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66]

Review Article

Modern treatment of retinoblastoma: A 2020 review

David Ancona-Lezama, Lauren A Dalvin1, Carol L Shields2

Retinoblastoma management remains complex, requiring individualized treatment based on International Access this article online
Classification of Retinoblastoma  (ICRB) staging, germline mutation status, family psychosocial factors Website:
and cultural beliefs, and available institutional resources. For this 2020 retinoblastoma review, PubMed www.ijo.in
was searched for articles dated as early as 1931, with an emphasis on articles from 1990 to the present DOI:
day, using keywords of retinoblastoma, chemotherapy, intravenous chemotherapy, chemoreduction, 10.4103/ijo.IJO_721_20
intra‑arterial chemotherapy, ophthalmic artery chemosurgery, intravitreal chemotherapy, intracameral PMID:
*****
chemotherapy, cryotherapy, transpupillary thermotherapy, laser, radiation, external beam radiotherapy,
plaque radiotherapy, brachytherapy, and enucleation. We discuss current treatment modalities as used in Quick Response Code:
the year 2020, including intravenous chemotherapy  (IVC), intra‑arterial chemotherapy  (IAC), intravitreal
chemotherapy  (IvitC), intracameral chemotherapy  (IcamC), consolidation therapies  (cryotherapy and
transpupillary thermotherapy  [TTT]), radiation‑based therapies  (external beam radiotherapy  [EBRT] and
plaque radiotherapy), and enucleation. Additionally, we present a consensus treatment algorithm based on
the agreement of three North American retinoblastoma treatment centers, and encourage further collaboration
amongst the world’s most expert retinoblastoma treatment centers in order to develop consensus management
plans and continue advancement in the identification and treatment of this childhood cancer.

Key words: Algorithm, eye, oncology, pediatric, retinoblastoma, treatment

Retinoblastoma, the most common ocular malignancy in childhood, identified in the localized intraocular stage, while newer
is lethal if left untreated. In high‑income countries  (HICs), therapies have been focusing on additional improvement in
retinoblastoma is considered a curable cancer with a near globe preservation and providing the best possible visual acuity
100% disease‑free survival rate.[1] However, the prognosis in outcome. The refinement of these curative strategies has led to
low‑and‑middle‑income countries  (LMICs) is often somber, unprecedented cure rates and globe salvage in centers where
where more than 80% of global cases occur.[2,3] Predictions indicate a complete armamentarium of treatment options is available.
that most retinoblastoma cases arise in Asia  (53%), followed
Herein we present a comprehensive review of the current
by Africa (29%), Latin America (8%), North America (3%), and
treatment modalities for retinoblastoma, along with their
Europe  (6%).[4] Given this distribution, global retinoblastoma
suggested indications and most common toxicities. PubMed
patient survival is calculated to be  <30%.[5‑7] This contrast is
was searched for articles dating back to 1931, with particular
supported by published data from developing countries, where
emphasis on articles published from 1990 to present day 2020.
survival is reported to be 40% (23‑70%) in low‑income countries
Keywords searched included retinoblastoma, chemotherapy,
and 79%  (54‑93%) in upper‑middle‑income countries.[8] With
intravenous chemotherapy, chemoreduction, intra‑arterial
regards to advanced retinoblastoma, enucleation has historically
chemotherapy, ophthalmic artery chemosurgery, intravitreal
been the standard of care, especially in LMICs.[9] However,
chemotherapy, intracameral chemotherapy, cryotherapy,
over the last three decades, major centers have decreased their
transpupillary thermotherapy, laser, radiation, external
enucleation rates in favor of globe‑salvaging techniques.[9‑12]
beam radiotherapy, plaque radiotherapy, brachytherapy
Management of retinoblastoma remains in constant and enucleation. The authors collate the current available
evolution and treatment can vary among different centers literature and present a treatment algorithm for intraocular
worldwide. However, the same primary goals of protecting retinoblastoma based on the expert consensus between three
life and preventing metastatic disease, followed by globe different retinoblastoma centers in North America, designed
preservation, and finally optimization of vision are commonly to provide referring physicians with a concise guideline for
shared among retinoblastoma specialists. The currently used decision making, thus shortening referral times. This model is
therapies maintain excellent survival rates when disease is intended for use by the retinoblastoma multidisciplinary team
as a means to guide and organize resources.

Ocular Oncology Service, Institute of Ophthalmology and Visual This is an open access journal, and articles are distributed under the terms of
Sciences, Tecnologico de Monterrey, Mexico, 1 Department of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License,
which allows others to remix, tweak, and build upon the work non‑commercially,
Ophthalmology, Mayo Clinic, Rochester, MN, 2Ocular Oncology
as long as appropriate credit is given and the new creations are licensed under
Service Wills Eye Hospital, Philadelphia, PA, USA the identical terms.
Correspondence to: Dr. Carol L Shields, Ocular Oncology Service, Suite
1440, Wills Eye Hospital, 840 Walnut Street, Philadelphia ‑ 19107, PA, For reprints contact: [email protected]
USA. E‑mail: [email protected]
Received: 29-Mar-2020 Revision: 23-May-2020  Cite this article as: Ancona-Lezama D, Dalvin LA, Shields CL. Modern treatment
of retinoblastoma: A 2020 review. Indian J Ophthalmol 2020;68:2356-65.
Accepted: 07-Jul-2020 Published: 26-Oct-2020

© 2020 Indian Journal of Ophthalmology | Published by Wolters Kluwer - Medknow

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November 2020 Ancona‑Lezama, et al.: RB Treatment in 2020 2357

Pretreatment Protocol myelosuppression and hemorrhagic cystitis. [15] Given

the reduction in tumor size, IVC is sometimes referred
The treatment of choice for retinoblastoma depends largely to as ‘chemoreduction’. [14] Focal consolidation with
on the International Classification of Retinoblastoma (ICRB) thermotherapy (cryotherapy or transpupillary thermotherapy)
staging [Table 1], the presence or absence of extraocular clinical often aids in tumor control. Cryotherapy administration
factors, germline testing results, the family psychosocial immediately preceding chemotherapy has been reported
situation, and available institutional resources.[13] An in‑depth to enhance drug availability to the intraocular spaces when
initial evaluation of the disease is important in order to decide administered within 48 hours of the thermal disruption.[16]
the extent of the desired treatment and avoid unnecessary side
effects. Even before examining the patient, a complete history Current indications for IVC include patients with bilateral
is of upmost importance. For example, a positive family history disease [Fig.  1], confirmed germline mutation, family history
should raise suspicion for a germline mutation and might of retinoblastoma, or cases with suspected optic nerve or
require the child to undergo systemic chemotherapy to prevent choroidal invasion.[14] Additionally, IVC plays a protective role
pineoblastoma, even if the disease presents unilaterally. Genetic in the prevention of long‑term second cancers, metastases,
testing is advisable in all cases of retinoblastoma, both for the and pineoblastoma.[17‑19] Other indications for IVC include
patient and for the rest of his/her nuclear family if germline patients weighing less than 6 kg awaiting intra‑arterial
disease is confirmed. All patients should undergo a baseline chemotherapy  (IAC), referred to as ‘bridge therapy’.[20] While
high‑resolution simple and contrast‑enhanced magnetic in some centers IVC might still be employed for unilateral
resonance imaging (MRI) of the brain and orbits with careful retinoblastoma, a study of 91 patients demonstrated superiority
attention for pineoblastoma or any features of optic nerve of IAC compared with IVC for globe salvage, including superior
invasion. Typically, complete blood count, urine sample, and control for solid tumor, sub retinal and vitreous seeding.[21] Hence,
general physical examination are performed by the pediatric the authors prefer IAC over IVC for unilateral retinoblastoma.
oncologist. The first office visit is usually complemented with
a careful examination under anesthesia, where ICRB staging As with most systemic chemotherapies, transient alopecia,
is confirmed and the first treatment can be applied. cytopenia, and fever can occur.[11] However, systemic toxicity
from IVC for retinoblastoma is usually mild. While transfusion of
The response to the first treatment can guide long‑term blood components might be occasionally required, granulocyte
outcomes. Hence, this might be the most important decision colony‑stimulating factor is generally not required with
made by the ocular oncologist, with the goal of delivering standard VEC doses, but is advisable with cyclophosphamide.
a potent therapy with the needed strength while avoiding Patients receive routine prophylaxis for Pneumocystis jirovecii
unnecessary toxicity. A  simplified consensus of three pneumonia. Chemotherapy‑related nausea, emesis, and
retinoblastoma centers on treatment protocol based on ICRB constipation can be medically managed. Ophthalmic toxicities
staging and laterality is presented in Table 2. The specific from IVC have not been observed. Long‑term renal toxicity
treatment modalities are discussed in detail below. is rare when chemotherapeutic agents are appropriately
dosed. Infertility rarely occurs with recommended doses of
Intravenous Chemotherapy (IVC) IVC, however, the addition of melphalan can risk infertility
Introduced in the early 1990s, systemic IVC remains an in males, especially when a cumulative dose of 140 mg/m2 is
essential tool for retinoblastoma treatment. IVC usually reached. Secondary acute myelogenous leukemia following
consists of 2, 3 or 4 chemotherapeutic agents administered IVC for retinoblastoma is also rare, and has been associated
monthly through a central or peripheral catheter for a with higher doses of chemotherapy, concomitant external beam
total of 6‑9 consecutive cycles.[14] The most frequently used radiotherapy  (EBRT) and other predisposing conditions.[19,22]
regimen consists of three drugs, including vincristine, Long‑term, real‑world outcomes at 20 years in a large cohort
etoposide, and carboplatin  (VEC).1413  In Monterrey, Mexico, of 964 eyes with retinoblastoma revealed lasting tumor control
vincristine is sometimes replaced with cyclophosphamide with avoidance of enucleation and/or EBRT for Group A (96%),
by the pediatric oncologist when concern for neurotoxicity Group B  (91%), Group C  (91%), Group D  (71%), and Group
is present, however, the former is more likely to induce E (32%).[23]

Table 1: Modern treatment of retinoblastoma: A 2020 Review. International classification of retinoblastoma (ICRB)

Group Mnemonic Features
A Small tumor Retinoblastoma ≤3 mm in basal diameter or thickness
B Bigger tumor Retinoblastoma >3 mm in basal diameter or thickness OR tumor location ≤3 mm
Beside the macula or optic nerve from foveola tumor location ≤1.5 mm from optic disc tumor‑associated subretinal
fluid ≤3 mm from tumor margin
C Contiguous seeds Retinoblastoma with subretinal seeds ≤3 mm from tumor vitreous seeds ≤3 mm
from tumor subretinal and vitreous seeds ≤3 mm from tumor
D Diffuse seeds Retinoblastoma with subretinal seeds >3 mm from tumor vitreous seeds >3 mm
from tumor subretinal and vitreous seeds >3 mm from tumor
E Extensive tumor Retinoblastoma occupying >50% of the globe OR neovascular glaucoma opaque
media from hemorrhage in subretinal space, vitreous, or anterior chamber invasion
of postlaminar optic nerve, choroid (>2 mm), sclera, orbit, anterior chamber
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2358 Indian Journal of Ophthalmology Volume 68 Issue 11

Following enucleation, a detailed analysis of the caution is recommended, especially for group D or E eyes
globe’s histopathological features is of utmost importance. with suspicion for high risk features. High risk retinoblastoma
Histopathology reports provide useful information to the warrants enucleation and additional 6‑9 cycles of high‑dose
ocular oncologist that can guide the course of treatment. In the IVC to prevent metastatic disease.[25,43,44] Due to small caliber
presence of high risk features, including post‑laminar optic vessels, use of IAC is typically reserved for patients older than
nerve invasion, massive choroidal invasion (>3 mm diameter), or 3 or 4 months.[19] In younger patients, bridge therapy with IVC
extraocular extension, adjuvant IVC is required for prevention is administered until weight reaches 6 kg.[14]
of metastases.[24‑26] On the contrary, if the ocular pathologist
Despite localized delivery of chemotherapeutic agents,
reports absence of said features, enucleation alone could be
systemic toxicity has been observed following IAC. Transient
curative and additional chemotherapy might not be necessary.
neutropenia has been observed in 12% of patients.[20] Femoral
artery occlusion together with blue toe syndrome can be
Intra‑Arterial Chemotherapy (IAC)
managed and reversed with anticoagulation.[30,45] More severe
In 1990, Akihiro Kaneko pioneered targeted chemotherapy complications like carotid artery dissection, stroke, and death,
of intraocular retinoblastoma.[4] Since then, this modality are seldom reported but can occur.[46] Patient selection is critical,
has earned a pivotal role in the modern treatment of as undetected extraocular extension, optic nerve or massive
retinoblastoma, especially for unilateral tumors.[27‑30] IAC is choroidal invasion can lead to metastasis when patients are
a complex and usually costly procedure ideally performed managed with IAC alone without systemic chemotherapy.
in an angiography suite by an experienced neurosurgeon or
Periocular side effects are often self‑limited and include
interventional neuroradiologist, in which a microcatheter is
periorbital edema, cutaneous hyperemia, madarosis,
guided by fluoroscopy to deliver chemotherapeutic agents
blepharoptosis, scalp hair loss, and extraocular dysmotility.[31,47,48]
supraselectively into the ophthalmic artery. Given the expense
Serious ophthalmic vascular events include choroidal occlusive
and specialized training required, IAC may not be a feasible
vasculopathy, branch or central retinal artery occlusion,
option in developing countries.[31] Compared with IVC, IAC
ophthalmic artery spasm or occlusion, vitreous hemorrhage, and
results in 10 times the chemotherapy dose delivered directly
others. Rhegmatogenous retinal detachment, possibly secondary
to the eye.[31,32] Chemotherapy generally consists of one, two, due to accelerated tumor regression of endophytic tumors has
or three drugs, typically delivered once a month for a mean been reported in 8‑16% of cases treated with primary IAC.[49]
of three sessions.[14,31,33] ICRB stages B and C usually require Vascular events do not correlate with decreased globe salvage
no more than single‑drug therapy with melphalan dosed at but can limit visual acuity.[4,42] Risk for vascular events is similar
5 mg.[34] However, more advanced disease with extensive when IAC is used as primary or following other therapies.[35]
vitreous or sub retinal seeding observed in ICRB stages D and
E, or refractory tumors might require dose escalation or the Intraocular Chemotherapy
addition of topotecan or carboplatin.[31] The latter (carboplatin)
has been falling into disuse as a first‑line drug due to high rates Intravitreal chemotherapy
of ophthalmic toxicity but is still used in tandem therapy of the Despite significant improvements in survival, tumor control,
fellow eye, discussed later in this section, as an alternative to and globe salvage in the IVC and IAC eras, several group
melphalan when the accumulative dose surpasses 0.4 mg/kg.[14] D and E eyes often required enucleation for vitreous seed
recurrence. [14,34] Intravitreal chemotherapy  (IvitC), first
Given the success of IAC for globe salvage in advanced cases introduced by Kaneko and Suzuki in 2003, was found useful
and refractory tumors, this treatment modality has become in combination with IAC for many eyes that otherwise would
more widely used over the past decade.[35‑38] Main indications for have been lost. Current indications for IvitC include the
IAC include both first‑line and globe salvage therapies. IAC is presence of refractory or recurrent vitreous seeds following
employed as primary therapy for non‑germline, unilateral, group other treatments [Fig. 3]. It is noteworthy to highlight that IvitC
B, C, D, or E retinoblastoma [Fig. 2] or as a secondary therapy is almost never used as primary therapy, but mostly as globe
for unilateral or bilateral advanced recalcitrant disease facing salvage therapy, given the limited efficacy on the primary
enucleation.[14,39,40] IAC is effective against sub retinal and vitreous tumor. Contraindications for IvitC include presence of tumor
seeds, especially when in close proximity to the retina.[41,31] or vitreous seeds at the planned site of needle entry, tumor
Other applications for IAC include tandem therapy invasion of the pars plana, and anterior chamber seeding.
for advanced bilateral cases, minimal exposure  (<2  cycles) Careful clinical examination with the aid of ultrasound
and rescue IAC for recurrence after previous IAC. Tandem biomicroscopy (UBM) can help administer IvitC safely.
therapy remains controversial due to the concern for increased The most commonly used drugs in IvitC are melphalan
vascular toxicity in the better seeing eye, unknown effect on and topotecan, either alone or in combination. The
pineoblastoma prevention, and limited effect on pre‑existing recommended doses of 20‑30 µg every 2‑4 weeks have been
metastases that could lead to increased child mortality.[14] In found to efficiently control vitreous seeds while avoiding
the three centers authoring this report, adjuvant IVC is often toxic side effects.[50,51] When the intended injection volume
considered as front‑line therapy for patients with known or surpasses 0.1 mL, especially when injecting more than
suspected germline mutation for prevention of metastasis, one drug, an anterior chamber paracentesis is performed
pineoblastoma, and second cancers and front‑line IAC is prior to the intravitreal injection. Following injection, the
reserved for those with unilateral, somatic mutation.[17,18,42] needle is withdrawn while simultaneous triple‑freeze‑thaw
Unfortunately, genetic mutation is not known at presentation cryotherapy is delivered at the entry site. The eye is gently
so a surrogate of age is used with youngest children  (<6 jiggled for 30 seconds to achieve homogenous distribution
months) at highest risk for germline mutation. Likewise, throughout the entire vitreous cavity, and copious irrigation
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November 2020 Ancona‑Lezama, et al.: RB Treatment in 2020 2359

of the ocular surface is performed with sterile saline. Parents density after 5‑years follow‑up.[65] Use of topotecan rather than
are instructed to avoid drop instillation, rubbing, or other melphalan might result in fewer adverse effects and could be
manipulation of the eye for 7 days following the procedure. similarly efficacious. In such cases, a transcorneal approach
These measures are termed ‘anti‑reflux mechanisms’ and with infusion into the anterior chamber aqueous is sufficient
avoid undesired spreading of tumor into the extraocular and repeated monthly as necessary.[63] A similar technique with
space. Prior to the implementation of anti‑reflux safety intracameral topotecan is employed by the authors.
measures, extraocular extension was reported in 0.4% of cases,
but studies reported a considerable decrease in risk which Focal Therapies
ranges from 0–0.08% with current injection techniques.[52‑55] Focal therapies are often used for tumor consolidation
Serious ocular adverse events can be associated with IvitC, in conjunction with IVC or IAC. [64] Currently used focal
including cataract, vitreous and sub retinal hemorrhage, therapies mainly include cryotherapy and transpupillary
ocular hypotony, phthisis bulbi, salt‑and‑pepper retinopathy, thermotherapy (TTT). Regardless of choice, all focal therapies
anterior segment toxicity, conjunctival chemosis and result in chorioretinal scarring to some extent and can lead to
congestion, injection‑site episcleral pigmentation, iris and reduction in visual field or visual acuity if lesions are treated
scleral thinning, iris heterochromia, posterior synechiae, inside the macula. Consideration should be given to alternative
anterior uveitis, optic disc edema, and hemorrhagic retinal chemotherapy‑based treatment regimens for tumors involving
necrosis.[54,56,60] The risk for such events can vary with injection the fovea, especially if both eyes are involved.
technique and ocular pigmentation.[60]
Cryotherapy
Precision intravitreal chemotherapy
Cryotherapy remains a reliable and regularly used treatment
First described in 2018, precision intravitreal chemotherapy in the management of retinoblastoma. Indications include
(p‑IvitC) was introduced to treat localized vitreous seeding.[61] treatment of small tumors and foci of sub retinal or preretinal
Modified from the standard technique which treats diffuse vitreous seeds. A modality termed ‘chemo‑cryo’ describes the application
seeds, p‑IvitC was designed to inject the chemotherapeutic
of cryotherapy to the peripheral ora serrata on the same day as
drug(s) in close proximity to a single or localized group of
IVC in order to improve drug concentration to the intraocular
vitreous seeds under indirect ophthalmoscopy, rather than
space.[14] Treatment is performed under indirect ophthalmoscopy,
directing the needle toward the center of the globe and dispersing
placing the cryotherapy probe on the conjunctiva for peripheral
the agent(s) throughout the vitreous cavity.[62] In p‑IvitC, the eye
lesions or directly on the sclera following a conjunctival incision
is not jiggled following the injection in order to avoid unwanted
for more posteriorly located lesions. A  triple‑freeze‑thaw
dispersion of the injected drug(s). Instead, the eye is kept still and
technique is preferably employed, visualizing the tumor
the head is positioned with the vitreous seed(s) located inferiorly,
becoming entirely encased in an ice ball and then waiting for
using gravity as an aid to minimize exposure to the macula or
a complete thaw prior to applying the following freeze cycle.
other unwanted sites.[62] This modality seems to improve drug
Presently, cryotherapy is rarely used as standalone therapy,
functionality, translating into a reduction of mean 4‑5 injections
and is more frequently used in combination with some sort
down to 2.6 injections. With prolonged tumor control observed
of chemotherapy, most commonly IVC but sometimes IAC.
at 10 months follow‑up, retinal pigment epithelial mottling was
Exudative and rhegmatogenous retinal detachment have been
observed in 13% of cases, and occurred distant from the foveola.[62]
reported following extensive cryotherapy.[14,66]
Intracameral chemotherapy
Transpupillary thermotherapy (TTT)
Introduced in 2017 by Munier et al., intracameral
Transpupillary thermotherapy with diode laser has largely
chemotherapy  (IcamC) was designed to provide sufficient
supplanted laser photocoagulation in the modern armamentarium
drug availability in the anterior chamber.[62] Previously, aqueous
of retinoblastoma treatment. As with cryotherapy, TTT can be
seeding remained an indication for immediate enucleation or
used in combination with chemotherapy as primary treatment
anterior chamber plaque radiotherapy given that conventional
for small tumors less than 3 mm in diameter and 2 mm in
routes of chemotherapy administration failed to reach
thickness [Fig. 4].[67] TTT is usually administered through indirect
tumoricidal doses in the anterior chamber.[63] The original
ophthalmoscopy, using a 810 nm diode laser on continuous
technique describes administration of oral acetazolamide
mode. Multiple spots are often required to cover the entire
5 mg/kg prior to injection in order to suppress aqueous humor
tumor. The goal is to provide sufficient application time until a
secretion and prevent drug dilution.[63] Aqueous humor was then
grey‑white uptake is achieved. Multiple TTT sessions, ranging
aspirated from the anterior and posterior chambers through a
from 2‑6, are usually required at 4 week intervals, to achieve the
transcorneal approach with a 34‑gauge long needle. Without
endpoint of a flat scar or completely calcified tumor. Indocyanine
removing the needle, a syringe exchange was then performed to
green  (ICG) can be used to enhance the effects of TTT in
replace a comparable volume of aqueous with melphalan (15‑20
cases with suboptimal response, tumor recurrence, or lightly
µg/0.05 mL) or topotecan  (7.5 µg/0.015 mL).[63] The dose was
pigmented fundus. ICG is usually infused at a dose of 0.3‑0.5
fragmented, distributing 1/3 of the dose to the anterior chamber,
mg/kg approximately one minute prior to TTT application.[14]
and the remaining 2/3 to the posterior chamber via a transiridal
approach. Following the injection, cryotherapy was applied to Complications associated with TTT include iris atrophy,
the entry site at the time of needle removal. IcamC has also been anterior or posterior synechiae, and focal cataract. More severe,
used in combination with plaque radiotherapy, with complete sight‑threatening complications are rare with appropriate
tumor control in one case after 3 years follow‑up.[63,64] Known use and include retinal vein occlusion, vitreous hemorrhage,
side effects include iris heterochromia and progressive cataract retinal neovascularization, vitreoretinal traction, and retinal
formation in the treated eye, with stable corneal endothelial cell detachment.[68‑70]
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2360 Indian Journal of Ophthalmology Volume 68 Issue 11

External Beam Radiotherapy the setting of extraocular tumor extension, orbital recurrence,
and positive optic nerve margin following enucleation.[71]
Prior to the introduction to IVC, external beam The combination of EBRT and IVC for treatment of orbital
radiotherapy (EBRT) was used as globe salvage therapy. Today, retinoblastoma has been reported to achieve tumor control
EBRT is mostly of historical significance in most developed in 71% of patients.[72] Radiation side effects associated with
nations, due to the many associated side effects and improved EBRT include tear deficiency, dry eye syndrome, filamentary
outcomes following introduction of effective chemotherapy keratopathy, cataract, radiation retinopathy, optic neuropathy,
for retinoblastoma. However, EBRT still maintains a role in and orbital growth retardation causing facial deformity.[73,74]
The most serious side effects of EBRT are the subsequent
development of second primary tumors in the field of radiation,

a b

a b

c d
Figure 1: Modern treatment of retinoblastoma. The role of intravenous
chemotherapy (IVC) in bilateral disease. A 4‑month‑old patient was
c d
diagnosed with a (a) Group B retinoblastoma in the right eye, and was
treated with 6 cycles of standard‑dose IVC, (b) achieving a complete Figure 2: Modern treatment of retinoblastoma. The role of intra‑arterial
regression of the tumor. Consolidation therapy with TTT was required chemotherapy  (IAC) in unilateral disease.  (a) Unilateral group B
during the course of the treatment, leaving flat scars (black arrows) retinoblastoma with macular involvement. Following 4 cycles of IAC,
and completely regressed tumors. The (c) left eye was diagnosed with (b) the majority of the macula had been spared without the need for
Group D retinoblastoma, regressing to a (d) smaller calcified scar in additional consolidation therapies. (c) Unilateral group D retinoblastoma
the macular region after treatment with macular involvement and serous retinal detachment. After 4 cycles
of IAC, the retina completely reattached leaving a (d) smaller calcified
macular scar and scattered calcified subretinal seeds

a b
Figure 3: Modern treatment of retinoblastoma. The role of intraocular
chemotherapy. Diffuse vitreous seeding from retinoblastoma managed a b
with intravitreal chemotherapy  (IvitC).  (a) Active vitreous seeds Figure 4: Modern treatment of retinoblastoma. The role of consolidation
surrounding the tumor and overlying the macula (black arrow), with therapies. Group A retinoblastoma managed with transpupillary
(b) resolution after two cycles of IvitC with melphalan and one cycle thermotherapy (TTT). (a) Subtle tumor (black arrow) temporal to the
of IvitC with topotecan macula, with (b) regression 1 month after treatment

a b c
Figure 5: Modern treatment of retinoblastoma. The role of enucleation and prosthetic rehabilitation. (a) Unilateral Group E retinoblastoma that
required (b) enucleation, with a dermo‑lipid graft placed for economic reasons. (c) On follow‑up 6 weeks later, a custom‑made prosthesis was
adjusted
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November 2020 Ancona‑Lezama, et al.: RB Treatment in 2020 2361

especially in patients with germline retinoblastoma. This risk era [Fig. 5]. It is usually reserved for massive group E tumors,
has been reported to be as high as 53% by age 50, making poor tumor visualization (e.g., due to vitreous hemorrhage),
patients with germline mutation more likely to die from second presence of extraocular extension, suspected invasion of the
cancers than from retinoblastoma itself.[75‑77] The most common optic nerve or choroid, or recalcitrant tumors that have failed
second primary tumor is osteosarcoma, followed by other previous globe salvage therapies  (e.g.,  IAC, IvitC, plaque
bone tumors, soft tissue sarcoma, melanoma, and epithelial radiotherapy, etc.).[11,86-88]
tumors (bladder, breast, colorectal, kidney, lung, nasal cavity,
Known complications include chemosis, conjunctival
prostate, retroperitoneum, thyroid, tongue, uterus). Due to
cysts, pyogenic granuloma, blepharoptosis, lagophthalmos,
these side effects, we recommend avoiding treatment with
superior sulcus defect, enophthalmos, symblepharon, implant
EBRT if other effective treatment methods are available.
exposure, and infection.[89] Orbital implant exposure requires
Plaque Radiotherapy urgent wound repair. Infection can be managed topically
or systemically with antibiotics but implant removal can
First described in 1929, plaque radiotherapy, also called be necessary in severe cases. Giant papillary conjunctivitis
brachytherapy, was initially used as globe salvage therapy secondary to continuous contact of the prosthesis can be
for recurrent tumor following EBRT.[78,79] In the present era, managed with antibiotic‑steroid ointments and copious
brachytherapy is typically used as secondary treatment for amounts of lubricants.
medium sized (≤16 mm in largest basal diameter and > 3 to ≤ 9
mm in thickness) chemoresistant tumors with or without Eye removal can lead to functional, physical, and
localized vitreous or sub retinal seeding, following recurrence psychological effects.[90] Hence, prosthetic rehabilitation is a
after IVC or IAC.[80] Plaque radiotherapy can also be used crucial event. Cosmetic rehabilitation following enucleation is
to manage diffuse anterior segment retinoblastoma with or generally advised with a conformer during the initial 6 weeks.[90]
without IVC in the absence of choroidal or retinal tumors. Following the sixth week, once risk for dehiscence, bleeding or
Typically, a 2 mm safety margin is added to the largest basal infection has diminished, molds are taken for a custom ocular
diameter for optimal tumor coverage. Tumors within 2 mm of prothesis. Some centers report that early prosthesis insertion
the optic nerve require a notched plaque, with deep notch used has been found to improve the quality of life.[90,91]
for 3 or more clock hours of tumor around the nerve. Iodine‑125
is the most commonly used isotope in the United States and Follow‑Up Protocol
the dose is customized to deliver 35‑40 Gy to the tumor apex. After the first treatment has been instated, follow‑up visits
When possible, secondary plaque radiotherapy is delivered are generally scheduled every 4 weeks to evaluate response to
1‑2 months following IVC in order to minimize side effects. therapy, identify side effects, and make decisions accordingly.
Compared to EBRT, plaque radiotherapy is convenient, The algorithm [Table 2] summarizes some situations where
given that it only takes 2‑4 days to deliver the complete dose, patients might be simply observed, globe salvage treatment
with the minor disadvantage of requiring two surgeries to place continued, adjusted, escalated, or replaced with enucleation.
and remove the plaque.[81,82] When compared to EBRT, many At any time during the course of the treatment, as
serious side effects are avoided with plaque radiotherapy, genetic results for the RB1 mutation become available, the
particularly ipsilateral orbit and facial hypoplasia, and most family should be advised of the impact results will have
importantly, second cancers.[83] Success of plaque radiotherapy for the long‑term follow‑up, and in vitro fertilization with
as secondary treatment following IAC has been reported to preimplantation diagnosis can be discussed as part of family
be 79%, even in the presence of localized vitreous seeding.[84] planning. Patients and their families are offered psychotherapy
Despite excellent tumor control following plaque radiotherapy, alongside medical treatment, where alarm signs are acted
side effects can occur and include cataract (20‑43%), radiation upon, and the grieving process is normalized. Additional
maculopathy (25%), radiation papillopathy (26%), and vitreous ancillary tests will be required by the pediatric oncologist
hemorrhage  (54%).[82,84,85] A comparison between primary and routinely, especially if standard‑dose or high‑dose IVC is being
secondary plaque radiotherapy revealed a higher incidence of administered. A high‑resolution simple and contrasted MRI
radiation retinopathy (27% vs. 40%) and cataract formation (33% of the brain and orbits should be rigorously repeated every 6
vs. 43%) with the latter.[81,83,85] Intravitreal anti‑vascular endothelial months until age 5 years old, and occasionally more extensive
growth factor  (anti‑VEGF) medications can be employed to workup, including blood samples, a lumbar puncture, or a
treat macular edema following plaque treatment. However, full‑body osseous gammagram may be required as directed
prior to confirmed tumor regression, intravitreal injections of by the pediatric oncologist.
non‑chemotherapeutic agents should be avoided to prevent
extraocular tumor extension. A  more conservative approach
Long‑Term Monitoring of the Cancer‑Free
to prevent or treat macular edema in such cases is the use of Patient
sub‑Tenon’s triamcinolone. Sector retinal laser photocoagulation A retinoblastoma survivor should ideally be monitored for life.
can be used in combination with prophylactic sub‑Tenon’s This is particularly true for patients with germline mutation
triamcinolone to prevent macular edema or proliferative radiation where second cancers can appear at times remote from primary
retinopathy following plaque radiotherapy.[82] cancer treatment. After complete tumor control has been
achieved, patients are followed with frequent eye exams until
Enucleation age 7, and then less frequently throughout the rest of their lives.
Despite great advances in retinoblastoma management, globe It is reassuring to know that most patients manifest recurrences
enucleation still remains a current treatment in the modern by 3 years after treatment with little recurrence thereafter.[92]
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2362 Indian Journal of Ophthalmology Volume 68 Issue 11

Table 2: Modern treatment of retinoblastoma: A 2020 Review. Treatment algorithm for retinoblastoma based on laterality and
International Classification of Retinoblastoma (ICRB) stage

However, very‑late onset recurrences can occur, as far as 11 years resources and level of experience, an algorithm is presented
after initial treatment.[93] Therefore, visits every 1‑2 years with to visually summarize the most up‑to‑date literature. The
the pediatric oncologist are warranted. Ophthalmology visits authors encourage further collaboration towards the creation
should be focused on monitoring long‑term effects secondary of a unifying treatment model based upon the agreement of
to the cancer treatment  (e.g.  amblyopia, glaucoma, cataract, the most renowned and state‑of‑the‑art retinoblastoma centers
vitreous hemorrhage, retinal detachment, etc.), preservation of throughout the world.
the fellow unaffected eye (if such is the case), as well as the usual Financial support and sponsorship
prevention for a patient of his/her age group (e.g. correction
Support provided in part by the Eye Tumor Research
of refractive errors).
Foundation, Philadelphia, PA (CLS). The funders had no role in
Conclusion the design and conduct of the study, in the collection, analysis
and interpretation of the data, and in the preparation, review or
Proper management of retinoblastoma is complex. Each case is approval of the manuscript. Carol L. Shields, M.D. has had full
unique, and treatment regimens must be carefully customized access to all the data in the study and takes responsibility for
for varying disease presentations, available equipment, and the integrity of the data and the accuracy of the data analysis.
regional culture or traditions. Close cooperation between the
Conflicts of interest
treating ocular oncologist and the multidisciplinary team is
critical to achieve treatment success, with all parties prioritizing There are no conflicts of interest.
patient safety and preservation of life.
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Commentary: Retinoblastoma in earlier diagnosis of retinoblastoma in our country and

ultimately resulting in improved outcomes
management—Where are we and 2. Sparse use of intra‑arterial chemotherapy  (IAC):
where do we go from here? The high cost of IAC in India has restricted its
widespread use resulting in the selection of intravenous
chemotherapy (IVC) to treat even unilateral tumors.[8] The
We are presented with an excellent review of contemporary cost of consumables used and paucity of governmental
retinoblastoma management in this issue of the Indian and nongovernmental trust hospitals offering this
Journal of Ophthalmology. [1] India along with other treatment make it unviable for large‑scale adoption of IAC
lower‑middle‑income countries contribute nearly 45% of in our country. Indigenous development of cost‑effective
retinoblastoma cases in the world. [2] We, in India, have consumables, rationalizing the costs, and increasing the
made rapid strides in the last two decades in managing number of centers offering the treatment can help the
retinoblastoma with outcomes comparable with those of transition from IVC to IAC
the developing countries. All the contemporary treatment 3. Poor penetration of genetic testing: We do not perform
modalities listed in the article are available to Indian genetic testing as often as we should, because of the paucity
retinoblastoma patients, albeit in select centers across our of testing centers and the high cost of the tests. While we
country. have the technical finesse to offer prenatal sampling and
diagnosis, the capabilities are restricted to a few urban
Where do we differ in comparison with the developed centers in the country. Awareness among clinicians of the
world: need for genetic testing, identifying/creating genetic testing
1. Delayed presentation of disease: Children with centers, and rationalizing the cost of the tests can mitigate
retinoblastoma present later in our country than those in this lacuna in retinoblastoma care in India
advanced countries. This is with a more advanced stage of 4. There is a paucity of support groups to help counsel and
the intraocular disease and, more often, with the extraocular educate the family and Retinoblastoma (RB) survivors in
disease (in certain pockets of the country).[3‑7] Improving our country. The involvement of retinoblastoma specific
awareness of retinoblastoma, increasing availability of nongovernmental organizations and a conscious effort by
ocular oncology care across the country, and possible the existing caregivers to create such groups will aid in
adoption of universal eye screening of all infants can result creating this much‑missed support structure