VOLUME

31

NUMBER

11

APRIL

10

2013

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Results of a Multicenter Prospective Study on the

Postoperative Treatment of Unilateral Retinoblastoma
After Primary Enucleation
Isabelle Aerts, Xavier Sastre-Garau, Alexia Savignoni, Livia Lumbroso-Le Rouic, Estelle Thebaud-Leculee,
Didier Frappaz, Carole Coze, Caroline Thomas, Marion Gauthier-Villars, Christine Levy-Gabriel,
Herve J. Brisse, Laurence Desjardins, and Francois Doz
Isabelle Aerts, Xavier Sastre-Garau,
Alexia Savignoni, Livia Lumbroso-Le
Rouic, Marion Gauthier-Villars, Christine
Levy-Gabriel, Herve J. Brisse, Laurence
Desjardins, and Francois Doz, Institut
Curie; Francois Doz, University Paris
Descartes, Sorbonne Paris Cite, Paris;
Estelle Thebaud-Leculee, Centre Oscar
Lambret, Lille; Didier Frappaz, Institut
dHemato-oncologie Pediatrique, Lyon;
Carole Coze, Hopital de la Timone,
Centre Hospitalier Universitaire (CHU)
Marseille; and Caroline Thomas,
CHU Nantes.
Published online ahead of print at
www.jco.org on March 4, 2013.
Supported by a grant from the Association Retinostop and by the local Rotary
Clubs in Saint-Cyr, la Cadire,
le Castellet, and le Beausset.
Authors disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Corresponding author: Isabelle Aerts,
MD, Department of Pediatric Oncology,
Institut Curie-Hopital, 26 rue dUlm
75248, Paris Cedex 05, France; e-mail:
isabelle.aerts@curie.net.
2013 by American Society of Clinical
Oncology

Purpose
The objective of this prospective study was to assess overall survival and event-free survival in
patients with intraocular unilateral retinoblastoma (Reese-Ellsworth group V) treated by primary
enucleation with or without adjuvant therapy depending on histopathologic risk factors.
Patients and Methods
Patients (n 123) were divided into three groups on the basis of risk factors for extraocular
relapse and metastasis assessed on centralized histologic examination of enucleated eyes. Group
1 (n 70) had minimal or no choroidal involvement and/or prelaminar or no optic nerve involvement
and received no adjuvant therapy. Group 2 (n 52) had massive choroidal involvement and/or intraor retrolaminar optic nerve involvement and/or anterior segment involvement and received four
courses of adjuvant chemotherapy. Group 3 (n 1) had invasion of the surgical margin of the optic
nerve and/or microscopic extrascleral involvement and received six courses of adjuvant chemotherapy with intrathecal thiotepa, consolidation chemotherapy, and autologous stem-cell rescue.
Genetic testing was also performed.
Results
Median follow-up for the 123 patients was 71 months. No disease progression, relapse, or distant
metastasis occurred during follow-up. No second malignancies occurred. This requires confirmation with longer follow-up. Secondary bilateralization occurred in two patients with identified RB1
germline mutation. Adjuvant chemotherapy was well tolerated, with limited toxicity. Molecular
testing found constitutional RB1 gene mutations in only nine of 100 evaluated patients.
Conclusion
The survival rate of 100% was excellent, including 57% of patients who received no adjuvant
therapy, suggesting that chemotherapy could be de-escalated in some patients, especially those
with massive choroidal involvement.
J Clin Oncol 31:1458-1463. 2013 by American Society of Clinical Oncology

0732-183X/13/3111-1458/$20.00
DOI: 10.1200/JCO.2012.42.3962

INTRODUCTION

Retinoblastoma (RB), the most common primary

intraocular tumor in children, occurs unilaterally in
60% of patients. In the vast majority of patients,
unilateral RB is nonhereditary, and only 10% to 15%
of patients carry a germline mutation.1,2
In developed countries, patients with unilateral
RB typically present at around 2 years of age with
disease that is still confined to the ocular globe but
has reached an advanced stage, so that conservative
treatment with chemotherapy and local adjuvant
therapy is often no longer an option.3 In most cases,
after ruling out regional extension on clinical and
radiologic findings, enucleation is performed. The
1458

cure rate is higher than 95%4; however, some patients are still at risk of secondary dissemination by
orbital or metastatic relapse, which has a poor vital prognosis.5-8
The risk is assessed on histologic examination of the enucleated eye to determine the nature
and extent of tumor invasion and adopt appropriate treatment strategies.5-12 Examination focuses
on features related to the two main metastatic
pathwaysthrough the ocular coats or via the
optic nerve (ON)as well as invasion of the anterior segment.13
Assessment of the histologic features has led to
the development of risk categories, although there is
no general consensus on the risks associated with the

2013 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on September 12, 2015. For personal use only. No other uses without permission.
Copyright 2013 American Society of Clinical Oncology. All rights reserved.

Retinoblastoma: Adjuvant Treatment After Enucleation

various criteria.9-12,14 Microscopic evidence of invasion of orbital soft

tissues and residual tumor at the surgical margin of the ON are uniformly accepted as high-risk factors.15,16 For many authors,5,17,18 but
not all,12 tumor involvement posterior to the lamina cribrosa is a
high-risk feature. Conversely, tumor involvement anterior to the lamina cribrosa is widely considered a low-risk feature.15-18 More controversial is the risk associated with tumor involving the ocular coats
and, in particular, isolated invasion of the choroid, since for some
authors, extensive choroidal involvement carries only a moderate
risk.9,10,12,19-21 When both choroidal and retrolaminar ON involvement are present, the risk is generally considered intermediate.9,12,17-19
Finally, invasion of the anterior segment has been reported to be a
moderate- to high-risk feature.13,21
Adjuvant chemotherapy and radiotherapy are uniformly recommended for patients with high-risk histologic features, such as residual
tumor at the surgical margin of the ON and/or microscopic orbital
disease.9,12,15,17 Some patients may also benefit from a more intensive
chemotherapeutic regimen with hematopoietic stem-cell rescue.6
However, there is no consensus on which other patients should receive
adjuvant chemotherapy or on the most effective chemotherapeutic
regimen.22 For patients with low- and intermediate-risk features, there
are no uniform protocols concerning the indication or regimen for
postoperative adjuvant chemotherapy, partially because of disparities
in defining and quantifying the risk features. Practices therefore vary
widely from one institution to another. The experience at the Institut
Curie does not support the use of adjuvant chemotherapy in patients
in the low-risk category (ie, those with prelaminar or no ON involvement and minor choroidal invasion)9 but strongly suggests it is needed
in intermediate-risk patients (ie, those with intra- or retrolaminar ON
involvement and/or massive choroidal involvement with or without
intrascleral invasion).
Over the years, the changing regimens, choice of drugs, and dose
reductions have primarily aimed at obtaining maximal efficacy by
using drugs that have proven effective in extraocular RB,7,8,16,21,23 and
at minimizing toxic adverse effects, including the potential risk of
second malignant neoplasms.

We report the results of a prospective study conducted by the

French Society for Pediatric Oncology (formerly SFOP, now
SFCE). Patients with intraocular unilateral RB treated by primary
enucleation were selectively included in centers across France. A
standardized approach to selecting the regimen for adjuvant therapy based on histopathologic risk factors was used in all centers,
with centralized reading to ensure homogeneous assessment. Patients in the low-risk category received no adjuvant chemotherapy,
those in the intermediate-risk group received moderately intensive
chemotherapy, and those in the high-risk group were to receive a
more intensive regimen that included autologous hematopoietic
stem-cell rescue and orbital irradiation. Overall survival and eventfree survival were assessed.
PATIENTS AND METHODS
This prospective, nonrandomized study was conducted in 14 centers in France
between May 2001 and November 2007. The study received ethics committee
approval and authorization from the French health authorities. Written informed consent was obtained from parents or legal guardians for participation
in the study and for constitutional DNA testing.
Eligible patients were those with nonhereditary unilateral RB presenting
as intraocular tumor requiring primary enucleation. The diagnosis of RB was
confirmed on examination of the ocular fundus under general anesthesia. All
patients were in group V according to the Reese-Ellsworth classification.24
Ocular and brain imaging were systematically performed at diagnosis to
rule out macroscopic extraocular invasion, by using ultrasound and either
computed tomography (CT) scan with contrast or gadolinium-enhanced
magnetic resonance imaging (MRI). In most cases, MRI was performed with
standard resolution. Later in the study, some patients underwent highresolution MRI obtained with orbit surface coils. A senior pediatric radiologist
prospectively reviewed all data, and a retrospective radiologic review was
performed at the end of the study, focusing on patients with retrolaminar ON
invasion on pathologic examination.
After enucleation, macroscopic and histologic examinations of the specimens were performed in each center, followed by prospective centralized
readings by a single pathologist. The specimens, prepared as previously reported,25 were examined by light microscopy for evidence of risk factors

Table 1. Histologic Risk Criteria

Eye Structures/Involvement
Choroid and sclera
No choroidal involvement
Minimal superficial
Minimal deep
Extensive deep (massive)
Intrascleral involvement
Extrascleral involvement
Optic nerve
No optic nerve involvement
Prelaminar
Intralaminar
Retrolaminar
Invasion of surgical margin
Anterior segment
Anterior segment involvement

www.jco.org

Criteria
Possible presence of tumor cells under the pigment epithelium but not beyond Bruchs membrane
Presence of at most three microscopic clusters of tumor cells beyond Bruchs membrane with no invasion of the
deeper vascular layers
Presence of a tumor cell cluster in contact with the sclera, with invasion of the vascular layers of the choroid
Presence of tumor cell clusters on several samples in the form of extensive bands, with involvement of the entire
choroid including the vascular layers and tumor cells in contact with the sclera
Presence of tumor cells within the sclera extending to one third to two thirds or to the entire thickness of the sclera
Presence of tumor cells extending to the entire thickness of the sclera with microscopic orbital involvement
Absence of tumor cells anywhere on the optic nerve
Presence of tumor cells on the optic disc or head of the optic nerve, not extending into the lamina cribrosa
Presence of tumor cells within the lamina cribrosa
Presence of tumor cells beyond the posterior margin of the lamina cribrosa but not extending to the resection line
of the optic nerve
Presence of tumor cells at the surgical margin of the optic nerve
Presence of tumor cells in the ciliary body or iris

2013 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on September 12, 2015. For personal use only. No other uses without permission.
Copyright 2013 American Society of Clinical Oncology. All rights reserved.

1459

Aerts et al

Table 2. Three-Level Risk Classification

Group

Criteria

Low risk
Intermediate risk
High risk

Minimal or no choroidal involvement and/or prelaminar involvement or absence of optic nerve involvement
Massive choroidal involvement and/or intra- and retrolaminar involvement and/or involvement of the anterior segment
Invasion of the surgical margin of the optic nerve and/or microscopic extrascleral involvement

Corresponding to stage II of new international retinoblastoma staging system.26

according to previously described criteria9 (Table 1). Patients were then assigned to one of three groups: low risk, intermediate risk or high risk (ie, stage
II of the international classification26; Table 2).
Patients in the intermediate- and high-risk groups underwent postoperative evaluation of distant metastasis, including lumbar puncture with examination of the cytospin and bone marrow cytology. These patients also
underwent hematologic, renal function, and hepatic function assessments, as
well as audiometry to determine their eligibility to receive one of two adjuvant
chemotherapy regimens (Table 3).
Patient follow-up in all three groups to monitor for disease progression
after treatment was essentially clinical, including monthly ophthalmologic
examination of the fundus oculi of the contralateral eye until age 18 months,
examination once every 2 months until age 2 years, and once every 3 months
thereafter. Patients in the intermediate- and high-risk groups were monitored
for chemotherapy-related toxicity by using the National Cancer Institute
Common Terminology Criteria for Adverse Events, version 2. Ototoxicity was
assessed by using Brocks grading system.27 Long-term sequelae were also
monitored, including annual audiometry, for 5 years. In addition, genetic
testing was routinely proposed to screen patients for RB1 gene sequence
alterations. Constitutional testing was performed as previously described.28
The sample size was estimated on the basis of expected overall survival of
96%, with 125 patients included over 5 years allowing calculation of the rate
with a precision of 2%. Overall and event-free survival were calculated by
using the Kaplan-Meier estimator and updated to June 2011.

Table 3. Chemotherapy Regimens, Intermediate- and High-Risk Groups

Drug

Dose (per day)

Intermediate-risk group
Etoposide
100 mg/m2 (3.3 mg/kg)
Carboplatin
160 mg/m2 (5.3 mg/kg)
Vincristine
1.5 mg/m2 (0.05 mg/kg)
Cyclophosphamide
300 mg/m2 (10 mg/kg)
High-risk group
Etoposide
100 mg/m2
Carboplatin
160 mg/m2
Thiotepa (intrathecal)
15 mg
Vincristine
1.5 mg/m2
Cyclophosphamide
1,000 mg/m2
CarboPEC
Etoposide
350 mg/m2
Carboplatin
350 mg/m2
Cyclophosphamide 1,600 mg/m2

Cycles
1 and 3
1 and 3
2 and 4
2 and 4

Days
1-5
1-5
1 and 5
1-5

1, 3, and 5
1, 3, and 5
1, 3, and 5
2, 4, and 6
2, 4, and 6

1-5
1-5
1
1
1-3

7
7
7

1-5
1-5
2-5

Treated in outpatient setting, cycles 21 days apart, and no supportive care

during therapy.
Dose adjusted in patients 1 year old and/or 10 kg.
Treated in outpatient setting only for cycles 1, 3, and 5; all cycles 21 days
apart. Supportive care during inpatient therapy: intravenous hydration, sodium
2-sulfanylethanesulfonate with cyclophosphamide, granulocyte-colony stimulating factor.
Followed by autologous hematopoietic stem-cell rescue on day 8.

1460

2013 by American Society of Clinical Oncology

RESULTS

A total of 123 patients (69 girls and 54 boys) were included, with a
median age of 23 months (range, 1 to 124 months) at enucleation. All
patients underwent initial radiologic examination, including CT scan
(59 patients), MRI scan (52 patients), or both (12 patients), which
confirmed the intraocular nature of the disease in all patients. The
median time to enucleation after onset of the initial signs of RB was 45
days (range, 6 to 1,045 days) in the 117 patients for whom the information was available. The initial signs were leukocoria in 69 patients
(56%), strabismus in 22 patients (18%), leukocoria and strabismus
in16 patients (13%), and other (13%). The median time from diagnosis to enucleation was 7 days (range, 0 to 45 days) in 121 patients and
15 days in 118 of 121 patients.
Histopathologic examination found low-risk features for 70
(57%) of 123 patients, intermediate-risk features for 52 patients
(42%), and high-risk features for one patient (1%). Histologic features
for the low-risk group are provided in Table 4 and for the
intermediate-risk group in Table 5. Postoperative evaluation of distant
metastasis was negative in all 53 patients with intermediate- or highrisk features.
In the subgroup of 12 patients with retrolaminar involvement,
retrospective review of radiologic data showed that in six patients
assessed by CT scan and in four patients assessed by conventional
MRI, imaging failed to detect ON abnormalities, whereas on pathologic examination, ON invasion was measured at between 0.7 and 2.5
mm beyond the lamina cribrosa. In two patients assessed by highresolution MRI, abnormal retrolaminar enhancement was retrospectively identified measuring 1 and 1.7 mm beyond the lamina cribrosa,
which is in good agreement with the pathologic findings (0.9 and 1.4
mm, respectively).
The patient in the high-risk group had massive choroidal involvement, and tumoral invasion at the surgical margin of the ON was
suspected. This patient underwent preoperative radiologic assessment

Table 4. Histologic Features in Low-Risk Group (n 70)

Feature

No Optic Nerve
Involvement

Prelaminar

Total

No choroidal involvement
Minimal choroidal involvement
Total

22
17
39

19
12
31

41
29
70

NOTE. Among the 70 patients, 41 (59%) had no choroidal involvement and 29

(41%) had minimal choroidal involvement; 39 patients (56%) had no optic
nerve involvement and 31 (44%) had prelaminar involvement; and 12 patients
(17%) had both choroidal and optic nerve involvement.

JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on September 12, 2015. For personal use only. No other uses without permission.
Copyright 2013 American Society of Clinical Oncology. All rights reserved.

Retinoblastoma: Adjuvant Treatment After Enucleation

Table 5. Histologic Features in Intermediate-Risk Group (n 52)

Involvement

No Optic Nerve Involvement

Prelaminar

Intralaminar

Retrolaminar

Total

No choroidal
Minimal superficial
Minimal deep
Extensive deep
Scleral
Total

2
1
5
6
0
14

0
0
6
5
0
11

6
3
2
2
2
15

1
2
2
7
0
12

9
6
15
20
2
52

NOTE. Among the 52 patients, nine (17%) had no choroidal involvement, six (12%) had minimal superficial involvement, 15 (29%) had minimal deep invasion,
20 (38%) had extensive deep invasion, and two (4%) had scleral invasion. Fourteen (27%) of the 52 patients had no optic nerve involvement, 11 (21%) had
prelaminar involvement, 15 (29%) had intralaminar involvement, and 12 (23%) had retrolaminar involvement. Seven (13%) had both retrolaminar and extensive
deep choroidal involvement.

Both patients also had anterior segment involvement.

Patient also had anterior segment involvement.
One patient also had anterior segment involvement.
One patient also had anterior segment involvement.

with CT scan alone, which failed to identify retrolaminar involvement.

Examination of the specimen by the central pathologist confirmed
that tumor cells were indeed present at the resection line, but they were
seen within the central ON vessels and not within the nerve fibers (Fig
1 and Appendix Fig A1, online only). After consultation with international experts, it was decided that the atypical high-risk histology did
not support a high risk of local relapse. Orbital radiotherapy, planned
in the protocol, was not performed. The patient nevertheless remained
in the high-risk group because of the risk of bone metastasis and
received six cycles of chemotherapy as planned, with carboplatin,
etoposide, and cyclophosphamide (CarboPEC) as consolidation.
In the intermediate-risk group, all 52 patients received four
courses of chemotherapy (as planned), with a median interval of 19
days (range, 11 to 88 days) between enucleation and initiation of the
first cycle. In total, 208 courses of chemotherapy were administered,
with a median total duration of 78 days (range, 66 to 95 days).
Toxicity
Expected hematotoxicity was observed in the intermediate-risk
group and in the high-risk patient. Only five serious adverse events

Fig 1. Transverse section of optic nerve resection margin (detail). Tumor is

present in the vessel (red arrow) but not in the surrounding nerve fibers.
www.jco.org

were reported in four patients in the intermediate-risk group: febrile

neutropenia and grade 4 mucositis in two patients, febrile neutropenia
with shock in one patient, vincristine-related sensory-motor neuropathy and septicemia due to Staphylococcus in one patient, and septicemia due to Pneumococcus in one patient. The high-risk patient
experienced three episodes of febrile neutropenia, including one with
septicemia due to Streptococcus. No deaths as a result of toxicity occurred. No late grade 3 or 4 ototoxicity was observed in the high-risk
patient or in the 36 intermediate-risk patients assessed. No late renal
toxicity was observed in the high-risk patient or in 18 intermediaterisk patients assessed.
Survival and Other Outcomes
Median follow-up time for the 123 patients was 71 months. One
patient with no histologic risk factors was lost to follow-up 4 months
after diagnosis. For the remaining 122 patients, post enucleation
follow-up ranged from 25 to 120 months. Median follow-up in the
intermediate-risk group was 56 months (range, 19 to 97 months); in
the high-risk patient, it was 68 months. No homolateral progression or
relapse of RB was observed, and no patients developed distant metastasis or second malignancy during the follow-up period. Secondary
bilateralization was observed in two patients: one in the low-risk group
11 months after enucleation in whom the primary tumor was diagnosed at 11 months of age, and one in the intermediate-risk group 14
months after enucleation in whom the primary tumor was diagnosed
at 4 months of age.
Genetic Tests
Molecular testing of the RB1 gene was performed in 100 (81%) of
123 patients. Constitutional RB1 mutations considered to be deleterious were identified in only nine patients (9%). In two of the nine
patients, metachronic bilateralization was observed. No cases of bilateralization were observed among the patients in whom no constitutional RB1 mutation was found.
Testing for somatic mutations was performed in 55 of 100 patients. In all 55 patients, both mutations were found to be somatic
events, and constitutional testing was negative. The mutations were
therefore considered to be postzygotic, and monitoring of siblings
could be lifted in these patients.
2013 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on September 12, 2015. For personal use only. No other uses without permission.
Copyright 2013 American Society of Clinical Oncology. All rights reserved.

1461

Aerts et al

Comments
The goal of adjuvant therapy after enucleation in patients with
unilateral RB is to prevent both local and distant relapses. The usual
approach is to identify patients with histopathologic risk factors on
examination of enucleated eyes and to provide adjuvant therapy
where appropriate. Our results indicate that this approach is effective,
since the overall survival rate, with a median 71 months of follow-up,
was 100%, and event-free survival was also 100% in our series of 123
patients. All patients underwent ophthalmologic follow-up, and secondary bilateralization was observed in only two patients, both of
whom had been diagnosed with RB before the age of 12 months and
were found to have constitutional RB1 mutations.
Only a few prospective studies have been performed that used
histologic risk factors as the basis for assigning adjuvant therapy.12,15,29
Our study differs somewhat from other studies in that we defined
three separate risk categories. In our series, 70 patients were assessed as
having low-risk features and received no adjuvant therapy. All of these
patients were alive with no disease dissemination at a median 51
months of follow-up. These results confirm the findings in other
studies29,30 that adjuvant therapy is not warranted in patients with
minimal or no choroidal involvement and/or prelaminar or no ON
involvement and no invasion of the anterior segment.
Our series also included 52 patients with intermediate-risk features who received four cycles of adjuvant chemotherapy. No relapses
or metastasis was observed with a median follow-up of 56
months. It is of particular note that in 10 of the 15 patients with
minimal deep choroidal involvement and in 12 of the 20 patients
with extensive deep choroidal involvement, invasion of the ocular
coat was not associated with either ON or anterior segment involvement. Thus, in our series, a total of 22 patients (42%) had
isolated deep (or massive) choroidal involvement. In a survey of
the literature, this particular subgroup has clearly been the focus of
much discussion concerning the need for adjuvant chemotherapy,
given that the relapse rate in patients in this subgroup who receive
no adjuvant therapy after enucleation is reportedly less than
5%.12,22,29 In addition, Chantada et al30 reported that, in a recent
study, only three (2.6%) of 114 patients with isolated choroidal
invasion developed relapse with no adjuvant therapy after enucleation. It is therefore conceivable that only a small proportion of the
22 patients in our series benefited from treatment, although the
others were exposed to avoidable toxicities. However, in our retrospective study,9 massive choroidal involvement was an identified
risk factor: the debate is between overtreating some patients by
providing adjuvant chemotherapy but without observing extraocular relapse versus not providing adjuvant chemotherapy and taking the risk of extraocular relapse, a life-threatening condition that
requires highly toxic treatment. Of course, our study, like all others, was not designed to compare adjuvant therapy versus no
adjuvant therapy within the intermediate-risk group or with regard to individual risk features taken in isolation: indeed, the
number of patients required for such a study makes it infeasible.
Only one patient in our series had high-risk features and received
six cycles of adjuvant chemotherapy followed by high-dose chemotherapy and hematopoietic stem-cell rescue. Because of the particular
nature of the ON involvement, the patient did not receive orbital
radiotherapy as planned in the protocol, but no local disease progression, relapse, or metastasis was observed at 68 months of follow-up.
However,theefficacyofadjuvanttherapyinvolvinganintensivechem1462

2013 by American Society of Clinical Oncology

otherapeutic regimen clearly cannot be assessed on the basis of a

single patient.
The main role of imaging in patients with RB is to rule out
extraocular extension. Extrascleral/orbital or regional lymph node
extension remain rare in developed countries, and the major issue for
radiologists is therefore to detect ON involvement. Our study is in
agreement with our previous results regarding the accuracy of preoperative imaging methods.31 Early-stage retrolaminar invasion (with
normal size ON) was not detected in the six patients assessed by CT
scan alone or in the four patients assessed by conventional MRI.
Conversely, high-resolution MRI, used in two patients, identified
subtle retrolaminar enhancement, which correlated well with
pathologic findings. The most recent imaging guidelines strongly
recommend the use of high-resolution MRI.32 The accuracy of highresolution MRI to differentiate intra- versus early retrolaminar invasion is not yet established, and pathology still remains the gold
standard. However, by using high-resolution MRI, it may be possible
to differentiate patients with early-stage retrolaminar invasion who
can be treated by primary enucleation from patients with more extensive retrolaminar invasion in whom front-line enucleation might lead
to microscopic residual tumor. Further studies are needed; however,
the use of high-resolution MRI for local staging at the time of diagnosis
could improve the prospect of complete tumor resection and inform
decisionsontherapeuticstrategies,includingneoadjuvantchemotherapy for either conservative treatment or locally advanced tumors.33
In a subsequent study by the French Society for Pediatric Cancer,
RB-SFCE 2009, which is currently enrolling patients with intraocular
unilateral RB treated by primary enucleation, we propose to use systematic high-resolution MRI for preoperative staging and a similar
standardized approach to assigning adjuvant therapy on the basis of
histologic risk factors. The three-level risk classification in this study
has been slightly modified. Patients with intralaminar involvement are
included in the low-risk group, according to the recent pathology
guidelines from the International Retinoblastoma Staging Working
Group.27 In the intermediate-risk group, we propose to de-escalate
adjuvant chemotherapy in patients with isolated massive choroidal
invasion and to provide these patients with only two cycles
of vincristine-carboplatin.
Furthermore, the workup for metastasis following enucleation
was negative in all 53 patients in the intermediate- and high-risk
groups. We propose, as others have,34,35 to select patients who require
screening and to perform the work-up only in stage II patients.26
This prospective study confirms that unilateral RB is rarely hereditary and that constitutional as well as somatic genetic studies
usefully contribute to the assessment of familial recurrence of RB and
to the follow-up of siblings.3
In conclusion, our study showed that risk assignment on the basis
of histopathologic features is an effective approach to selecting appropriate adjuvant therapy since all patients were alive and event-free at a
median 71 months of follow-up. Clearly, any effective strategy of
treatment adaptation based on risk factors relies on a thorough knowledge of which regimens are best adapted to the various risk features. A
prospective study has recently been started to further refine our standardized approach and to confirm the excellent results obtained in this
study, which indicate that adjuvant chemotherapy is safe and effective
overall, with no secondary cancer, and could be reduced in some
patients in the intermediate-risk group, particularly those with isolated choroidal involvement.
JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on September 12, 2015. For personal use only. No other uses without permission.
Copyright 2013 American Society of Clinical Oncology. All rights reserved.

Retinoblastoma: Adjuvant Treatment After Enucleation

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS

OF INTEREST
The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS
Conception and design: Xavier Sastre-Garau, Didier Frappaz, Carole
Coze, Laurence Desjardins, Francois Doz

REFERENCES
1. Blanquet V, Turleau C, Gross-Morand MS, et
al: Spectrum of germline mutations in the RB1 gene:
A study of 232 patients with hereditary and nonhereditary retinoblastoma. Hum Mol Genet 4:383-388,
1995
2. Lohmann DR: RB1 gene mutations in retinoblastoma. Hum Mutat 14:283-288, 1999
3. Aerts I, Lumbroso-Le Rouic L, Gauthier-Villars
M, et al: Retinoblastoma. Orphanet J Rare Dis 1:31,
2006
4. Howarth C, Meyer D, Hustu HO, et al: Stagerelated combined modality treatment of retinoblastoma: Results of a prospective study. Cancer 45:
851-858, 1980
5. Doz F, Khelfaoui F, Mosseri V, et al: The role
of chemotherapy in orbital involvement of retinoblastoma: The experience of a single institution with
33 patients. Cancer 74:722-732, 1994
6. Namouni F, Doz F, Tanguy ML, et al: Highdose chemotherapy with carboplatin, etoposide and
cyclophosphamide followed by a haematopoietic
stem cell rescue in patients with high-risk retinoblastoma: A SFOP and SFGM study. Eur J Cancer
33:2368-2375, 1997
7. Doz F, Neuenschwander S, Plantaz D, et al:
Etoposide and carboplatin in extraocular retinoblastoma: A study by the Societe Francaise dOncologie
Pediatrique. J Clin Oncol 13:902-909, 1995
8. Chantada G, Fandino A, Casak S, et al: Treatment of overt extraocular retinoblastoma. Med Pediatr Oncol 40:158-161, 2003
9. 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 77:1206-1213, 1996
10. Kopelman JE, McLean IW, Rosenberg SH:
Multivariate analysis of risk factors for metastasis in
retinoblastoma treated by enucleation. Ophthalmology 94:371-377, 1987
11. Messmer EP, Heinrich T, Hopping W, et al:
Risk factors for metastases in patients with retinoblastoma. Ophthalmology 98:136-141, 1991

Provision of study materials or patients: Isabelle Aerts, Xavier

Sastre-Garau, Livia Lumbroso-Le Rouic, Francois Doz
Collection and assembly of data: Isabelle Aerts, Xavier Sastre-Garau,
Livia Lumbroso-Le Rouic, Estelle Thebaud-Leculee, Didier Frappaz,
Carole Coze, Caroline Thomas, Marion Gauthier-Villars, Christine
Levy-Gabriel, Laurence Desjardins, Francois Doz
Data analysis and interpretation: Alexia Savignoni, Carole Coze, Herve
J. Brisse, Francois Doz
Manuscript writing: All authors
Final approval of manuscript: All authors

12. Schvartzman E, Chantada G, Fandino A, et al:

Results of a stage-based protocol for the treatment
of retinoblastoma. J Clin Oncol 14:1532-1536, 1996
13. Haik BG, Dunleavy SA, Cooke C, et al: Retinoblastoma with anterior chamber extension. Ophthalmology 94:367-370, 1985
14. Uusitalo MS, Van Quill KR, Scott IU, et al:
Evaluation of chemoprophylaxis in patients with
unilateral retinoblastoma with high-risk features on
histopathologic examination. Arch Ophthalmol 119:
41-48, 2001
15. Zelter M, Damel A, Gonzalez G, et al: A
prospective study on the treatment of retinoblastoma in 72 patients. Cancer 68:1685-1690, 1991
16. Freeman CR, Esseltine DL, Whitehead VM, et
al: Retinoblastoma: The case for radiotherapy and
for adjuvant chemotherapy. Cancer 46:1913-1918,
1980
17. Shields CL, Shields JA, Baez K, et al: Optic
nerve invasion of retinoblastoma: Metastatic potential and clinical risk factors. Cancer 73:692-698, 1994
18. Hungerford J: Factors influencing metastasis
in retinoblastoma. Br J Ophthalmol 77:541, 1993
19. Shields CL, Shields JA, Baez KA, et al:
Choroidal invasion of retinoblastoma: Metastatic
potential and clinical risk factors. Br J Ophthalmol
77:544-548, 1993
20. Redler LD, Ellsworth RM: Prognostic importance of choroidal invasion in retinoblastoma. Arch
Ophthalmol 90:294-296, 1973
21. Rubin CM, Robison LL, Cameron JD, et al:
Intraocular retinoblastoma group V: An analysis of
prognostic factors. J Clin Oncol 3:680-685, 1985
22. Chantada GL, Dunkel IJ, de Davila MT, et al:
Retinoblastoma patients with high risk ocular pathological features: Who needs adjuvant therapy? Br J
Ophthalmol 88:1069-1073, 2004
23. Pratt CB, Fontanesi J, Chenaille P, et al:
Chemotherapy for extraocular retinoblastoma. Pediatr Hematol Oncol 11:301-309, 1994
24. Reese AB, Ellsworth RM: The evaluation and
current concept of retinoblastoma therapy. Trans
Am Acad Ophthalmol Otolaryngol 67:164-172, 1963
25. Sastre X, Chantada GL, Doz F, et al: Proceedings of the consensus meetings from the Interna-

tional Retinoblastoma Staging Working Group on

the pathology guidelines for the examination of
enucleated eyes and evaluation of prognostic risk
factors in retinoblastoma. Arch Pathol Lab Med
133:1199-1202, 2009
26. Chantada G, Doz F, Antoneli CB, et al: A
proposal for an international retinoblastoma staging
system. Pediatr Blood Cancer 47:801-805, 2006
27. Brock PR, Bellman SC, Yeomans EC, et al:
Cisplatin ototoxicity in children: A practical grading
system. Med Pediatr Oncol 19:295-300, 1991
28. Houdayer C, Gauthier-Villars M, Lauge A, et al:
Comprehensive screening for constitutional RB1
mutations by DHPLC and QMPSF. Hum Mutat 23:
193-202, 2004
29. Chantada G, Fandino A, Davila MT, et al:
Results of a prospective study for the treatment of
retinoblastoma. Cancer 100:834-842, 2004
30. Chantada GL, Fandino A, Guitter MR, et al:
Results of a prospective study for the treatment of
unilateral retinoblastoma. Pediatr Blood Cancer 55:
60-66, 2010
31. Brisse HJ, Guesmi M, Aerts I, et al: Relevance
of CT and MRI in retinoblastoma for the diagnosis of
postlaminar invasion with normal-size optic nerve: A
retrospective study of 150 patients with histological
comparison. Pediatr Radiol 37:649-656, 2007
32. de Graaf P, Goricke S, Rodjan F, et al: Guidelines for imaging retinoblastoma: Imaging principles
and MRI standardization. Pediatr Radiol 42:2-14,
2012
33. Bellaton E, Bertozzi AI, Behar C, et al: Neoadjuvant chemotherapy for extensive unilateral retinoblastoma. Br J Ophthalmol 87:327-329, 2003
34. Azar D, Donaldson C, Dalla-Pozza L: Questioning the need for routine bone marrow aspiration and
lumbar puncture in patients with retinoblastoma.
Clin Experiment Ophthalmol 31:57-60, 2003
35. Zacharoulis S, Abramson DH, Dunkel IJ: More
aggressive bone marrow screening in retinoblastoma patients is not indicated: The Memorial SloanKettering Cancer Center experience. Pediatr Blood
Cancer 46:56-61, 2006

www.jco.org

2013 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on September 12, 2015. For personal use only. No other uses without permission.
Copyright 2013 American Society of Clinical Oncology. All rights reserved.

1463