlying RPE alterations, but in these cases, the RPE
atrophy has been diffuse in previously uninvolved areas.
The evolving sequence of diffuse, homogeneous choroidal atrophy might be suggestive of slow-onset involutional atrophy (Figure 3), perhaps from chemotherapy
toxic effects more so than an acute embolic or traumatic
event, which would more likely produce sector damage.
Scrutiny of previously published articles reveals printed
illustrations showing choroidal atrophy that was not recognized by the authors.15,21 We speculate that subtle cases
could be overlooked and this finding could be much more
common than anticipated. Furthermore, we have examined in consultation children who were treated with IAC
at other centers in whom choroidal atrophy was unequivocally evident over time. This finding can be subtle
and delayed over several months.22 Munier et al22 identified sector choroidal atrophy as a particular concern in
15% of cases. The implications of choroidal atrophy on
ultimate visual acuity in children could be profound. However, it should be realized that most of these eyes would
have otherwise been enucleated and had complete loss
of vision.
Intra-arterial chemotherapy has been used for other
systemic malignant neoplasms, and the technique has been
complicated by vascular toxic effects, similar to our experience with retinoblastoma. For example, Madaje-
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wicz et al23 found IAC to be more beneficial for survival
if delivered before rather than along with radiotherapy
for glioblastoma multiforme. However, other trials showed
contrasting findings.24,25 Grimson et al24 emphasized that
IAC for brain malignant neoplasms could lead to dosedependent eye pain, vision loss, and encephalopathy, particularly if the injection into the internal carotid artery
was below the take-off of the ophthalmic artery. Shapiro et al25 compared IAC vs intravenous chemotherapy
in 448 patients with malignant glioma and showed reduced survival for the IAC group plus related toxic effects of encephalopathy (9.5%) and ipsilateral vision loss
(15.5%). Fortunately, we have not witnessed any evidence of toxic effects in the brain in our patients during
this 2-year period.
For pediatric malignant neoplasms, IAC has been used
for osteosarcoma. When used as a monotherapy, intraarterial infusion of cisplatin appeared to be more effective against osteosarcoma than intravenous infusion.26
However, other reports showed that intra-arterial superiority was diminished when multiagent therapy was
needed.27,28 One report entitled “Intraarterial Chemotherapy for Osteosarcoma: Does the Result Really Justify the Effort?” by Bielack et al28 highlighted the risks
of this procedure. They indicated that the risks and discomforts of IAC for osteosarcoma were considerable, intractable pain occurred in more than 50% of the infusions, and local complications of vasculopathic ischemic
necrosis, thrombosis, infection, and neuropathy were
found.
With regard to retinoblastoma, a major concern is the
potential for metastatic disease, especially if the eye shows
features of high-risk retinoblastoma with tumor invasion into the choroid or postlaminar optic nerve. Often
this is not clinically apparent and is found only on histopathologic examination following enucleation.29-32 In
a comprehensive histopathologic analysis of nearly 300
eyes, high-risk features were found in 18.5% of cases, with
retrolaminar optic nerve invasion in 10.4% and massive
choroidal invasion in 8.1%.32 Eyes with high-risk features develop metastasis (leading to death) in 24%, unless intervention with systemic intravenous chemotherapy is delivered, reducing the metastatic rate to 4%.33
Intra-arterial chemotherapy is designed to selectively treat
the eye and would likely be insufficient for remote subclinical metastatic disease. Over time, this could be a threat
to the patient’s life prognosis. Fortunately, in our series,
there was no evidence of metastatic retinoblastoma. However, we are aware of 3 cases of metastatic retinoblastoma from other centers using this technique.
The technique of IAC requires fluoroscopy for accurate guidance of the catheter. The cumulative radiation
exposure with potential risk for toxic effects has been
explored by Vijayakrishnan et al.34 They found doses of
19 173 mrad to the affected eye, 3533 mrad to the contralateral eye, and 5560 mrad to the brain. Other sensitive organs like thyroid, bone marrow, and gonads received a small dose far below the minimal toxic level,
but the dose to the lens was possibly cataractogenic.
They cautioned that fluoroscopic use should be minimized to avoid radiation-related toxic effects in these
patients.
In summary, despite dramatic response of retinoblastoma to IAC,1,6,13-16 there is concern for toxic effects from
both chemotherapy and radiotherapy exposure. With this
in mind, we cautiously use IAC for retinoblastoma in selected cases.
Submitted for Publication: January 6, 2011; final revision received April 5, 2011; accepted April 6, 2011.
Published Online: June 13, 2011. doi:10.1001
/archophthalmol.2011.151
Correspondence: Carol L. Shields, MD, Ocular Oncology Service, Ste 1440, Wills Eye Institute, 840 Walnut
St, Philadelphia, PA 19107 (carol.shields@shieldsoncology
.com).
Author Contributions: Dr C. L. Shields had full access to
all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Financial Disclosure: None reported.
Funding/Support: This study was supported by the Eye
Tumor Research Foundation, Philadelphia, Pennsylvania (Drs C. L. Shields and J. A. Shields).
Role of the Sponsor: The funder had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation,
review, or approval of the manuscript.
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