The

Oncologist ®

Pediatric Oncology
Retinoblastoma: Review of Current Management

MURALI CHINTAGUMPALA,a,c,d PATRICIA CHEVEZ-BARRIOS,b,h EVELYN A. PAYSSE,b,c

SHARON E. PLON,c–e RICHARD HURWITZa–c,f,g
a
Texas Children’s Cancer Center, bDepartment of Ophthalmology, cDepartment of Pediatrics, dSection of
Hematology/Oncology, eDepartment of Molecular and Human Genetics, fCenter for Cell & Gene Therapy,
and gDepartment of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, USA;
h
Department of Pathology, Weill Medical College of Cornell University at The Methodist Hospital,
Houston, Texas, USA

Key Words. Retinoblastoma • Chemotherapy • Genetics of retinoblastoma • Second malignancies • Animal models

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

LEARNING OBJECTIVES
After completing this course, the reader will be able to:
1. Discuss the need for a multidisciplinary approach to the management of children with retinoblastoma.
2. Identify the patient factors that need to be considered when choosing the most appropriate initial and subsequent
treatment for a child with retinoblastoma.
3. Describe the role of genetics in the follow-up of retinoblastoma patients.
CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com

ABSTRACT
The most common ocular cancer in children is retino-
blastoma. It affects approximately 300 children in the
U.S. every year. It can affect one or both eyes and the
disease can be inherited. Altered discoloration of the pu-
pil and strabismus are the usual symptoms that lead to
medical attention. Subsequent appropriate diagnostic
studies and care provided by a multidisciplinary team,
including an ophthalmologist, a pediatric oncologist, a
radiation oncologist, and a geneticist, among others, of-
ten result in optimal short-term and long-term care.
The best initial and subsequent treatments are based on
whether the child has unilateral or bilateral disease, the
stage of the disease, and the age of the child. Enucle-
ation, chemotherapy, and various forms of radiation
therapy along with local ophthalmic therapies can be
used in the treatment of retinoblastoma. Cure rates are
high in children when the tumor is confined to the eye
and has not spread systemically or into the orbit or
brain. Children with the heritable form of retinoblas-
toma are at high risk for developing subsequent malig-
nancies, most commonly sarcomas. This risk is greater
for those children with the heritable form of the disease
who were exposed to ionizing radiation at age <1 year.
Exciting discoveries using animal models are provid-
ing new insights into the development of this disease
and opening new avenues for targeted therapies that
may lead to high cure rates with minimal toxicities.
The Oncologist 2007;12:1237–1246

Correspondence: Murali Chintagumpala, M.D., 6701 Fannin Street, Clinical Care Center, 14th Floor, MC CC1410, Houston, Texas
77030, USA. Telephone: 832-822-1482; Fax: 832-825-1503; e-mail: mxchinta@txccc.org Received February 28, 2006; accepted for
publication July 17, 2007. ©AlphaMed Press 1083-7159/2007/$30.00/0 doi: 10.1634/theoncologist.12-10-1237

The Oncologist 2007;12:1237–1246 www.TheOncologist.com


1238
EPIDEMIOLOGY
Retinoblastoma is the most common malignant ocular tu-
mor in childhood and affects approximately 1 in 18,000
children ⬍5 years of age in the U.S. [1]. The incidence is
higher in developing countries, and in some countries in
Central and South America retinoblastoma is one of the
most common solid tumor malignancies in children [2].
The reason for this higher incidence is not clear. Lower so-
cioeconomic status and the presence of human papilloma
virus sequences in the retinoblastoma tissue have been im-
plicated [3]. A higher risk for diseases like retinoblastoma
in children born through in vitro fertilization was described
previously, but a recent large study does not support this as-
sociation [4]. Approximately 80% of children with retino-
blastoma are diagnosed before 3 years of age. The diagnosis
of retinoblastoma in children 6 years or older is extremely
rare. Children with bilateral retinoblastoma constitute
about 20%–30%. Patients with bilateral disease usually
present at a younger age (14 –16 months) than patients with
unilateral disease (29 –30 months) [5, 6]. In approximately
20% of children diagnosed with bilateral retinoblastoma,
there is a family history of the disease [7]. Histologically,
retinoblastoma develops from immature retinal cells and re-
places the retina and other intraocular tissues. It displays a
high mitotic and apoptotic rate, and because of this elevated
turnover of tumor cells, there are many areas of necrosis
and dystrophic calcification.
GENETICS
The study of retinoblastoma has provided valuable insights
into the genetic basis of cancer. A “two-hit” model, as pro-
posed by Knudson, was developed based on the finding that
children with bilateral retinoblastoma developed multifo-
cal, bilateral tumors at an earlier age than children with uni-
lateral, unifocal tumors [8, 9]. According to the two-hit
model, two events are necessary for the retinal cell or cells
to develop into tumors. The first mutational event can be
inherited (germline or constitutional) and would then be
present in all cells in the body. The second event or “hit”
results in the loss of the remaining normal allele and occurs
within a particular retinal cell or cells with dysregulation of
the cell cycle and inappropriate entry into S phase [10].
In the sporadic, nonheritable form of retinoblastoma,
both mutational events occur within a single retinal cell af-
ter fertilization (somatic events), resulting in unilateral ret-
inoblastoma. Unilateral multifocal retinoblastoma can
develop if the first mutation occurs during development
such that more than one retinal cell contains this hit. Con-
versely, not all children with unilateral disease represent so-
matic events. Overall, 85% of children with unilateral
disease represent somatic events, but 15% represent the he-
1549490x, 2007, 10, Downloaded from https://theoncologist.onlinelibrary.wiley.com/doi/10.1634/theoncologist.12-10-1237 by Nat Prov Indonesia, Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Current Management of Retinoblastoma
reditary form with constitutional mutations in the RB1 gene
[11]. The RB1 gene was localized and then cloned based on
rare children with retinoblastoma who carry a cytogeneti-
cally visible constitutional deletion at chromosome
13q14.2 [12]. Even in cases of bilateral retinoblastoma, the
majority of children do not have a family history of the dis-
ease, and disease is a result of de novo mutations in the RB1
gene that primarily occur during spermatogenesis [13, 14].
This suggests that mutations in the retinoblastoma gene lo-
cus (RB1) occur more commonly during spermatogenesis
or that the paternal chromosome in the early embryo is at a
higher risk for mutation. Studies of retinoblastoma tumors
in both the hereditary and nonhereditary forms reveal that
the second hit or mutation frequently results in loss of het-
erozygosity of polymorphic markers that flank the RB1
gene in the tumor. Loss of heterozygosity can arise from al-
lelic loss, mitotic recombination, or loss of whole chromo-
some 13.
Genetic counseling in families with retinoblastoma is an
important aspect in their care and should be coordinated
with a medical geneticist or genetic counselor who is part of
the retinoblastoma team. The identification of genetically
susceptible family members can lead to early diagnosis that
cannot only be life saving but may avoid the need for enu-
cleation of the affected eye. Genetic analysis also provides
important information with regard to the risk for parents
(and long-term survivors of retinoblastoma) to have addi-
tional children with retinoblastoma. For example, healthy
parents of a child with bilateral retinoblastoma have a 7%
risk with each pregnancy of having a child with retinoblas-
toma because of the possibility of germline mosaicism (i.e.,
more than one sperm or egg carrying an RB1 mutation). Ge-
netic testing for RB1 mutations is clinically available in
certified DNA diagnostic laboratories (http://www.
genetests.org) and can detect constitutional mutations in
approximately 90% of patients with bilateral disease [15].
Patients with bilateral disease can be assumed to have a
constitutional mutation and DNA obtained from a blood
sample is examined directly for mutations. Children with
unilateral tumors may or may not have a germline constitu-
tional mutation. Therefore, for these cases, a frozen tumor
specimen and a blood sample are sent for analysis. There is
a wide variety of different RB1 mutations, including whole
gene deletions, and small frameshift, nonsense, splice site,
and missense mutations. Somatic changes can also include
silencing of the RB1 promoter by methylation. Therefore,
genetic analysis often includes complete sequencing of
the coding region, analysis for deletions and rearrange-
ments, methylation analysis, and RNA analysis [16].
Mutation(s) identified in the tumor are then studied in a
DNA sample obtained from blood. Presence of the muta-

Chintagumpala, Chevez-Barrios, Paysse et al.
tion in blood is presumptive evidence of a germline or con-
stitutional mutation. Once the germline mutation is
identified then all siblings or offspring of the patient should
be tested for that specific mutation in order to determine the
need for surveillance for retinoblastoma [17]. Identification
of the same mutation in another young family member
should prompt frequent evaluations by an ophthalmologist
using appropriate examination techniques. The frequency
of such evaluations may be every 1–2 months for the first
year of life, followed by every 2–3 months for the next year,
and then every 3 months until 3 years of age, and finally
every 4 – 6 months until the age of 6. This schedule can be
modified by the examiner based on his own clinical expe-
rience.
Knowledge of the specific mutation identified in the
family has also been used to perform preimplantation ge-
netic diagnosis in order to implant in vitro fertilized em-
bryos that are unlikely to carry the mutation [18]. Even with
extensive molecular analysis, the causative mutation is not
always identified. In these cases, if there are multiple family
members with retinoblastoma, then predictive genetic test-
ing can be performed by linkage analysis using polymor-
phic markers that flank the RB1 gene, a technique also
referred to as indirect genetic testing.
CLINICAL PRESENTATION AND DIAGNOSIS
The most common presentation of retinoblastoma in the de-
veloped world is leukocoria (an abnormal white discolora-
tion in one or both pupils). This is usually first noticed by a
parent or relative [19]. Leukocoria is the result of an altered
pupillary red reflex in the eye and usually occurs when there
is a large tumor present; however, it can occur also with
smaller tumors associated with retinal detachment. Because
retinoblastoma has a white appearance, the normal red re-
flex is replaced by a white or creamy pink discoloration of
the pupil and can be better visualized with dilation of the
pupil and the aid of an ophthalmoscope. The second most
common sign of retinoblastoma is strabismus [20]. Strabis-
mus (misalignment of the eye) in this case results from a
loss of central vision in one or both eyes causing the ocular
misalignment. Heterochromia (different color of pupils),
hyphema (blood in the anterior chamber), glaucoma (in-
creased intraocular pressure), and orbital cellulitis/inflam-
matory presentation are less common presentations [21]. In
patients with more advanced disease, the presenting signs
and symptoms correlate with the degree of extraocular in-
vasion, which can result in orbital swelling and proptosis.
Funduscopy typically reveals a large white to creamy
colored main tumor, frequently with satellite lesions in the
retina, subretinal space, and/or vitreous. The satellite tu-
mors of the subretinal space and vitreous are referred to as
www.TheOncologist.com
1549490x, 2007, 10, Downloaded from https://theoncologist.onlinelibrary.wiley.com/doi/10.1634/theoncologist.12-10-1237 by Nat Prov Indonesia, Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1239
“seeds.” A secondary serous retinal detachment is often as-
sociated with large retinal tumors and subretinal seeds. To
confirm the presence of the tumor, a detailed examination
under anesthesia through dilated pupils is performed.
Ultrasonography of the eyes is often performed to iden-
tify and analyze the intraocular mass. Heterogeneity and
calcifications provide strong evidence for the diagnosis of
retinoblastoma. Ultrasonography is not as sensitive as com-
puted tomography (CT), which is the ideal imaging format
to detect intraocular calcifications. CT, however, raises the
concern of exposure to radiation in children ⬍1 year of age
with germline mutations [22]. However, it is still frequently
used to confirm the diagnosis. Magnetic resonance imaging
(MRI) of the brain and orbits is the most sensitive means of
evaluating for extraocular extension. It gives better delin-
eation of the optic nerve and also the pineal area [23]. Pine-
oblastoma is a malignancy that is associated with
retinoblastoma in rare cases and when present it is referred
to as trilateral retinoblastoma.
MRI of the brain and spinal cord and cytologic exami-
nation of cerebral spinal fluid are also indicated when there
is gross evidence of involvement of the optic nerve by im-
aging studies or microscopic involvement beyond the lam-
ina cribrosa on histopathologic examination of the
enucleated eye. A bone marrow examination and a bone
scan are indicated only when the clinical examination is
suggestive of metastases or a blood count abnormality is
present.
The diagnosis of retinoblastoma is based on examina-
tion by an ophthalmologist and imaging studies. A biopsy is
rarely indicated because the procedure carries a theoretical
risk for extraocular dissemination that would convert an in-
traocular, curable tumor into extraocular, metastatic disease
with an extremely poor prognosis. Therefore, in the absence
of a tissue diagnosis, benign conditions that can mimic the
more ominous retinoblastoma must be carefully excluded.
These diseases usually can be differentiated from retino-
blastoma by an ophthalmologist skilled in ocular oncology.
These conditions include Toxocara canis endophthalmitis,
persistent hyperplastic primary vitreous, and Coats’ disease
[24 –27]. These conditions usually produce total loss of vi-
sion in the affected eye and therefore, to establish the cor-
rect diagnosis, enucleation is an accepted procedure in
cases where the diagnosis is still in question from clinical
examination.
Retinoblastoma can invade the optic nerve into the chi-
asm or disseminate through the subarachnoid space. From
the subarachnoid space the tumor cells can spread to the
brain and spinal cord. Tumors can also invade the choroid
and the vascular layer, and spread hematogenously to the
bone and bone marrow [28 –32]. Tumors can spread ante-

1240
riorly and involve the aqueous venous channels, conjunc-
tiva, and lymphatics or invade the sclera into the orbit with
eventual spread to regional lymph nodes.
TREATMENT
Management of a child with retinoblastoma requires a mul-
tidisciplinary approach. Ophthalmologists, pediatric on-
cologists, pediatric radiation oncologists, pathologists,
genetic counselors, social workers, nurses, and others play
important roles in the cure of the disease, salvage of vision,
and support of the child with vision loss and potential long-
term sequelae. Many therapeutic options are available, and
the indications for a specific modality or a combination of
modalities vary with each patient. Furthermore, manage-
ment varies for children with intraocular disease and ex-
traocular spread of the tumor. Most patients with unilateral
disease present with advanced intraocular disease and
therefore usually undergo enucleation, which results in a
cure rate ⬎95%. Children with involvement of both eyes at
diagnosis usually require multimodality therapy (chemo-
therapy, local therapies). Failure to control disease in chil-
dren with bilateral disease may lead to external beam
radiation (EBR) therapy. Enucleation is usually reserved
for eyes with recurrent disease and no useful vision.
Management of Intraocular Disease
Staging of the disease has facilitated the assessment of
treatments and measurement of outcomes in oncology. The
Reese-Ellsworth (R-E) classification for intraocular retino-
blastoma, developed in the 1960s, was used during the last
40 years in assessing outcomes of therapy, and this classi-
fication facilitated the comparison of results from various
studies [33]. The R-E classification was devised to predict
prognosis in eyes that were treated with EBR therapy. The
classification scheme has five groups. Eyes with disease
consistent with the lower groups have a lower risk for enu-
cleation following EBR and group V eyes have the highest
risk for enucleation. With the advent of other therapies, in-
cluding chemotherapy, which has increasingly replaced
EBR therapy in the treatment of intraocular disease, the
usefulness of the R-E scheme is less apparent. Several al-
ternative schemes have been proposed recently by Shields
et al. [34] and by Murphree [35], among others [34 –35].
The classification proposed by Murphree is the basis for
several protocols for the treatment of intraocular retinoblas-
toma within the Children’s Oncology Group (COG). While
the R-E classification and the classification proposed by
Murphree and others address intraocular disease, another
classification system has been proposed by Chantada et al.
[36] to address extraocular disease and microscopic disease
following enucleation.
1549490x, 2007, 10, Downloaded from https://theoncologist.onlinelibrary.wiley.com/doi/10.1634/theoncologist.12-10-1237 by Nat Prov Indonesia, Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Current Management of Retinoblastoma
Enucleation
Most children with unilateral retinoblastoma present with
advanced disease, and most of them require enucleation.
Other indications for enucleation are for children with bi-
lateral disease where enucleation may be indicated for the
eye with the most advanced disease that does not respond to
chemotherapy (rarely, enucleation is indicated for both
eyes), for the eye that has failed all known effective thera-
pies, when active tumor is present in an eye with no vision,
when glaucoma is present as a result of neovascularization
of the iris or tumor invasion into the anterior chamber, and
when direct visualization of an active tumor is obstructed
by conditions including hemorrhage, corneal opacity, or
cataract [37]. Enucleation is curative in ⬎95% of patients
with unilateral disease. Care should be taken to avoid per-
foration of the globe during surgery and to obtain a long
segment of the optic nerve in order to minimize the chance
of leaving tumor at the surgical margin [38]. Orbital
implants made of silicone, plastic, hydroxyapatite, and
MedPore are used at major treatment centers. By con-
necting the implants to the orbital muscles, excellent cos-
metic appearance can be achieved. Complications such
as wound dehiscence and conjunctival erosion, although
rare, may be seen with all types of implants.
EBR Therapy
EBR therapy is an effective means of curing retinoblas-
toma. The most common indication for EBR is for the eye
in a young child with bilateral retinoblastoma who has ac-
tive or recurrent disease after completion of chemotherapy
and local therapies. Children with small tumors within the
macula that do not respond to chemotherapy or have recur-
rent disease following chemotherapy can benefit from
EBR. With EBR therapy, the entire tumor-bearing area of
the globe is included along with at least 1 cm of the optic
nerve. The prescribed dose to the tumor ranges from 42 Gy
to 46 Gy, with the radiosensitive lens receiving signifi-
cantly less. Preservation of the eye with control of the dis-
ease using EBR therapy is in the range of 58%– 88%.
Radiation therapy has only a 50% local control rate in R-E
groups IV and V disease, with a 95% rate of preservation of
the eye in R-E groups I–III. In a report of 63 R-E group Vb
eyes (tumors with vitreous seeds) that were irradiated at ini-
tial diagnosis, the ocular survival rate was 53.4% at 10 years
[39]. However, the probability of developing a second can-
cer following initial EBR therapy for group Vb disease in
patients with bilateral disease was 29.7% by 10 years after
diagnosis.
Patients with hereditary disease who received EBR ther-
apy are reported to have a cumulative incidence of second
cancers of 35%, compared with 6% for those who did not

Chintagumpala, Chevez-Barrios, Paysse et al.
receive EBR [40]. Furthermore, patients who are ⬍1 year
of age and who receive radiation therapy are several times
more likely to develop second and subsequent malignancies
than those who are ⬎12 months of age and receive radiation
therapy [41]. In a cohort of patients with hereditary retino-
blastoma, a strong relationship between radiation dose and
the development of soft tissue sarcomas was reported [42].
In subsequent follow-up of this cohort, significantly
higher risks for melanoma, cancers of the bone, nasal cav-
ities, and brain, and soft tissue sarcomas (with an excess of
leiomyosarcoma) were documented [43, 44]. Cataracts, op-
tic nerve damage, total retinal vascular occlusion, vitreous
hemorrhage, and facial and temporal bone hypoplasia are
other complications associated with EBR therapy [45]. Pro-
ton beam radiation therapy offers promise in reducing the
significant long-term side effects associated with conven-
tional EBR therapy [46].
Brachytherapy
Brachytherapy involves the placement of a radioactive im-
plant (plaque), usually on the sclera adjacent to the base of
a tumor. Iodine-125 (125I), gold, and more recently ruthe-
nium have been used [47]. The intention is to deliver a dose
of 4,000 – 4,500 cGy transclerally to the apex of the tumor
over a period of 2– 4 days. This treatment is limited to tu-
mors that are ⬍16 mm in base and 8 mm in thickness, and
can be used as the primary treatment or, more frequently, in
patients who had failed initial therapy including previous
EBR therapy [48 –51]. This modality can also be used when
there is a peripheral tumor with focal vitreous seeding
around it. Relative contraindications include larger tumors
and those that involve the macula. Good tumor control has
been reported with this modality [52]. Side effects are less
common than with EBR and include optic neuropathy, ra-
diation retinopathy, and cataract formation. Second malig-
nancies do not appear to be associated with this type of local
therapy. An orbital implant with 125I seeds was shown to be
effective in treating patients who were at high risk for or-
bital recurrence after enucleation [53].
Thermotherapy
Thermotherapy involves the application of heat directly to
the tumor, usually in the form of infrared radiation. A tem-
perature between 45°C and 60°C is the goal of this thera-
peutic approach and is below the coagulative threshold and
therefore spares the retinal vessels from coagulation [54,
55]. Thermotherapy alone can be used for small retinoblas-
tomas that are ⱕ3 mm in diameter without vitreous or sub-
retinal seeds. In a study of 91 tumors, 92% of the tumors
that were ⬍1.5 mm in diameter were controlled with ther-
motherapy alone [56].
www.TheOncologist.com
1549490x, 2007, 10, Downloaded from https://theoncologist.onlinelibrary.wiley.com/doi/10.1634/theoncologist.12-10-1237 by Nat Prov Indonesia, Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1241
Chemothermotherapy
Larger tumors or tumors with subretinal seeds are usually
treated with a combination of thermotherapy and chemo-
therapy. Tractional and vaso-occlusive complications that
can be seen with thermotherapy alone appear to be less fre-
quent when thermotherapy is used in combination with che-
motherapy (chemothermotherapy). Chemotherapy and
thermotherapy are delivered within hours of each other. In
one study of 188 retinoblastomas, tumor control was
achieved in 86% of cases [57]. The complications of che-
mothermotherapy included focal iris atrophy, paraxial lens
opacity, sector optic disk atrophy, retinal traction, optic
disk edema, retinal vascular occlusion, retinal detachment,
and corneal edema. Chemothermotherapy may be espe-
cially useful for patients with small tumors adjacent to the
fovea and optic nerve, where radiation therapy or laser pho-
tocoagulation may result in significant visual loss.
Laser Photocoagulation
Laser photocoagulation is recommended only for small
posterior tumors [58 – 60]. The treatment is delivered with
an argon or diode laser or a xenon arc. The purpose of this
treatment is to coagulate all the blood supply to the tumor.
Indirect ophthalmoscope laser photocoagulation has signif-
icantly improved the delivery of photocoagulation. Effec-
tive therapy usually requires 2–3 sessions at monthly
intervals. Complications of this treatment include retinal
detachment, retinal vascular occlusion, retinal traction, and
preretinal fibrosis.
Cryotherapy
Cryotherapy induces tumor tissue to freeze rapidly, re-
sulting in damage to the vascular endothelium with sec-
ondary thrombosis and infarction of the tumor tissue.
Cryotherapy may be used as primary therapy for small
peripheral tumors or for small recurrent tumors previ-
ously treated with other modalities. Tumors are typically
treated three times per session, with one or two sessions
at monthly intervals. Ninety percent of tumors ⬍3 mm in
diameter are cured permanently, and complications are
few and rarely serious [61, 62]. Transient conjunctival
edema and transient localized serous retinal detachments
can occur. Vitreous hemorrhage can be observed in large
or previously irradiated tumors.
Chemotherapy
Chemotherapy has been used to treat intraocular retinoblas-
toma since the early 1990s. Chemotherapy is used to reduce
the size of the tumor to allow local ophthalmological ther-
apies, including cryotherapy and laser photocoagulation, or
thermotherapy, to eradicate the remaining disease. This

1242
combination of therapies has been promoted to avoid EBR
therapy and/or enucleation and thereby decrease the poten-
tial for long-term side effects while salvaging some useful
vision. The common indications for chemotherapy for in-
traocular retinoblastoma include tumors that are large and
that cannot be treated with local therapies alone in children
with bilateral tumors. Chemotherapy can also be used in pa-
tients with unilateral disease when the tumors are small but
cannot be controlled with local therapies alone. Such pa-
tients constitute only 10%–15% of all patients with unilat-
eral disease. Most patients with unilateral disease are
diagnosed with advanced intraocular disease and undergo
enucleation. Numerous studies have been published that
show that chemotherapy is very effective in eliminating the
need for EBR/enucleation in R-E group I–III eyes, while
proving to be significantly less successful in eyes with
group IV or V disease [34, 63–70]. Selected patients with
group IV disease have also had a very good response to che-
motherapy, and EBR and enucleation were avoided. The
chemotherapy regimen commonly used consists of carbo-
platin, vincristine, and etoposide. Cyclosporine has been
used in addition to these three agents in some institutions in
order to try to overcome drug resistance [71]. Others have
used carboplatin and vincristine without etoposide and
older studies used cyclophosphamide and doxorubicin. The
chemotherapy regimens from the different groups of inves-
tigators vary in the number and frequency of chemotherapy
cycles. All these regimens are well tolerated, with the ex-
pected side effects of myelosuppression and its conse-
quences, which include invasive bacterial infections.
Ototoxicity and renal toxicities are rare. There is also the
potential risk for second malignancies, especially when us-
ing etoposide (an epipodophyllotoxin) [72, 73]. The RE
groups I–III and part of group IV correspond to group B dis-
ease of the new international classification scheme that is a
modification of the one proposed by Murphree. Patients
who have group B disease will be treated with carboplatin
and vincristine in the proposed COG trial, and their event-
free survival (EFS) at 2 years will be estimated, where an
event is described as the need for nonprotocol chemother-
apy or EBR/enucleation.
Chemotherapy alone is not very effective in avoiding
EBR/enucleation in patients with R-E group V eyes, es-
pecially those with vitreous seeds. Friedman et al. [70]
showed that only 53% of 30 group V (C, D, or E in the
proposed classification) eyes could be controlled with
chemotherapy alone. Data from Chan et al. [74] and Vil-
lablanca et al. [75] suggested that approximately 40% of
group C and 70% of group D eyes failed systemic che-
motherapy alone. Based on these data, the trial proposed
by the COG involves systemic chemotherapy with car-
1549490x, 2007, 10, Downloaded from https://theoncologist.onlinelibrary.wiley.com/doi/10.1634/theoncologist.12-10-1237 by Nat Prov Indonesia, Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Current Management of Retinoblastoma
boplatin, vincristine, and etoposide along with subtenon
carboplatin for group C and D eyes [76, 77]. Eyes with
diffuse vitreous seeding present a particularly difficult
management problem and, as mentioned above, rarely
respond to chemotherapy alone. Although EBR therapy
is modestly successful in patients with vitreous seeds,
new approaches are needed. A recent phase I study using
adenoviral vectors to deliver the herpes simplex thymi-
dine kinase gene followed by ganciclovir demonstrated
durable clinical and histopathologic responses in heavily
pretreated patients with vitreous seeds [78].
Management of Extraocular Disease
Patients with extraocular disease have a very poor progno-
sis with respect to survival. Recently, there have been en-
couraging data to suggest that patients with regional
extraocular disease may benefit from a combination of con-
ventional chemotherapy and EBR and those with distant
metastatic disease may benefit from high-dose chemother-
apy and EBR in conjunction with bone marrow stem cell
transplantation. Regional extraocular disease includes pa-
tients with orbital, preauricular disease and patients with tu-
mor found at the optic nerve surgical margin. Chantada et
al. [79] reported a 5-year EFS rate of 84% in 15 patients
with orbital or preauricular disease treated with chemother-
apy that included vincristine, doxorubicin, and cyclophos-
phamide or vincristine, idarubicin, cyclophosphamide,
carboplatin, and etoposide. These patients also received
EBR of 4,500 cGy administered to the optic nerve chiasm
for patients with orbital disease and to the involved nodes
for those with preauricular lymphadenopathy. A subse-
quent study showed that 12 patients with positive optic
nerve surgical margins were all event-free survivors fol-
lowing chemotherapy as above and orbital radiation ther-
apy of 4,000 – 4,500 cGy. A similar successful study was
reported from Brazil [80].
Patients with metastatic extraocular disease have a poor
prognosis when treated with regimens of conventional
doses of chemotherapy. There are several reports now sug-
gesting that high-dose chemotherapy with stem cell rescue
combined with EBR for areas of bulky disease at diagnosis
is beneficial, with some long-term survivors among pa-
tients with metastatic disease not involving the central ner-
vous system (CNS) [81– 85]. It is rare for a patient with
metastatic CNS involvement to survive using the therapies
described above. The proposed trial by the COG for pa-
tients with metastatic disease involves conventional che-
motherapy, stem cell harvest, high-dose chemotherapy with
stem cell rescue, and EBR of involved sites.

Chintagumpala, Chevez-Barrios, Paysse et al.
HIGH-RISK HISTOPATHOLOGIC FEATURES IN
ENUCLEATED EYES OF PATIENTS WITH
UNILATERAL RETINOBLASTOMA
There is no consensus on the histopathologic prognostic
factors present in enucleated eyes that could predict dissem-
ination of the disease. Postlamina optic nerve spread of tu-
mor, massive choroidal invasion, and extrascleral extension
have been recognized as risk factors for dissemination of
disease. Other factors like focal choroidal, anterior cham-
ber, ciliary body, and iris involvement by tumor have not
been clearly established as risk factors for spread of the dis-
ease. Extensively necrotic retinoblastoma was also recently
described as a high-risk factor [86].
When there is evidence of active tumor at the surgical
margin of the optic nerve at the time of enucleation, the as-
sociated mortality rate has been described to be as high as
50%– 81% [32, 87–94]. When tumor cells are present in the
optic nerve posterior to the lamina cribrosa, the mortality
rate is in the range of 13%– 69% [32, 38, 87–98]. It is gen-
erally accepted that tumor involvement anterior to the lam-
ina cribrosa is not associated with greater mortality.
The significance of choroid involvement and its effect
on the prognosis are less clear. There are reports that claim
that choroidal invasion by tumor does not contribute to a
poor outcome, while others claim that choroidal invasion
can result in mortality in the range of 11%– 81% [32, 87–
102]. The combination of choroidal invasion along with
any degree of optic nerve invasion has also been recognized
as a risk factor with an adverse influence on outcome by
some groups [48, 103].
Recent studies suggest that adjuvant chemotherapy ef-
fectively reduced the incidence of metastases in patients
with retinoblastoma with massive choroidal invasion or
postlaminar optic nerve invasion [104, 105]. These statisti-
cal figures have been drawn from several retrospective
studies performed in the past and are difficult to interpret
because of the significant variations in the definition of
high-risk features and the different treatment regimens used
for each series. Therefore, to study this issue prospectively
the COG has opened a clinical trial to study the pathology of
the enucleated eyes in all unilateral patients from participat-
ing institutions in North America and assign high-risk sta-
tus based on well-defined histopathologic features. These
patients are then eligible to receive adjuvant chemotherapy
consisting of six cycles of carboplatin, vincristine, and eto-
poside. Patients who do not have high-risk features as de-
fined by the protocol do not require further therapy and will
be observed. This will represent the first study in North
America to prospectively evaluate histopathologic features
and outcome in patients with unilateral disease. Similar
studies have been initiated in Europe.
www.TheOncologist.com
1549490x, 2007, 10, Downloaded from https://theoncologist.onlinelibrary.wiley.com/doi/10.1634/theoncologist.12-10-1237 by Nat Prov Indonesia, Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1243
PRECLINICAL MODELS
Current therapies contribute significantly to vision salvage
in patients with intraocular disease and overall cure rates in
patients with extraocular disease. However, these therapies
are not without significant morbidities. A better under-
standing of the pathogenesis of retinoblastoma may lead to
therapies with fewer long-term morbidities. To this end,
emphasis is placed on the development of preclinical mod-
els [106]. Retinoblastoma is uniquely a human disease; no
natural occurring animal model exists. Xenograft models of
retinoblastoma using cell lines derived from patients’ tu-
mors and injected into the vitreous have been developed in
immunocompromised mice and have been found to be use-
ful in studying therapeutic modalities [107–109]. These
models resemble patients with vitreous seeds and closely
mimic the progression of nonmetastatic as well as meta-
static human disease; however, the response of primary tu-
mors and the immune component of the therapy cannot be
studied. Transgenic mouse models of retinoblastoma have
also been developed [110, 111]. Because RB1 gene muta-
tions do not result in retinoblastoma in mice, multiple mem-
bers of the RB gene family have been genetically deleted or
sequestered using the targeted expression of simian virus 40
T-antigen [112]. These animals are immunologically com-
petent but exhibit multifocal disease that is genetically and
phenotypically distinct from human disease. Although nei-
ther model is identical to human disease, both models have
been useful in preclinical testing of novel approaches to
treating retinoblastoma [113, 114]. A recent study with pre-
clinical models suggests a potential target for chemother-
apy in retinoblastoma [115, 116]. This potential target is the
MDMX–p53 interaction, which is antagonized by nutlin-3
and efficiently kills retinoblastoma cells. Local delivery
of nutlin-3 is considered a potential option to treat
retinoblastoma.
SUMMARY
Imaging techniques and a variety of treatment modalities
have resulted in vast improvements in the management of
children with retinoblastoma. There is at present great co-
operation among various investigators internationally to
share experiences and identify common areas of clinical
and biologic research in retinoblastoma. There is wide-
spread acknowledgment that awareness of the symptoms of
the disease and early detection accompanied by early inter-
vention will significantly reduce visual and systemic mor-
bidity and mortality. Molecular genetic studies with
identification of germline mutations have made a tremen-
dous impact on the management of the siblings and off-
spring of affected individuals and have obviated the need
for prolonged clinical screening under anesthesia for many

1244
unaffected children. They have also enabled the possibility
of preimplantation genetic diagnosis, an option that is likely
to be considered by many affected individuals. Epidemio-
logic and biologic studies to understand the factors that pro-
mote dissemination of the disease are increasingly gaining
REFERENCES
1 Devesa SS. The incidence of retinoblastoma. Am J Ophthalmol 1975;80:
263–265.
2 Leal-Leal C, Flores-Rojo M, Medina-Sanson A et al. A multicentre report
from the Mexican Retinoblastoma Group. Br J Ophthalmol 2004;88:
1074 –1077.
3 Orjuela M, Castaneda VP, Ridaura C et al. Presence of human papilloma
virus in tumor tissue from children with retinoblastoma: An alternative
mechanism for tumor development. Clin Cancer Res 2000;6:4010 – 4016.
4 Lidegaard O, Pinborg A, Andersen AN. Imprinting diseases and IVF:
Danish National IVF cohort study. Hum Reprod 2005;20:950 –954.
5 Draper GJ, Sanders BM, Brownbill PA et al. Patterns of risk of hereditary
retinoblastoma and applications to genetic counselling. Br J Cancer 1992;
66:211–219.
6 Abramson DH, Frank CM, Susman M et al. Presenting signs of retinoblas-
toma. J Pediatr 1998;132:505–508.
7 Newsham IF, Hadjistilianou T, Cavenee WK. Retinoblastoma. In: Vo-
gelstein B, Kinzler KW, eds. The Genetic Basis of Human Cancer. New
York: McGraw-Hill, 1998:363–392.
8 Knudson AG Jr. Mutation and cancer: Statistical study of retinoblastoma.
Proc Natl Acad Sci U S A 1971;68:820 – 823.
9 Hethcote HW, Knudson AG Jr. Model for the incidence of embryonal can-
cers: Application to retinoblastoma. Proc Natl Acad Sci U S A 1978;75:
2453–2457.
10 Harbour JW, Dean DC. Rb function in cell-cycle regulation and apoptosis.
Nat Cell Biol 2000;94:E65–E67.
11 Van Quill KR, O’Brien JM. The Role of the Retinoblastoma Protein in
Health, Malignancy, and the Pathogenesis of Retinoblastoma. In: Albert
DM, Polans A, eds. Ocular Oncology. New York: Marcel Dekker, Inc.,
2003:103–128.
12 Friend SH, Bernards R, Rogelj S et al. A human DNA segment with prop-
erties of the gene that predisposes to retinoblastoma and osteosarcoma.
Nature 1986;323:643– 646.
13 Dryja TP, Mukai S, Petersen R et al. Parental origin of mutations of the
retinoblastoma gene. Nature 1989;339:556 –558.
14 Zhu XP, Dunn JM, Phillips RA et al. Preferential germline mutation of the
paternal allele in retinoblastoma. Nature 1989;340:312–313.
15 Houdayer C, Gauthier-Villars M, Lauge A et al. Comprehensive screening
for constitutional RB1 mutations by DHPLC and QMPSF. Hum Mutat
2004;23:193–202.
16 Lohmann DR, Gallie BL. Retinoblastoma: Revisiting the model proto-
type of inherited cancer. Am J Med Genet C Semin Med Genet 2004;
129:23–28.
17 Richter S, Vandezande K, Chen N et al. Sensitive and efficient detection
of RB1 gene mutations enhances care for families with retinoblastoma.
Am J Hum Genet 2003;72:253–269.
18 Simpson JL, Carson SA, Cisneros P. Preimplantation genetic diagnosis
(PGD) for heritable neoplasia. J Natl Cancer Inst Monogr 2005;(34):
87–90.
1549490x, 2007, 10, Downloaded from https://theoncologist.onlinelibrary.wiley.com/doi/10.1634/theoncologist.12-10-1237 by Nat Prov Indonesia, Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Current Management of Retinoblastoma
importance. Animal models to better understand the patho-
genesis and treatment of retinoblastoma are being pursued
vigorously. Initiation of cooperative group trials will fur-
ther define the effectiveness of therapeutic options for this
rare disease.
19 Shields JA, Shields CL, Parsons HM. Differential diagnosis of retinoblas-
toma. Retina 1991;11:232–243.
20 Shields JA, Augsburger JJ. Current approaches to the diagnosis and man-
agement of retinoblastoma. Surv Ophthalmol 1981;25:347–372.
21 Yoshizumi MO, Thomas JV, Smith TR. Glaucoma-inducing mechanisms
in eyes with retinoblastoma. Arch Ophthalmol 1978;96:105–110.
22 Smith EV, Gragoudas ES, Kolodny NH et al. Magnetic resonance imag-
ing: An emerging technique for the diagnosis of ocular disorders. Int Oph-
thalmol 1990;14:119 –124.
23 Brenner D, Elliston C, Hall E et al. Estimated risks of radiation-induced
fatal cancer from pediatric CT. AJR Am J Roentgenol 2001;176:289 –296.
24 Kuker W, Ramaekers V. Persistent hyperplastic primary vitreous: MRI.
Neuroradiology 1999;41:520 –522.
25 Kaste SC, Jenkins JJ 3rd, Meyer D et al. Persistent hyperplastic primary
vitreous of the eye: Imaging findings with pathologic correlation. AJR
Am J Roentgenol 1994;162:437– 440.
26 Chang MM, McLean IW, Merritt JC. Coats’ disease: A study of 62 histo-
logically confirmed cases. J Pediatr Ophthalmol Strabismus 1984;21:
163–168.
27 Morgan KS, McLean IW. Retinoblastoma and persistent hyperplastic vit-
reous occurring in the same patient. Ophthalmology 1981;88:1087–1089.
28 Spencer WH. Optic nerve extension of intraocular neoplasms. Am J Oph-
thalmol 1975;80:465– 471.
29 Karcioglu ZA, al-Mesfer SA, Abboud E et al. Workup for metastatic ret-
inoblastoma. A review of 261 patients. Ophthalmology 1997;104:307–
312.
30 Tosi P, Cintorino M, Toti P et al. Histopathological evaluation for the
prognosis of retinoblastoma. Ophthalmic Paediatr Genet 1989;10:173–
177.
31 Croxatto JO, Fernandez Meijide R, Malbran ES. Retinoblastoma mas-
querading as ocular inflammation. Ophthalmologica 1983;186:48 –53.
32 Kopelman JE, McLean IW, Rosenberg SH. Multivariate analysis of risk
factors for metastasis in retinoblastoma treated by enucleation. Ophthal-
mology 1987;94:371–377.
33 Reese AB, Ellsworth RM. Management of retinoblastoma. Ann N Y Acad
Sci. 1964;114:958 –962.
34 Shields CL, Mashayekhi A, Demirci H et al. Practical approach to man-
agement of retinoblastoma. Arch Ophthalmol 2004;122:729 –735.
35 Linn Murphree A. Intraocular retinoblastoma: The case for a new group
classification. Ophthalmol Clin North Am 2005;18:41–53.
36 Chantada G, Doz F, Antoneli CB et al. A proposal for an international ret-
inoblastoma staging system. Pediatr Blood Cancer 2006;47:801– 805.
37 Abramson DH. Treatment of retinoblastoma. In: Blodi FC, ed. Retino-
blastoma. New York: Churchill Livingstone, 1985:3–93.
38 Abramson DH, Ellsworth RM. The surgical management of retinoblas-
toma. Ophthalmic Surg 1980;11:596 –598.
39 Abramson DH, Beaverson KL, Chang ST et al. Outcome following initial

Chintagumpala, Chevez-Barrios, Paysse et al.
external beam radiotherapy in patients with Reese-Ellsworth Group Vb
retinoblastoma. Arch Ophthalmol 2004;122:1316 –1323.
40 Roarty JD, McLean IW, Zimmerman LE. Incidence of second neoplasms
in patients with bilateral retinoblastoma. Ophthalmology 1988;95:1583–
1587.
41 Abramson DH, Frank CM. Second nonocular tumors in survivors of bi-
lateral retinoblastoma: A possible age effect on radiation-related risk.
Ophthalmology 1998;105:573–579; discussion 579 –580.
42 Wong FL, Boice JD Jr, Abramson DH et al. Cancer incidence after reti-
noblastoma: Radiation dose and sarcoma risk. JAMA 1997;278:1262–
1267.
43 Kleinerman RA, Tucker MA, Tarone RE et al. Risk of new cancers after
radiotherapy in long-term survivors of retinoblastoma: An extended fol-
low-up. J Clin Oncol 2005;23:2272–2279.
44 Kleinerman RA, Tucker MA, Abramson DH et al. Risk of soft tissue sar-
comas by individual subtype in survivors of hereditary retinoblastoma.
J Natl Cancer Inst 2007;99:24 –31.
45 Imhof SM, Mourits MP, Hofman P et al. Quantification of orbital and mid-
facial growth retardation after megavoltage external beam irradiation in
children with retinoblastoma. Ophthalmology 1996;103:263–268.
46 Krengli M, Hug EB, Adams JA et al. Proton radiation therapy for retino-
blastoma: Comparison of various intraocular tumor locations and beam
arrangements. Int J Radiat Oncol Biol Phys 2005;61:583–593.
47 Schueler AO, Fluhs D, Anastassiou G et al. Beta-ray brachytherapy of ret-
inoblastoma: Feasibility of a new small-sized ruthenium-106 plaque.
Ophthalmic Res 2006;38:8 –12.
48 Shields CL, Shields JA, De Potter P et al. Plaque radiotherapy in the man-
agement of retinoblastoma. Use as a primary and secondary treatment.
Ophthalmology 1993;100:216 –224.
49 Hernandez JC, Brady LW, Shields CL et al. Conservative treatment of ret-
inoblastoma. The use of plaque brachytherapy. Am J Clin Oncol 1993;16:
397– 401.
50 Desjardins L, Levy C, Labib A et al. An experience of the use of radioac-
tive plaques after failure of external beam radiation in the treatment of ret-
inoblastoma. Ophthalmic Paediatr Genet 1993;14:39 – 42.
51 Shields JA, Shields CL, De Potter P et al. Plaque radiotherapy for residual
or recurrent retinoblastoma in 91 cases. J Pediatr Ophthalmol Strabismus
1994;31:242–245.
52 Shields CL, Shields JA, Cater J et al. Plaque radiotherapy for retinoblas-
toma: Long-term tumor control and treatment complications in 208 tu-
mors. Ophthalmology 2001;108:2116 –2121.
53 Sealy R, Stannard C, Shackleton D. Improved cosmesis in retinoblastoma
patients treated with iodine-125 orbital irradiation. Ophthalmic Paediatr
Genet 1987;8:95–99.
54 Murphree AL, Villablanca JG, Deegan WF 3rd et al. Chemotherapy plus
local treatment in the management of intraocular retinoblastoma. Arch
Ophthalmol 1996;114:1348 –1356.
55 Murphree AL, Munier FL. Retinoblastoma. In: Ryan SJ, ed. Retina, 2nd
ed. St Louis: Mosby-Year Book Inc., 1994:605– 606.
56 Abramson DH, Schefler AC. Transpupillary thermotherapy as initial
treatment for small intraocular retinoblastoma: Technique and predictors
of success. Ophthalmology 2004;111:984 –991.
57 Shields CL, Santos MC, Diniz W et al. Thermotherapy for retinoblastoma.
Arch Ophthalmol 1999;117:885– 893.
58 Shields JA, Shields CL, Parsons H et al. The role of photocoagulation in
the management of retinoblastoma. Arch Ophthalmol 1990;108:205–208.
59 Shields CL, Shields JA, Kiratli H et al. Treatment of retinoblastoma with
www.TheOncologist.com
1549490x, 2007, 10, Downloaded from https://theoncologist.onlinelibrary.wiley.com/doi/10.1634/theoncologist.12-10-1237 by Nat Prov Indonesia, Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1245
indirect ophthalmoscope laser photocoagulation. J Pediatr Ophthalmol
Strabismus 1995;32:317–322.
60 Shields JA. The expanding role of laser photocoagulation for intraocular
tumors. The 1993 H. Christian Zweng Memorial Lecture. Retina 1994;14:
310 –322.
61 Abramson DH, Ellsworth RM, Rozakis GW. Cryotherapy for retinoblas-
toma. Arch Ophthalmol 1982;100:1253–1256.
62 Shields JA, Parsons H, Shields CL et al. The role of cryotherapy in the
management of retinoblastoma. Am J Ophthalmol 1989;108:260 –264.
63 Gallie BL, Budning A, DeBoer G et al. Chemotherapy with focal therapy
can cure intraocular retinoblastoma without radiotherapy. Arch Ophthal-
mol 1996;114:1321–1328.
64 Shields CL, De Potter P, Himelstein BP et al. Chemoreduction in the ini-
tial management of intraocular retinoblastoma. Arch Ophthalmol 1996;
114:1330 –1338.
65 Shields CL, Honavar SG, Shields JA et al. Factors predictive of recurrence
of retinal tumors, vitreous seeds, and subretinal seeds following chemore-
duction for retinoblastoma. Arch Ophthalmol 2002;120:460 – 464.
66 Shields CL, Shelil A, Cater J et al. Development of new retinoblastomas
after 6 cycles of chemoreduction for retinoblastoma in 162 eyes of 106
consecutive patients. Arch Ophthalmol 2003;121:1571–1576.
67 Kingston JE, Hungerford JL, Madreperla SA et al. Results of combined
chemotherapy and radiotherapy for advanced intraocular retinoblastoma.
Arch Ophthalmol 1996;114:1339 –1343.
68 Greenwald MJ, Strauss LC. Treatment of intraocular retinoblastoma with
carboplatin and etoposide chemotherapy. Ophthalmology 1996;103:
1989 –1997.
69 Gunduz K, Shields CL, Shields JA et al. The outcome of chemoreduction
treatment in patients with Reese-Ellsworth group V retinoblastoma. Arch
Ophthalmol 1998;116:1613–1617.
70 Friedman DL, Himelstein B, Shields CL et al. Chemoreduction and local
ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 2000;18:
12–17.
71 Chan HS, DeBoer G, Thiessen JJ et al. Combining cyclosporin with che-
motherapy controls intraocular retinoblastoma without requiring radia-
tion. Clin Cancer Res 1996;2:1499 –1508.
72 Le Deley MC, Vassal G, Taibi A et al. High cumulative rate of secondary
leukemia after continuous etoposide treatment for solid tumors in children
and young adults. Pediatr Blood Cancer 2005;45:25–31.
73 Bayar E, Robinson MG, Kurczynski TW. Unilateral retinoblastoma with
acquired monosomy 7 and secondary acute myelomonocytic leukemia.
Cancer Genet Cytogenet 1998;105:79 – 82.
74 Chan HSL, Heon E, Budning A et al. Improvement of the cure rate of in-
traocular retinoblastoma without significantly increasing toxicity with
higher dose carboplatin teniposide in a cyclosporine multidrug reversal
regimen. Presented at the 10th International Symposium on Retinoblas-
toma, Ft. Lauderdale, FL, May 4, 2001.
75 Villablanca JG, et al. Clinical outcome of group V eyes treated with cy-
closporin A/carboplatin/etoposide/vincristine. Presented at the 10th Inter-
national Symposium on Retinoblastoma, Ft. Lauderdale, FL, May 4,
2001.
76 Abramson DH, Frank CM, Dunkel IJ. A phase I/II study of subconjunc-
tival carboplatin for intraocular retinoblastoma. Ophthalmology 1999;
106:1947–1950.
77 Villablanca JG, Jubran RF, Murphree LA. Phase I study of subtenon car-
boplatin with systemic high dose carboplatin/etoposide/vincristine for

1246
eyes with disseminated intraocular. Presented at the 10th International
Symposium on Retinoblastoma, Ft. Lauderdale, FL, May 4, 2001.
78 Chevez-Barrios P, Chintagumpala M, Mieler W et al. Response of retino-
blastoma with vitreous tumor seeding to adenovirus-mediated delivery of
thymidine kinase followed by ganciclovir. J Clin Oncol 2005;23:7927–
7935.
79 Chantada G, Fandino A, Casak S et al. Treatment of overt extraocular ret-
inoblastoma. Med Pediatr Oncol 2003;40:158 –161.
80 Antoneli CB, Steinhorst F, de Cassia Braga Ribeiro K et al. Extraocular
retinoblastoma: A 13-year experience. Cancer 2003;98:1292–1298.
81 Namouni F, Doz F, Tanguy ML et al. High-dose chemotherapy with car-
boplatin, etoposide and cyclophosphamide followed by a haematopoietic
stem cell rescue in patients with high-risk retinoblastoma: A SFOP and
SFGM study. Eur J Cancer 1997;33:2368 –2375.
82 Dunkel IJ, Aledo A, Kernan NA et al. Successful treatment of metastatic
retinoblastoma. Cancer 2000;89:2117–2121.
83 Dunkel IJ, Aledo A, Finlay JL et al. Intensive multimodality therapy for
metastatic retinoblastoma. Pediatr Blood Cancer 2004;43:378.
84 Kremens B, Wieland R, Reinhard H et al. High-dose chemotherapy with
autologous stem cell rescue in children with retinoblastoma. Bone Mar-
row Transplant 2003;31:281–284.
85 Rodriguez-Galindo C, Wilson MW, Haik BG et al. Treatment of meta-
static retinoblastoma. Ophthalmology 2003;110:1237–1240.
86 Chong EM, Coffee RE, Chintagumpala M et al. Extensively necrotic ret-
inoblastoma is associated with high-risk prognostic factors. Arch Pathol
Lab Med 2006;130:1669 –1672.
87 Zimmerman LE. The Registry of Ophthalmic Pathology: Past, present and
future. Trans Am Acad Ophthalmol Otolaryngol 1961;65:51–113.
88 Brown DH. The clinicopathology of retinoblastoma. Am J Ophthalmol
1966;61:508 –514.
89 Ellsworth RM. Orbital retinoblastoma. Trans Am Ophthalmol Soc 1974;
72:79 – 88.
90 de Sutter E, Havers W, Hopping W et al. The prognosis of retinoblastoma
in terms of survival. A computer assisted study. Part II. Ophthalmic Pae-
diatr Genet 1987;8:85– 88.
91 Magramm I, Abramson DH, Ellsworth RM. Optic nerve involvement in
retinoblastoma. Ophthalmology 1989;96:217–222.
92 Messmer EP, Heinrich T, Hopping W et al. Risk factors for metastases in
patients with retinoblastoma. Ophthalmology 1991;98:136 –141.
93 Scott MH, Richard JM. Retinoblastoma in the state of Oklahoma: A clin-
icopathologic review. J Okla State Med Assoc 1993;86:111–118.
94 Rootman J, Hofbauer J, Ellsworth RM et al. Invasion of the optic nerve by
retinoblastoma: A clinicopathological study. Can J Ophthalmol 1976;11:
106 –114.
95 Carbajal UM. Observations on retinoblastoma. Am J Ophthalmol 1958;
45:391– 402.
96 Haye C, Desjardins L, Elmaleh C et al. Prognosis and treatment of retino-
blastoma. 105 cases treated at Institut Curie. Ophthalmic Paediatr Genet
1989;10:151–155.
97 MacKay CJ, Abramson DH, Ellsworth RM. Metastatic patterns of retino-
blastoma. Arch Ophthalmol 1984;102:391–396.
1549490x, 2007, 10, Downloaded from https://theoncologist.onlinelibrary.wiley.com/doi/10.1634/theoncologist.12-10-1237 by Nat Prov Indonesia, Wiley Online Library on [29/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Current Management of Retinoblastoma
98 Rubin CM, Robison LL, Cameron JD et al. Intraocular retinoblastoma
group V: An analysis of prognostic factors. J Clin Oncol 1985;3:680 – 685.
99 Schvartzman E, Chantada G, Fandino A et al. Results of a stage-based pro-
tocol for the treatment of retinoblastoma. J Clin Oncol 1996;14:1532–
1536.
100 Chantada G, Fandino A, Davila MT et al. Results of a prospective study
for the treatment of retinoblastoma. Cancer 2004;100:834 – 842.
101 Khelfaoui F, Validire P, Auperin A et al. Histopathologic risk factors in
retinoblastoma: A retrospective study of 172 patients treated in a single
institution. Cancer 1996;77:1206 –1213.
102 Herm RJ, Heath P. A study of retinoblastoma. Am J Ophthalmol 1956;41:
22–30.
103 Kobrin JL, Blodi FC. Prognosis in retinoblastoma: Influence of his-
topathologic characteristics. J Pediatr Ophthalmol Strabismus 1978;15:
278 –281.
104 Uusitalo MS, Van Quill KR, Scott IU et al. Evaluation of chemoprophy-
laxis in patients with unilateral retinoblastoma with high-risk features on
histopathologic examination. Arch Ophthalmol 2001;119:41– 48.
105 Honavar SG, Singh AD, Shields CL et al. Postenucleation adjuvant ther-
apy in high-risk retinoblastoma. Arch Ophthalmol 2002;120:923–931.
106 Zhang J, Schweers B, Dyer MA. The first knockout mouse model of ret-
inoblastoma. Cell Cycle 2004;3:952–959.
107 Gallie BL, Albert DM, Wong JJ et al. Heterotransplantation of retinoblas-
toma into the athymic “nude” mouse. Invest Ophthalmol Vis Sci 1977;16:
256 –259.
108 Rowe SG, Lee WH, Madreperla S. Subretinal and vitreal growth of human
retinoblastoma cells in the mouse eye. Invest Ophthalmol Vis Sci 1992;
33:875.
109 del Cerro M, Seigel GM, Lazar E et al. Transplantation of Y79 cells into
rat eyes: An in vivo model of human retinoblastomas. Invest Ophthalmol
Vis Sci 1993;34:3336 –3346.
110 Albert DM, Griep AE, Lambert PF et al. Transgenic models of retinoblas-
toma: What they tell us about its cause and treatment. Trans Am Acad
Ophthalmol Soc 1994;92:385– 400; discussion 400 – 401.
111 Howes KA, Lasudry JGH, Albert DM et al. Photoreceptor cell tumors in
transgenic mice. Invest Ophthalmol Vis Sci 1994;35:342–351.
112 al-Ubaidi MR, Font RL, Quiambao AB et al. Bilateral retinal and brain
tumors in transgenic mice expressing simian virus 40 large T antigen un-
der control of the human interphotoreceptor retinoid-binding protein pro-
moter. J Cell Biol 1992;119:1681–1687.
113 Chévez-Barrios P, Hurwitz MY, Louie K et al. Metastatic and nonmeta-
static models of retinoblastoma. Am J Pathol 2000;157:1405–1412.
114 Hurwitz MY, Marcus KT, Chévez-Barrios P et al. Suicide gene therapy
for treatment of retinoblastoma in a murine model. Hum Gene Ther 1999;
10:441– 448.
115 Elison JR, Cobrinik D, Claros N et al. Small molecule inhibition of HDM2
leads to p53-mediated cell death in retinoblastoma cells. Arch Ophthalmol
2006;124:1269 –1275.
116 Laurie NA, Donovan SL, Shih CS et al. Inactivation of the p53 pathway in
retinoblastoma. Nature 2006;444:61– 66.