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\begin{document}

\title{HOW WE APPROACH CONSERVATIVE TREATMENT OF RETINOBLASTOMA IN SOUTH
AMERICA IN THE ERA OF LOCAL OCULAR TREATMENTS. A CONSENSUS OF THE GRUPO
AMERICA LATINA DE ONCOLOGIA PEDIATRICA (GALOP)}



\author[1]{Juan López }%
\author[2]{Claudia Sampor}%
\author[3]{Nathalia Grigorovski}%
\author[4]{Alejandro Ceciliano}%
\author[2]{Adriana Fandino}%
\author[5]{Diego Ossandon}%
\author[6]{Veronica Perez}%
\author[7]{Rafaela Caixeta}%
\author[7]{Joaquim  Caetano de Aguirre Neto}%
\author[8]{Sandra Alarcon}%
\author[9]{Sónia Silva}%
\author[10]{Luiz Teixeira}%
\author[11]{Celia Antoneli}%
\author[3]{Clarissa Matosinho}%
\author[12]{Carlos Leal Leal}%
\author[9]{Guilherme Castela}%
\author[2]{Flavio Requejo}%
\author[13]{Jaume Catala}%
\author[11]{Carla Pacheco Donato Macedo}%
\author[4]{Guillermo Chantada L}%
\affil[1]{Universidad de Chile Santiago Chile}%
\affil[2]{Hospital de Pediatria Prof Dr Juan P Garrahan}%
\affil[3]{Instituto Nacional de Cancer}%
\affil[4]{Hospital Universitario Austral Pilar Argentina}%
\affil[5]{Clinica Alemana de Santiago SA}%
\affil[6]{Hospital San Juan de Dios Santiago Chile}%
\affil[7]{Hospital Santa Casa Belo Horizonte Brazil}%
\affil[8]{Instituto Nacional de Enfermedades Neoplasicas}%
\affil[9]{Centro Hospitalar e Universitario de Coimbra EPE}%
\affil[10]{Universidade Federal de Sao Paulo Escola Paulista de Medicina Sao Paulo Brazil}%
\affil[11]{Universidade Nove de Julho Sao Paulo Brazil}%
\affil[12]{Hospital Infantil Privado Mexico City Mexico}%
\affil[13]{Hospital Sant Joan de Deu}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Local therapies replaced systemic chemotherapy for ocular preservation
in retinoblastoma. In middle income countries, these techniques pose
specific challenges mostly related to more advanced disease at
diagnosis. The Grupo de America Latina de Oncologia Pediatrica (GALOP
developed a consensus document for the management of conservative
therapy for retinoblastoma. Intra-arterial chemotherapy (OAC) is the
preferred therapy, except those with less advanced disease or age
younger than 6 months. OAC allowed for the elimination of the use of
external beam radiotherapy in our setting. Intravitreal chemotherapy is
the preferred treatment for vitreous seeding. Enucleation is the
treatment of choice for advanced eyes.%
\end{abstract}%



\sloppy


\textbf{HOW WE APPROACH CONSERVATIVE TREATMENT OF RETINOBLASTOMA IN
SOUTH AMERICA IN THE ERA OF LOCAL OCULAR TREATMENTS. A CONSENSUS OF THE
GRUPO AMERICA LATINA DE ONCOLOGIA PEDIATRICA (GALOP)}

Juan Pablo Lopez Garin\textsuperscript{1}, Claudia
Sampor\textsuperscript{2}, Nathalia Grigorovski\textsuperscript{3},
Alejandro Ceciliano\textsuperscript{4}, Adriana
Fandi\selectlanguage{ngerman}ño\textsuperscript{2}, Diego Ossandon\textsuperscript{5,6},
Veronica Perez\textsuperscript{6}, Rafaela Caixeta\textsuperscript{7},
Joaquim Caetano Aguirre Neto\textsuperscript{7}, Sandra
Alarcon\textsuperscript{8}, Sonia Silva\textsuperscript{9}, Luiz
Teixeira\textsuperscript{10}, Celia Gianotti
Antoneli\textsuperscript{11}, Clarissa Matosinho\textsuperscript{3},
Carlos Leal-Leal,\textsuperscript{12} Guilherme
Castella\textsuperscript{9}, Flavio Requejo\textsuperscript{2}, Jaume
Catala\textsuperscript{13}, Carla Macedo\textsuperscript{11}, Guillermo
L Chantada\textsuperscript{4,13,14}

1: Universidad de Chile. Santiago, Chile

2: Hospital de Pediatría SAMIC Juan P Garrahan, Buenos Aires, Argentina

3: Instituto Nacional do Cancer. INCA. Rio de Janeiro, Brazil

4: Hospital Universitario Austral. Pilar. Argentina

5: Clínica Alemana de Santiago, Chile

6: Hospital San Juan de Dios, Santiago, Chile

7: Hospital Santa Casa, Belo Horizonte, Brazil

8: Instituto Nacional de Enfermedades Neoplasicas, INEN, Lima, Peru

9: Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal

10: Universidade Federal de Sao Paulo Escola Paulista de Medicina. Sao
Paulo, Brazil

11: Universidade Nove de Julho, Sao Paulo, Brazil

12: Hospital Infantil Privado, Mexico City, Mexico

13: Hospital Sant Joan de Deu, Barcelona, Spain

14: Instituto de Investigacion en Medicina Traslacional, IIMT.
Universidad Austral-CONICET. Pilar, Argentina

Corresponding author: Guillermo L Chantada, MD, PhD. Hospital Sant Joan
de Deu, Passeig Sant Joan de Deu 2, Barcelona, Spain. Hospital
Universitario Austral: Av Peron 1500. Pilar, Provincia Buenos Aires,
Argentina. Phone: +54 230 448-2000

Email: gchantada@yahoo.com

Word Count for:

a) Abstract:100 b) Main Text: 3498

--Number of Tables: 3

--Short running title: How we treat retinoblastoma in South America

--Keywords: Retinoblastoma, intra-arterial chemotherapy, intra-vitreal
chemotherapy

--Abbreviation list\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
EBRT & External beam radiotherapy\tabularnewline
\midrule
\endhead
OAC & Ophthalmic artery chemosurgery\tabularnewline
UBM & Ultra bio-microscopy\tabularnewline
HRPF & High risk pathology features\tabularnewline
Ct DNA & Circulating tumoral DNA\tabularnewline
\bottomrule
\end{longtable}

ABSTRACT

Local therapies replaced systemic chemotherapy for ocular preservation
in retinoblastoma. In middle income countries, these techniques pose
specific challenges mostly related to more advanced disease at
diagnosis. The Grupo de America Latina de Oncologia Pediatrica (GALOP
developed a consensus document for the management of conservative
therapy for retinoblastoma. Intra-arterial chemotherapy (OAC) is the
preferred therapy, except those with less advanced disease or age
younger than 6 months. OAC allowed for the elimination of the use of
external beam radiotherapy in our setting. Intravitreal chemotherapy is
the preferred treatment for vitreous seeding. Enucleation is the
treatment of choice for advanced eyes.

BACKGROUND

Since the mid-1990s, conservative treatment of retinoblastoma includes
tumor chemoreduction with systemic chemotherapy using Carboplatin,
Etoposide and Vincristine followed by focal
therapies\textsuperscript{1,2}. In our setting, this resulted in an
increase rate of ocular preservation while reducing the use of external
radiotherapy (EBRT), albeit at the cost of a higher use of
resources\textsuperscript{3,4} since this treatment is associated with
hospitalizations due to chemotherapy complications such as transfusions,
neutropenic fever and long-term effects such as ototoxicity as well as
chemotherapy-induced acute leukemia\textsuperscript{5-7}. In Latin
America, up to one third of the patients present with advanced bilateral
retinoblastoma, so avoidance of EBRT could be achieved in less than a
third of the patients\textsuperscript{4}. The results of this treatment
in eyes with vitreous or subretinal seeding were modest, therefore,
several major institutions in high income countries implemented ocular
chemotherapy techniques such as intra-arterial (OAC) and intra-vitreal
chemotherapy in order to allow greater delivery of chemotherapy to the
eye with fewer systemic effects\textsuperscript{8}. As opposed to other
pediatric malignancies, these outstanding results were not achieved by
international cooperative groups performing prospective studies.
Therefore, most referral centers for retinoblastoma in South America
also moved from systemic to ocular delivery of chemotherapy for the
conservative treatment resulting in unprecedented ocular salvage rates
and near total elimination of EBRT\textsuperscript{9-11}. This document
is the result of a consensus of the current management in institutions
participating in the GALOP group, which included collaborating
institutions in Spain and Portugal.

INTRA-ARTERIAL CHEMOTHERAPY

In 2008, Abramson and Gobin et al optimized the technique for OAC by
directly catheterizing the ophthalmic artery, achieving a so-called
''superselective'' administration, since the ophthalmic artery was
directly accessed allowing for the use of low absolute doses of
chemotherapy\textsuperscript{12}. The best results were seen in patients
with extensive retinal detachment and cases with massive intra-retinal
tumors and subretinal seeding\textsuperscript{13,14}. No major
complications due to the procedure were observed, and only mild adverse
events were seen\textsuperscript{13}. In Latin America, OAC was first
introduced by the Argentinian group after training in New York in 2009
as a result of a long-term collaboration\textsuperscript{10,15}.
However, as opposed to the North American experience, in Argentina (and
later in other Latin American countries), OAC was mostly used for the
treatment of relapsed or advanced bilateral disease and less frequently
for patients with unilateral disease\textsuperscript{9,10}. Later, this
treatment was gradually introduced in other countries included in this
consensus document\textsuperscript{9,11,16}.

However, there are still unanswered questions about the use of OAC for
retinoblastoma. Current treatments are basically empirical in terms of
dose and frequency of treatment. The most widely used drug has been
Melphalan, but its use is based on incompletely reported \emph{in
vitro}chemosensitivity studies carried out several years ago in
Japan\textsuperscript{17}. The New York and Argentinian groups, among
others, have also used Topotecan and Carboplatin with good results in
terms of efficacy and toxicity\textsuperscript{10,13}. The
pharmacokinetic profile of this combination, described by members of
this group, was useful to determine the systemic exposure to drugs and
with it, its relationship with toxicity and efficacy, allowing a
rational design of the therapeutic scheme of administration of
OAC\textsuperscript{18,19}. Although many groups use Melphalan as a
single agent in this indication, drug combinations tend to be more
active in avoiding resistance mechanisms and also useful to reduce
toxicity of chemotherapeutic drugs by distributing the different
toxicities of various drugs in order to reduce their accumulated doses.

Although the technique is called superselective, predictably, plasma
chemotherapy levels are found in patients treated with this modality,
being higher in patients receiving treatment in both eyes correlating
with myelotoxicity if the dose is greater than 0.48
mg/kg\textsuperscript{18}. Topotecan is an attractive agent for OAC
because of its greater vitreous penetration compared to
Melphalan\textsuperscript{20}. However, no convincing response was seen
when used as single agent for OAC\textsuperscript{21}. Additionally, in
vitro cytotoxicity studies of Topotecan and Melphalan showed that both
drugs are synergistic in their activity in human retinoblastoma cell
lines\textsuperscript{19}. The New York group pioneered the use of
carboplatin by this route\textsuperscript{22}. Carboplatin has been
extensively studied in retinoblastoma, whose activity has been proven
from the clinic to animal models\textsuperscript{23,24}. No significant
toxicity associated to Carboplatin given intra-arterially were reported
and in the series from Argentina no differences were observed in terms
of ocular preservation in eyes treated with Carboplatin (+/- Topotecan)
compared to Melphalan\textsuperscript{10,22}. For all these reasons,
this consensus proposes a first-line chemotherapy scheme including
combinations of the 3 active drugs, Melphalan, Topotecan, and
Carboplatin, especially when used as a tandem treatment or for advanced
cases.

THE OAC PROCEDURE

It is essential that OAC should be performed by an experienced
interventional radiologist or neuro-surgeon, preferably in a center with
high patient numbers. The procedure is performed under general
anesthesia in the angiography room, with the patient in the supine
position. Chemotherapy must be prepared at the oncology pharmacy at the
time of administration or, in special circumstances, directly in the
angiography suite. Ideally, chemotherapy is requested to the pharmacy as
the patient enters the angiography suite so that it is ready for
administration at the time of the procedure. After complete disinfection
of the groin region, the right or left common femoral artery is
punctured. Ultrasound guidance for access may be used in difficult
cases, small infants, or according to institutional policies. Following
local anesthesia, a 3-French pediatric arterial sheath is placed into
the arterial lumen using the Seldinger technique. It is then guided into
the internal carotid artery over a 0.008 inch microguide or Sychro 0.010
microguide under fluoroscopic guidance in conjunction with a flow
microcatheter (Magic) or microguide-guided microcatheters such as the
Marathon microcatheter. In patients older than 4 years, a 4 French
Pediatric introducer and a 4 French guide catheter are used. The
microcatheters in this group are passed through the 4 French guiding
catheter.

Systemic heparinization should be performed intravenously, with an
initial heparin bolus of 20 IU/kg. In addition, an intra-arterial
catheter drip perfusion (heparinated NaCl solution; 60-70 IU heparin/kg
patient weight) is established for the duration of the procedure as a
preventive measure against secondary thromboembolism that may be caused
by continued presence of the intracarotid catheter.

A flow-guided coaxial microcatheter, 1.2 or 1.5 French (diameter 0.4 and
0.5 mm respectively), is mounted on a 0.007'' or 0.014'' guide needle,
which is directed to the ostium of the ophthalmic artery but not into
the artery itself After fluoroscopic confirmation of the correct
position of the microcatheter tip as evidenced by a correct choroidal
blush, chemotherapy is infused. If an optimal choroidal blush is not
obtained or the ophthalmic artery cannot be accessed, it is mandatory to
explore an alternative route without further delay, such as use of a
micro balloon catheter in the internal carotid artery or catheterization
of the external carotid artery (infusing the middle meningeal
artery)\textsuperscript{25}.

The total volume of the drugs to be infused must be 30 ml of 0.9\% NaCl,
dividing the volumes into 15 ml for the administration of each of the
drugs (or 10 ml when the three drugs are used in the same eye). The
total duration of the infusion is between 20 and 30 minutes, always
using a pulsatile technique to allow the drug to get to the inside wall
of the artery since laminar flow would not allow to reach the arterial
branches if the drugs are simply infused continuously. The microcatheter
must be flushed between the 2 chemotherapy injections. Prior to
chemotherapy infusion, anti-emetic treatment with ondansetron should be
administered intravenously and some groups add vasoconstrictive drops
and sprays to the forehead and into the nose respectively in order to
shut off blood supply to the nose and supratrochlear artery.

When the infusion is complete, all catheters and the arterial introducer
are removed. Hemostasis is achieved by initial manual compression of the
femoral artery for 10 minutes, followed by a pressure bandage held in
place for 4 hours. Once extubated, the patient is awakened in the
angiography recovery room and then transferred to a day hospital or a
post-surgical recovery room according to institutional practice, and
subsequently discharged from the hospital after 4-8 hours if no
complications occur.

The use of systemic corticosteroids (dexamethasone 0.15 mg/kg) in order
to prevent orbital edema is routinely considered in cases when the three
drugs are administered in the same eye or when erythema is confirmed at
the end of the procedure or orbital edema, especially when an external
carotid artery approach has been used. Depending on institutional
practice, some groups routinely use corticosteroids eye drops. The use
of modern equipment and limited exposure times are essential, in order
to deliver a minimum dose of radiation\textsuperscript{26}.

DRUGS AND DOSAGES FOR OAC

The combination of Melphalan and Topotecan was the preferred initial
regimen in this consortium for mono-ocular treatments. Carboplatin may
be used in case of lack of availability of Melphalan. If both eyes
should be treated, our group recommends tandem OAC (i.e. sequential
chemotherapy administration to both eyes in the same
procedure)\textsuperscript{27}. For bilateral Group D eyes, we agreed to
use upfront tandem OAC\textsuperscript{27}. In these cases, the
chemotherapy combination is decided individually for each patient using
the doses indicated in Table 1, but deciding upon the tumor response and
tolerance. The most common practice is to give Melphalan-Topotecan to
one eye and Carboplatin-Topotecan to the contralateral eye (Table 2). It
is possible to alternate this combination in each eye when response is
asymmetrical or toxicity occurs. We discourage the routine use of
bilateral injections of Melphalan either at full doses or in reduced
doses, preferring the use of the 3-drug combination. Factors such as
vascular anatomy play an important role in the efficacy of this
treatment\textsuperscript{25}. In certain circumstances, doses may vary,
increasing them in cases of insufficient response and good tolerance or
decreasing them in cases where tolerance is not adequate. Therefore, the
dose decision is taken jointly by the treating medical team, considering
the activity and toxicity presented in previous cycles, and it may be
adjusted according to clinical criteria or need for treatment in both
eyes. The number of cycles will depend on the response, being generally
less than 4-6. Our group discourages prolonged attempts to conserve eyes
with additional cycles of OAC in order to avoid increasing the risk of
metastatic relapse\textsuperscript{8}.

INTRAVITREAL CHEMOTHERAPY

The technique for intravitreal injection is adapted from Munier et
al\textsuperscript{28}. Ultra-biomicroscopy (UBM), if available, is
recommended in order to more accurately characterize the injection site.
In most cases, the quadrant for injection can be easily identified with
ophthalmologic examination, so the use of UBM would not be mandatory
every time. However, in eyes with extensive vitreous seeding, especially
when there is no response to chemotherapy, the use of UBM is preferred.
Ultrasound examination is also recommended to assess the status of the
hyaloid in order to avoid a subsequent injection behind it in case it
had become detached. In all cases, a tumor-free quadrant of the retina
is preferred in order to administer the drug safely. Paracentesis of the
anterior chamber, taking up to 0.1 ml of aqueous humor is done at the
beginning of the procedure by most groups. We prefer a fine needle,
32-34 G, although in some centers only 30 G needles are available as a
smallest size. Since there are no randomized studies comparing the drug
efficacy, we propose to use Topotecan (30 micrograms in 0.15 ml of
saline) as initial treatment, based on its more favorable toxicity
profile, especially in single eyes or those with good vision, reserving
Melphalan (20 or 30 micrograms in 0.10-0.15 ml) for cases of incomplete
response or relapse\textsuperscript{29,30}. Both drugs can be previously
prepared and stored in a freezer at -20C (with adequate temperature
monitoring) since their stability has been
reported\textsuperscript{31,32}. Intravitreal injection is performed
using a microscope, injecting the drug through the pars plana in the
quadrant opposite the tumor lesion. Cryocoagulation is applied to the
puncture tract to minimize the risk of seeding along the tract. Some
groups additionally recommend shaking the eyeball and washing it with
abundant distilled water to further minimize the risk of contamination,
although reports and experimental studies show that it is a rare
phenomenon\textsuperscript{33,34}. There is controversy regarding the
frequency of intravitreal chemotherapy applications from weekly
injections to injections every 3-4 weeks. For this consensus, it was not
given preference to any schedule, however, most participants agreed that
in cases of massive vitreous seeding, especially in the form of a cloud,
weekly application (at least in the first doses) might be advisable
closely observing response and toxicity. It is recommended that the
number of applications be a minimum of 2 for seeding in the form of
dust, 3 for the form of spheres and 4 for the form of clouds, up to a
(theoretical) maximum of 8 applications. It is also possible to apply an
''induction'' on a weekly basis and after observing a response,
''consolidate'' with 1 or 2 additional applications at 3 or 4 weeks. It
is preferable that the tumor is initially treated with OAC before
intravitreal chemotherapy is administered. The results of intravitreal
chemotherapy after systemic chemotherapy are not known.

SYSTEMIC CHEMOTHERAPY FOR LESS ADVANCED INTRAOCULAR TUMORS

Systemic chemotherapy for group B or C eyes is considered by most groups
as standard treatment which may avoid the potential for ocular toxicity
of OAC with a comparable success rate\textsuperscript{35}. OAC may be
used for relapse or incomplete response. However, patients with group
B-C eyes with macular involvement benefit from the treatment with
OAC\textsuperscript{36}. In patients with unilateral group B-C
retinoblastoma, we propose the indistinct use of systemic or OAC
according to the experience of each group and local availability
(favoring the use of OAC when available) in patients older than 6 months
of age or over 6 kilos based on reports of shorter treatments and lower
toxicity\textsuperscript{37}.

Although a study showed that two drugs (Vincristine and Carboplatin) are
inferior to combinations with three drugs in the conservative treatment
of retinoblastoma, our group decided to use the two-drug combination,
without the use of Etoposide for patients receiving systemic
chemoreduction\textsuperscript{38}. The group agreed that the use of
Etoposide is not justified in centers that have OAC since it has been
associated with higher risk of secondary leukemias, even at doses
considered safe in other neoplasms\textsuperscript{39}.

In patients with bilateral disease presenting with one eye group B or C
and the contralateral eye group D (the most common presentation in our
continent), the use of tandem OAC is also preferred as this would
provide better chances of success in the treatment of the D eye. In
cases of limited access to OAC or in groups with less experience in the
use of tandem therapy, the use of systemic chemotherapy followed by OAC
(+/- intravitreous chemotherapy) only for consolidation of the D eye may
be an alternative.

MANAGEMENT OF PATIENTS WITH GROUP D SPORADIC UNILATERAL RETINOBLASTOMA

Considering the need for high utilization of resources and limited
functional outcomes in unilateral eyes treated conservatively, we agreed
that initial enucleation of most patients with sporadic unilateral
disease with group D and all group E eyes is the standard
treatment\textsuperscript{40}. However, group D eyes includes many
clinical situations from eyes with advanced disease with multiple
vitreous seeding and low probability of useful vision, to eyes with
smaller tumors, occasionally sparing the macula and presenting vitreous
and/or subretinal seeding, in whom conservative treatment may preserve
vision. Affected families may prefer conservative therapy and OAC should
be offered when there is a reasonable chance of vision
preservation\textsuperscript{41}. It is important to consider that in
our setting, it is seldom possible to have timely results of the
presence of the germinal mutation of the RB1 gene so it can be
considered in the initial therapeutic decision. Also, of note, we use
the international classification of intraocular retinoblastoma in its
original Murphree version\textsuperscript{42}. Other groups use the
Philadelphia modification where involvement of more than 2/3 of the
retina is considered group E, rather to group D as in the Murphree
classification\textsuperscript{43}. No case with group E disease,
according to the Murphree classification, will it be treated with
conservative treatment in our setting.

MANAGEMENT OF PATIENTS UNDER 6 MONTHS OR 6 KILOS

In general, children under 6 months are not candidates for OAC, although
this treatment may be possible in patients weighing more than 5 kg. Each
situation will be assessed individually and in those that are considered
to be ineligible to receive this treatment, a limited number of cycles
of ``bridge'' systemic chemoreduction with single agent carboplatin (in
a dose adapted to the age and gestational age) may be indicated until
their weight makes them candidates for receiving
OAC\textsuperscript{44}.

A summary of the treatment recommendations is presented in Table 3.

MANAGEMENT OF PATIENTS WITH BILATERAL RETINOBLASTOMA AND RISK FACTORS IN
THE ENUCLEATED EYE

In patients with bilateral retinoblastoma and one eye of group E, in
whom initial enucleation is indicated and conservative treatment with
OAC of the contralateral eye is considered, the result of the pathology
of the other eye should be awaited to indicate definitive treatment. In
the event of pathology risk factors, systemic chemotherapy will be
indicated according to current recommendations or protocols in the GALOP
group\textsuperscript{40}. In case one or both eyes present with severe
buphthalmos, we recommend neo-adjuvant systemic chemotherapy followed by
secondary enucleation and systemic adjuvant therapy regardless of the
HRPF\textsuperscript{45}. If there is still active intraocular disease
in the remaining eye, OAC may be used for secondary treatment.

CRITIQUE TO SELECTIVE OCULAR TREATMENTS

Lack of the ``protective effect of systemic chemotherapy''

Retinoblastoma offers a period of ``metastatic grace'' when it is
possible to give eye-conservative therapy with a low probability of
metastatic dissemination\textsuperscript{8}. The risk of metastatic
relapse is restricted to patients with advanced intra-ocular disease who
are usually not considered as candidates for eye salvage therapies and
show pathologic risk factors. Recent studies suggest that
retinoblastoma's biological subtypes may have different risk of
metastasis and also patients with higher risk of metastasis show higher
levels of circulating tumor DNA (ctDNA) at the moment of
enucleation\textsuperscript{46,47}. Hence, as OAC became more widely
used for conservative therapy, some authors gave a word of caution for
the putative loss of the ``protective effect'' of systemic chemotherapy
to prevent metastatic dissemination\textsuperscript{48}. Systemic
chemotherapy is effective for the prevention of metastatic relapse in
enucleated patients who present high risk pathology features, but this
protective effect would not be needed in patients treated conservatively
when adequately selected, because their risk of metastatic dissemination
is minimal\textsuperscript{40}. In fact, there are now more than 200
peer-reviewed papers in the past 15 years on survival after OAC and all
reported a very low (\textless{}1\%) risk of metastases in patients
receiving this treatment, despite a low chemotherapy exposure in the
systemic compartment\textsuperscript{49}. In addition, OAC attains very
high levels of chemotherapy to the optic nerve and choroid, giving
enhanced ``protection'' to major sites of fatal retinoblastoma
dissemination\textsuperscript{50}. In fact, CNS relapse after OAC has
been rarely reported and the few cases showing metastatic dissemination
after OAC had systemic or orbital dissemination or in some cases, in
middle income countries failed to comply with
therapy\textsuperscript{49}. The recognition that higher risk pathologic
features exist before treatment and that enucleation does not prevent
metastases in these eyes (as evidenced by the development of metastasis
following enucleation) has spurred the use of eye and vision saving
techniques even in eyes with some higher risk features in high income
countries. \textsuperscript{51} Our ability for non-invasively
identifying patients at higher risk for developing metastatic disease or
those with MYCN amplified tumors who are not candidates for eye
salvaging is improving. Liquid biopsy studies reveal that patients who
subsequently developed metastatic relapse had higher levels of
ctDNA\textsuperscript{47}. In these patients, ctDNA levels could be an
indicator of higher tumor burden, and if ctDNA fails to disappear after
enucleation it would show impending extraocular relapse in unilateral
cases and in bilateral patients with controlled tumors. It may be
possible that traditional treatment with initial enucleation in group E
eyes may be challenged with these observations so that what was
considered high risk pathologic features as prognostic indicators of
risk of extraocular relapse would move to a more personalized management
based on actual minimal dissemination to guide therapeutic decisions.
This is also relevant for eyes that have received a high number of
conservative treatments either local or systemic over a long period of
time. In these patients, the ``state of metastatic grace'' may be lost
and metastatic disease may develop.

Lack of protection for trilateral disease

Early results with the use of systemic chemotherapy suggested a possible
effect in reducing the risk of trilateral disease in patients with
germline \emph{RB1} mutation\textsuperscript{52}. However, they were
based on a small number of cases and later studies failed to confirm
this observation\textsuperscript{4}. Subsequent studies revealed that
the overall prevalence of trilateral retinoblastoma is lower after new
and better designed studies were done and studies using OAC did not
report an increased prevalence of trilateral retinoblastoma and the
avoidance of EBRT by the use of OAC would further reduce its
prevalence\textsuperscript{53}.

ACKNOWLDGEMENT: The authors acknowledge the support and teachings of Dr
David H Abramson during the production of this consensus. This work was
supported in part by the Fund for Ophthalmic Knowledge, New York, NY,
USA

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