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Top cited articles David H. Abramson
Top downloaded articles
Our comprehensive search Weill-Cornell Medical College, Memorial Sloan-Kettering Cancer Center, New York,
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New York 10021; email: abramsod@mskcc.org

Annu. Rev. Med. 2014. 65:17184 Keywords

The Annual Review of Medicine is online at
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This articles doi:
10.1146/annurev-med-061312-123455
Copyright  c 2014 by Annual Reviews.
All rights reserved
cancer, pediatrics, chemotherapy, radiation, intra-arterial, ophthalmic
artery chemosurgery
Abstract
Retinoblastoma has gone from >95% mortality to >95% survival in the
past 100 years. Once enucleation techniques were perfected, the major-
ity of children survived, but without the eye (or vision in that eye). Over
the past 100 years, progressively better techniques have been developed
for salvaging vision without sacricing patient survival. Presently, 99%
of children treated at our center survive their cancer, >99% retain at
least one eye, and >90% retain normal vision in at least one eye. The
introduction of ophthalmic artery chemosurgery has been the most dra-
matic, non-radiation-based mode to maximally preserve vision.

171
 ME65CH12-Abramson ARI 19 December 2013 8:8
THE FIRST TECHNIQUES FOR
RETINOBLASTOMA
TREATMENT
Retinoblastoma is the most common primary
cancer to affect the eyes of children with 250
300 cases per year in the United States and
6,0008,000 per year worldwide. It is usually
detected by a parent who notices leukocoria
(Figure 1) in the childs eye. Although Incan
sculptures suggest its recognition more than
2,000 years ago, Petrus Pawius of Amsterdam
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is usually credited with the rst description,
in 1657, of retinoblastoma in a three-year-old
child (1). The natural, untreated course of the
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disease was described by William Hayes in
1805 (2).
Enucleation
James Wardrop, writing in 1809, believed (and
was proved correct in the next century) that
the tumor originated in the retina and that,
untreated, it extended into the optic nerve,
brain, and widespread metastases. This was
why he felt that enucleation (removal of the
entire eye) might be a way to prevent spread
of the cancer and the obligate death of a
young child. He did perform enucleations,
but in all cases the children died. Wardrop was
severely criticized by colleagues. He wrote:
Figure 1
Leukocoria, also known as the cats eye reex. The
cancer is directly visible behind the dilated pupil.
172 Abramson
The operation . . . has in many instances,
alleviated the patients sufferings, but I have
no hesitation in saying that it has also in many
cases hastened the patients death (3). This
pattern of strong advocacy for an unproven
treatment criticized by contemporaries was to
be repeated often during the next 200 years in
the history of retinoblastoma treatment.
Enucleation (the only treatment available)
was then performed widely, and as anesthe-
sia improved, the procedure became less trau-
matic. Von Graefe (18281870) recognized that
retinoblastoma often grew into and down the
optic nerve into the brain, and he advocated the
removal of a long stump of the nerve in the enu-
cleation, which remains the standard practice
even now. From the mid-nineteenth through
mid-twentieth century, enucleation remained
the sole treatment for retinoblastoma, and its
survival rates improved (48). As recently as
1967, Duke-Elder wrote that enucleation of
the globe at the earliest opportunity is the safest
and still most effective method of the treatment
of retinoblastoma (7). Retinoblastoma is uni-
lateral in 75% of cases and bilateral in 25% of
cases, so although survival had increased during
these hundred years (though it then plateaued),
every child treatedwhether cured or not
received one or two enucleations. This meant
that all children with bilateral disease who sur-
vived were blinded at an early age, and all chil-
dren with unilateral disease retained only one
eye (and even then, half died). Enucleation did
indeed save lives, but with survival around 50%
and blindness common, clinicians sought alter-
natives that could cure the cancer and retain at
least one eye without compromising survival.
Radiation was to be the answer.
Radiation
Radiation was rst reported to be successful
in a 1903 report by Hilgartner (9). In 1919,
Schoenberg (10) reported successful treatment
of bilateral retinoblastoma with X-rays, al-
though the patient died of a sarcoma 23 years
later (11).
 ME65CH12-Abramson ARI 19 December 2013 8:8
As a result of pioneering work by Stallard
(12) in England and Reese (13) in the United
States, radiation became the only way to save a
retinoblastoma eye. In fact, retinoblastoma has
turned out to be one of the very few solid can-
cers (in children or adults) that can be cured
with radiation alone. Initially dosage was based
on the skin reaction (skin tolerance), and
techniques did not exist to quantify what dose
was given. The energy of the source was low, so
penetration was a problemsupercial struc-
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tures such as skin and bone received a higher
dose than the eye. By 1922 there were 37 ra-
diated cases in the literature, and only ve ap-
Annu. Rev. Med. 2014.65:171-184. Downloaded from www.annualreviews.org
peared cured.
By 1952 Reese was able to report on
his experience in radiating 203 patients with
retinoblastoma. He delivered 16,000 rads in
400-rad fractions over 31/2 months; 36% were
cured and 24% had useful vision. The dose
often led to intractable complications (7). At
the same time, Stallard was pioneering a dif-
ferent radiation approach. Moore had demon-
strated that a radon needle passed through
the sclera and into the globe could destroy
retinoblastoma (14). Stallard realized that there
was a safer way to deliver radiation close to the
tumor and developed plaques (initially asbestos
paper impregnated with radium salt cased in
platinum) with radioactive cobalt (60 Co) em-
bedded in a platinum sheath and curved to t
the eye. Holes allowed the plaque to be sutured
on the sclera directly over the tumor. In 1948
he designed a radioactive plaque (applicator)
shaped to t a childs eye and designed to de-
liver 4,000 rads to the apex of a tumor. It was
thought that bringing the therapeutic artillery
as close as possible to the target to hit it hard and
precisely should be effective, Stallard wrote,
and should eliminate some of the more seri-
ous complications which follow the radiation
from a more remote source (15).
In 1961 Stallard reported on long-term re-
sults with his plaques. In the 70 patients so
treated, complications were common: six de-
veloped a cataract, four developed retinal exu-
dates, 15 developed intraocular hemorrhages,
one developed degeneration of the choroid,
four developed vascular sheathing in the retina,
and others developed glaucoma, keratitis, and
iritis (16). Nevertheless, Stallard felt that his
complications were fewer than those seen with
external-beam radiation. More encouraging re-
sults were subsequently reported by Stallard in
1964 (17) and Bedford in 1975 (18).
Lommatzch, working in Germany, devel-
oped similar plaques that used a lower-energy
emitter (ruthenium) with beta rays. They could
be shielded (with silver) and were able to deliver
high doses to the tumor while avoiding many of
the complications seen with cobalt. In 1978 he
reported on 22 patients with ve-year follow-
up (21 with bilateral disease), of whom 18 were
successfully treated (19).
Both Reese and Stallard gained more experi-
ence with external-beam radiation but felt that
it should only be used for bilateral retinoblas-
toma. Reese noted that attempts to treat uni-
lateral tumors by irradiation have never been
successful in eradicating the disease and pre-
serving any vision in the treated eye (7).
Retinoblastoma was the rst human cancer
treated with a linear accelerator. After the intro-
duction of this treatment in 1956, success rates
increased and complication rates decreased
(20). A classication scheme was introduced by
Reese and Ellsworth that accurately predicted
local success with lateral photon radiation
(Table 1) (21). For eyes in Reese-Ellsworth
groups IIII, we reported 63 of 74 eyes were
cured (although some required additional laser
or cryotherapy) (22). For Reese-Ellsworth
IV and V eyes, we reported 20 of 64 eyes
were salvaged and 88% of patients were cured
of retinoblastoma (23). Finally, of eyes with
extensive vitreous seeding (Vb) that were not
primarily enucleated, 50% were saved (24).
The combination of lateral portal irradia-
tion, proper fractionation (ve times per week),
an appropriate dose per fraction (200 cGy), and
case selection certainly increased local success
and minimized side effects. But one side effect
was to be the end of external-beam radiation for
retinoblastoma.
www.annualreviews.org Retinoblastoma, Survival, and Vision 173
 ME65CH12-Abramson ARI 19 December 2013 8:8

Table 1 Reese-Ellsworth classification scheme for intraocular retinoblastoma

Group I a. Solitary tumor, <4 disc diameters in size, at or behind the equator
b. Multiple tumors, none >4 disc diameters in size, all at or behind the equator
Group II a. Solitary tumor, 410 disc diameters in size, at or behind equator
b. Multiple tumors, 410 disc diameters in size, all at or behind the equator
Group III a. Any lesion anterior to the equator
b. Solitary tumors >10 disc diameters behind the equator
Group IV a. Multiple tumors, some >10 disc diameters
b. Any lesion extending anteriorly to the ora serrata
Group V a. Massive tumors involving over half the retina
b. Vitreous seeding
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Risk of Second Nonocular Cancers the accepted terminology, but some might in-
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with Radiation terpret the name to mean the second cancer

outside the eye to develop.
The most common cause of death in retinoblas-
Which retinoblastoma patient develops a
toma patients is not retinoblastomait is the
second nonocular cancer is not random. There
second nonocular cancers that are caused by
are genetic and environmental contributions,
the Rb1 gene defect and further increased by
but the greatest risk factor is genetic. Those
external-beam irradiation and chemotherapy.
with the genetic (germinal) form of the
Children with retinoblastoma who survive ther-
disease have a many-thousand-fold greater
apy are at signicant, lifelong risk to develop
chance of developing second cancers than non-
additional cancers (Figure 2). I named them
retinoblastoma controls. This category encom-
second nonocular tumors (25) to emphasize
passes all bilateral patients (whether or not
that they are the second cancers in these chil-
there is a family history of retinoblastoma)
dren and that they are not in the eye. That is
and some of the unilateral cases. The unilat-
35 eral cases that are at risk include children born
into families with a history of retinoblastoma
30 30.3 4.8% and those in whom germline defects have been
Cumulative mortality (%)

demonstrated. Clinically, these unilateral pa-

25 tients often have tumors in the macula, are diag-
nosed at a young age (under one year), and have
20
Radiotherapy multifocal intraocular disease. They comprise
15 >40% of retinoblastoma patients and are at a
high risk for developing second cancers even if
10 they receive no radiation or chemotherapy and
6.4 3.8% are treated with enucleation(s) only.
5 No radiotherapy Radiation is the second most important
contributor to second tumors in the population
0
1 10 20 30 40 genetically at risk for retinoblastoma. External-
Time after diagnosis (years)
beam irradiation (not plaques) changes the inci-
Radiotherapy 835 593 359 134 25 dence, timing, and distribution of these cancers.
No radiotherapy 84 70 45 27 11 Without radiation, two-thirds of the second
Number of children with bilateral retinoblastoma cancers are not in the head, with mean latent
Figure 2 periods of 2030 years. With radiation, two-
Kaplan-Meier curves demonstrating long-term incidence of second nonocular thirds of the second cancers develop in the head,
cancers in retinoblastoma: irradiated patients versus no radiation. and their latent periods are 1020 years shorter.

174 Abramson
 ME65CH12-Abramson ARI 19 December 2013 8:8

Ages when these areas are at risk for second tumors (in years)
5 10 15 20 25 30 35 40
Soft tissues of the head (most common)
No radiation
Radiation when older than 1 year
Radiation when younger than 1 year

Skull
No radiation
Radiation when older than 1 year
Radiation when younger than 1 year

Skin
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Level of risk is the same in patients

with and without radiation treatment
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Bones (arms and legs)

Level of risk is the same in patients
with and without radiation treatment

Brain (least common)

No radiation
Radiation when older than 1 year
Radiation when younger than 1 year

Level of risk per year

Low Medium High
(9<1/1,000) (1/1,000-250) (>1/250)

Figure 3
Graphic representation of timing, location, and type of second cancers in genetic retinoblastoma and their relative frequency in
nonirradiated patients, irradiated patients, and those irradiated in the rst year of life.

In other words, as a result of external-beam ir-
radiation, children develop their second can-
cers sooner, these cancers are more often in the
head, and, because most are sarcomas, the pa-
tients die younger than nonirradiated bilateral
cases (2630). In addition, our studies showed
that the younger the child, the greater the
chance of developing a second cancer. Radia-
tion in the rst year of life increases the chances
of a second cancer by eightfold (31). Figure 3
illustrates the location, timing, and impact of
radiation, especially in the rst year of life.
Children who survive their second cancers
have a 50% chance of developing a third can-
cer, and 50% of them die. Children who survive
their third cancer have a 50% chance of devel-
oping a fourth cancer, and the story is similar
for a fth cancer (32).
Thus, the rst treatment that allowed sal-
vage of the eyes with vision actually shortened
patients lives by many years. It was a cruel blow
to the retinoblastoma community, and clini-
cians searched for alternative ways to accom-
plish their goal of curing cancer, saving eyes,
and retaining vision.
FOCAL TECHNIQUES
Three other techniques were developed world-
wide (one of historical value only) in an attempt
to cure small intraocular tumors.
Weve treated small tumors with diathermy.
The tip of the diathermy probe was applied to
the sclera overlying an intraocular tumor fo-
cus and weak currents were applied for a rel-
atively long time (33, 34). Of 14 eyes treated,

www.annualreviews.org Retinoblastoma, Survival, and Vision 175

 ME65CH12-Abramson ARI 19 December 2013 8:8

11 had progressive disease and were enucleated

with pathology proving the presence of viable
cells. Of the remaining three eyes, one lost all
sight. Surface diathermy led to rupture of the
sclera in 50% of the cases, and with penetrating
diathermy, tumor oozed out the site of pene-
tration. Few others tried this approach.
Light coagulation (initially with white light
from a xenon arc bulb) has been used suc-
cessfully since the late 1940s. The laser most
commonly used today for retinoblastoma is an
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810-nm (invisible light, near infrared) device

that delivers light via the indirect ophthalmo-
scope under anesthesia through dilated pupils.
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The energy is well absorbed by pigment (the

pigment epithelium), and burns just over 1 mm
are easily made. Small retinoblastomas can be
treated directly and/or by simply destroying
their retinal blood supply. Modications of this
technique are used by all centers worldwide.
Ninety percent of small tumors can be cured
with this technique alone (35), and the average
tumor needs between one and two laser sessions
to be successful (Figure 4). In tumors that ab-
sorb energy poorly, success can be enhanced by
simultaneous intravenous injection of ICG (in-
docyanine green), which greatly enhances laser
energy absorption (36).
Cryotherapy was introduced by Lincoff in
1967 (37) and has been used by all centers since
then. A rounded tip is applied to the sclera (usu-
ally through the overlying conjunctiva), and
with a nitrous oxide source the tip freezes at
the rate of 90 C per minute. Intracellular wa-
ter immediately turns to ice, ruptures cell mem-
branes, and eliminates the tumor, leaving only a
pigmented scar. For tumors smaller than 3 mm Figure 4
in base diameter, local control exceeds 95% Fundus photographs before (top), immediately after
(Figure 5) (38). (middle), and weeks after (bottom) successful
As valuable as these focal techniques are, treatment of retinoblastoma with an 810-nm laser.
they cannot cure the majority of eyes because
>80% of tumors at presentation are too large SYSTEMIC CHEMOTHERAPY
or have subretinal and/or vitreous seeding. In Systemic chemotherapy was rst used in 1953
an attempt to eliminate the use of external- (39). Reese quickly adopted it with the hope
beam radiation, clinicians worldwide searched of being able to decrease the dose of radiation
for alternatives to the standard ways of treating (40). It was abandoned because of unaccept-
larger tumors (radiation and enucleation) and able side effects and because it could not
explored the use of systemic chemotherapy. cure the canceronly shrink it temporarily.

176 Abramson
 ME65CH12-Abramson ARI 19 December 2013 8:8
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Figure 5
Fundus photograph before (top), immediately after
(middle), and months after (bottom) successful
treatment with cryotherapy.
Twenty-ve years later in New York we tried
using systemic chemotherapy with the idea of
shrinking tumors and then curing them with
laser, cryotherapy, or plaques (41), but we
again abandoned it because of unacceptable
chemotherapy toxicity.
Following the discovery that carboplatin
was a powerful drug for retinoblastoma,
all centers began using carboplatin-based
chemotherapy, and nearly 200 publications
in the past 18 years have supported its use.
Because the Reese-Ellsworth classication
scheme had been specically created for lateral
photon radiation, a new classication scheme,
the International Classication of Retinoblas-
toma (ICRB), was created (Table 2). It better
predicted the response to chemotherapy-based
regimens and incorporated subretinal seeding,
as it was recognized that subretinal seeding
(not in the Reese-Ellsworth scheme at all) was
a predictor of failure with chemotherapy.
The results of systemic chemotherapy have
been mixed. Although many eyes have been
saved with this approach, there has been pro-
gressive disenchantment for four reasons:
1. Chemotherapy rarely (some series say
never) cures intraocular retinoblastoma
by itself, although for eyes classied in
ICRB groups A and B (Reese-Ellsworth
IIII), it can be helpful in shrinking tu-
mors so that they can be cured with focal
techniques. Unfortunately, these are en-
countered in <25% of eyes.
2. Group C eyes managed with systemic
chemotherapy fail treatment 40% of the
time (42). Enucleation or radiation is then
needed. Eyes that require radiation af-
ter systemic chemotherapy have signi-
cantly more ocular complications (vitre-
ous hemorrhage and loss of vision) than
those receiving either modality alone.
3. Group D eyes (with Group E) represent
the bulk of the eyes seen worldwide
and the greatest challenge for clinicians.
The majority of Group D eyes fail
chemotherapy. Rates of failure in the
literature vary from 60% to 100% (43).
For eyes with subretinal seeding, failure
rates approach 100%.
4. Group E eyes cannot be treated with sys-
temic chemotherapy because of universal
failure.
Toxicity, as mentioned, has also been a
problem with systemic chemotherapy. Tox-
icity from chemotherapy is well accepted in
oncology, but for retinoblastoma, where the
chemotherapy is not curative and alternatives
exist for curing the child, it has been vexing.
www.annualreviews.org Retinoblastoma, Survival, and Vision 177
 ME65CH12-Abramson ARI 19 December 2013 8:8

Table 2 International Classification for Retinoblastoma (ICRB)

Group A: All tumors are 3 mm or smaller in greatest dimension, conned to the retina and
Small intraretinal tumors away from All tumors are located farther than 3 mm from the foveola and 1.5 mm from the optic disc
foveola and disc
Group B: All other tumors conned to the retina not in Group A
All remaining discrete tumors conned Tumor-associated subretinal uid <3 mm from the tumor with no subretinal seeding
to the retina
Group C: Tumor(s) are discrete
Discrete local disease with minimal Subretinal uid, present or past, without seeding involving up to one-quarter of the retina
subretinal or vitreous seeding Local ne vitreous seeding may be present close to discrete tumor
Local subretinal seeding <3 mm (2DD) from the tumor
Group D: Tumor(s) may be massive or diffuse
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Diffuse disease with signicant vitreous Subretinal uid present or past without seeding, involving up to total retinal detachment
or subretinal seeding Diffuse or massive vitreous disease may include greasy seeds or avascular tumor masses
Diffuse subretinal seeding may include subretinal plaques or tumor nodules
Annu. Rev. Med. 2014.65:171-184. Downloaded from www.annualreviews.org

Group E: Tumor touching the lens

Presence of any one or more of these
poor prognosis features
Tumor anterior to anterior vitreous face involving ciliary body or anterior segment
Diffuse inltrating retinoblastoma
Neovascular glaucoma
Opaque media from hemorrhage
Tumor necrosis with aseptic orbital cellulitis
Phthisis bulbi

Children usually require ports, which have DELIVERING CHEMOTHERAPY

well-known side effects, including infection. TO THE EYE
Bone marrow suppression develops, requiring
These observations led us and others to ex-
transfusion and its associated problems; the
plore ways of delivering more chemotherapy
frequency has been poorly documented in
into the eye with less systemic exposure. Animal
the literature, but the majority of children
and human studies demonstrated that periocu-
experience this. Fever/neutropenia and hospi-
lar injection allowed carboplatin to enter the
talization for treatment are also common (and
eye within a half hour and attained levels ten
poorly documented in the literature). Perma-
times higher in the eye than intravenous de-
nent hearing loss has been reported to develop
livery, with one-tenth the amount detectable in
in 533% of children, and this is especially
blood. Responses in the eye were near universal
difcult for children who have vision prob-
(45). There was some worrisome toxicity; one
lems. Secondary acute myelogenous leukemia
child lost sight, and half of those treated devel-
(sAML) is a well-documented consequence of
oped a pseudocellulitis. The technique was used
some chemotherapies. More than 20 cases of
worldwide and incorporated into some clinical
sAML in retinoblastoma children have been
trials, but our long-term data suggested that in
reported worldwide, and although the true
almost all cases the effect was transitory (46).
incidence is not known, it is also not known
One case in that series was informative. A child
if these drugs contribute to increased ocular
who had been treated with systemic carboplatin
survival (compared to two-drug regimens with
progressed with vitreous seeds, and when that
carboplatin and vincristine) (44). At least seven
same child was treated with periocular carbo-
children worldwide have died simply from the
platin a measurable response was seen. This
administration of systemic chemotherapy.
suggested that the problem with chemotherapy

178 Abramson
 ME65CH12-Abramson ARI 19 December 2013 8:8
success was simply related to dose and led us to
pursue another avenue.
Intraarterial Chemotherapy
Just as Stallard had tried bringing radiation
closer to the eye in an attempt to minimize side
effects, Reese was the rst to bring chemother-
apy close to the eye with the goal of lowering
the concurrent dose of radiation delivered. In
the 1950s he began injecting TEM (triethylene
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melamine) directly into the carotid artery on the
side of ocular disease, and by 1960 could report
a 40% success rate in 54 patients (47). He called
Annu. Rev. Med. 2014.65:171-184. Downloaded from www.annualreviews.org
this approach intraarterial chemotherapy.
Japanese investigators led by Kaneko were
the second group to attempt intraarterial
chemotherapy (4851). Their reasons were
completely different. In Japan and much of Asia,
there is a belief that removal of an eye pre-
vents humans from moving on to the next (and
more important) phase of existence, so families
choose to have a child die with a diseased eye
rather than live with removal of an eye. Thus,
Kaneko and colleagues attempted to maximally
treat all eyes with retinoblastoma despite the
ophthalmic consequences. In the same eye they
gave external-beam radiation with hyperther-
mia and intravitreal injections of melphalan in
addition to delivering arterial chemotherapy by
a novel technique. Via the femoral artery, a
catheter was passed retrograde through the ar-
terial tree into the carotid artery on the side
to be treated. They then inated a balloon
just above the orice of the ophthalmic artery
for many minutes (sometimes as long as 20,
but more often ve), during which they in-
jected melphalan, which they had identied as
the most potent chemotherapeutic drug avail-
able. Since they had occluded the carotid, it was
hoped that the blood ow and drug would sim-
ply go into the ophthalmic artery. They called
this technique selective ophthalmic artery in-
fusion of chemotherapy. In their 20-year re-
view of 1,452 procedures, they reported ve-
year patient survivals of >97%; were able to do
the procedure in nearly 99% of attempts; and
reported no strokes, sepsis, or leukocytosis
(52). They salvaged 100% of group A eyes, 88%
of group B, 65% of group C, and 45% of group
D. Group E eyes are enucleated when systemic
chemotherapy is used, but Kanekos groups ap-
proach salvaged 30% of these eyes. Across all
ve groups, 51% of eyes had visual acuity better
than 20/40. These results demonstrated a no-
table improvement in eye salvage (with vision)
and fewer systemic side effects than systemic
chemotherapybased approaches, but because
the patients also received intravitreal injections
(and about half of them external-beam irradia-
tion), it was difcult to know the true contribu-
tion of intraarterial chemotherapy.
Ophthalmic Artery Chemosurgery
We decided to modify intraarterial chemother-
apy. Instead of using a balloon, we placed
the tip of the catheter just into the ori-
ce of the ophthalmic artery (see video
clips in Supplemental Material, http://www.
annualreviews.org/supmat/supmat.asp) and Supplemental Material
deliver drug(s) in a pulsatile fashion. We ini-
tially called this approach superselective infu-
sion of chemotherapy.
At rst we only treated advanced eyes that
were scheduled for enucleation and were able to
salvage eight of nine treated eyes (53). Soon we
learned that the orbital arterial anatomy varied
so much that there was no normal anatomy
(54). In 5% of cases, the blood supply for
the eye came from the external (not internal)
carotid. In some cases, large middle meningeal
arteries shunted blood away from the eye.
We developed techniques for delivering
chemotherapy via the external carotid artery in
cases where ophthalmic artery cannulation was
impossible (55). In 5% of cases we used the
Japanese balloon, although we occluded the
carotid for a shorter period of time. The largest
proportion of blood ow from the ophthalmic
artery does not go to the eye, but usually to
the supratrochlear artery, whose territory is
the median forehead and upper lid. Signicant
blood ow normally goes to this and into
branches of the nose (anterior and posterior
ethmoidal artery), so to divert blood we initially
www.annualreviews.org Retinoblastoma, Survival, and Vision 179
 ME65CH12-Abramson ARI 19 December 2013 8:8

occluded the forehead in the region of the

supratrochlear artery and then switched to rou-
tinely using nasal spray with sympathomimetics
that effectively minimized blood ow into the
nose. Because decisions about treatment must
be made in real time, adjusting the planned
approach, we have renamed our approach
ophthalmic artery chemosurgery (OAC).
We were then able to identify which eyes
are the best candidates for this approach.
Treatment-naive eyes do better than previously
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treated eyes (56); 81.7% of all naive eyes were

salvaged at two years, including eyes with such
advanced disease that they had been scheduled
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for enucleation. By using OAC we were also

able to save 58% of eyes that had failed con-
ventional treatments. About 30% of eyes were
cured with chemotherapy alonein many cases
with single-agent chemotherapy (57).
Eyes with retinal detachments responded
the best. Two-year Kaplan Meier ocular sur-
vival for eyes with extensive retinal detach-
ment exceeded 95% (Figure 6) (58). Even more
striking was the fact that eyes with subreti-
nal seeding (even when extensive) were cured
in nearly all cases. Conventional multiagent
chemotherapy virtually never cures subretinal
seeds. From the beginning, we monitored elec-
troretinogram (ERG) responses before and af-
ter each intraarterial session. We were reas-
sured that there was rarely any degradation
of signal as a consequence of treatment and
delighted when we discovered that some eyes
(20% of cases) showed large improvements in
ERG function after treatment (59).
We monitored hematologic toxicity care-
fully and recorded events in the Common
Terminology Criteria for Adverse Events
format. Only 1% of the naive children required
transfusion or developed fever/neutropenia.
No ports were needed, and there have been
no deaths from retinoblastoma in children
treated with intraarterial chemotherapy since
we began in 2006.
We then began to treat both eyes in bilateral
cases in the same session (tandem therapy)
(60). We had established that if the melphalan
dose was lower than 0.4 mg/kg no signicant
Figure 6
Fundus photograph before (top) and three months
after (bottom) successful treatment of retinoblastoma
with ophthalmic artery chemosurgery.
hematologic toxicity was noted, so when we
started treating both eyes, we began using car-
boplatin in one eye and melphalan in the other
to minimize the overall dose of melphalan. We
often added topotecan to one or both eyes
depending on extent of disease. In the doses
used, there was no measurable effect on blood
counts with carboplatin or topotecan. Most eyes
worldwide with vitreous seeds are enucleated.
Our two-year Kaplan-Meier (KM) probability
of saving eyes with seeds was 83% for naive eyes
and 76% for eyes that had failed conventional
management (61). Though vitreous seeding re-
mains the most common reason for failure with
OAC, the technique has changed the landscape
for retinoblastoma childrenfrom the major-
ity of eyes with seeding requiring enucleation
to the majority being saved.

180 Abramson
 ME65CH12-Abramson ARI 19 December 2013 8:8

Children with retinoblastoma diagnosed in
the rst three months of life have been treated
by intraarterial chemotherapy in Japan, but we
have concerns about cannulating the femoral
artery at this age, so we developed a staged strat-
egy called bridge therapy in which single-
agent systemic carboplatin is given once, twice,
or three times (until the childs weight reaches
6 kg) and then intraarterial chemotherapy is
given. Again no signicant systemic or ocular
side effects were noted and nearly 100% of such
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them. In our New York series this happened in
56% of cases we initially treated with systemic
chemotherapy. It is known that these children
have a defect in the Rb1 gene at or shortly
after conception, and the assumption was
that the second hit in the retina developed
during the rst few months or years of life.
Because the retina grows from the optic nerve
forward, it made sense that these subsequent
tumors would appear in the peripheral, anterior
retina. With OAC we learned that new anterior

eyes were saved (62). tumors rarely developed. This suggests that the
Finally, we noted that OAC completely second hit occurs in utero too, and treatment
changed the natural history of treated is effective for submicroscopic tumor foci that
Annu. Rev. Med. 2014.65:171-184. Downloaded from www.annualreviews.org

retinoblastoma (63). In genetic cases it is com- cannot be seen ophthalmoscopically.

mon that despite successful treatment (with any OAC has transformed the management of
modality or combination of modalities), new intraocular retinoblastoma worldwide, and its
peripheral tumors developusually many of impact is summarized in Table 3.

Table 3 Summary of impact of ophthalmic artery chemosurgery

Ophthalmic artery chemosurgery
has led to
Elimination of primary external beam
radiation
Elimination of primary systemic
chemotherapy
Successful treatment of eyes with
advanced disease
Successful treatment of subretinal
seeds
Successful treatment of vitreous seeds
Return of electroretinagram in blind
eyes
Effect on retinoblastoma patients
No temporal bone defects
No radiation cataracts
No radiation-related second cancers
Prolongs patient survival
Avoids cost of radiation
No chemotherapy deaths
No need for ports
No need for transfusions
No fever/neutropenia
No permanent hearing problems
No chemotherapy related leukemia (sAML)
Possible (unproven) elimination of infertility/sterility
Cost savings due to elimination of ports, transfusions,
fever/neutropenia, and potentially life-threatening infection
No need for enucleation in 90% of cases
Saves eyes with subretinal seeds (formerly radiated or enucleated)
Saves >50% of eyes previously lost
More children retain sight; it is not known how this compares to
radiation or systemic chemotherapy because no study has been
done with those techniques

www.annualreviews.org Retinoblastoma, Survival, and Vision 181

 ME65CH12-Abramson ARI 19 December 2013 8:8

DISCLOSURE STATEMENT
The author is not aware of any afliations, memberships, funding, or nancial holdings that might
be perceived as affecting the objectivity of this review.

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184 Abramson