Copyright 2006 American Academy of Ophthalmology Published by Elsevier Inc.

Original Article
The International Classification of Retinoblastoma Predicts Chemoreduction Success
Carol L. Shields MD
1,
, Arman Mashayekhi MD
1
, Angela K. Au BS
1
, Craig Czyz MD
1
, Ann
Leahey MD
2
, Anna T. Meadows MD
2
and Jerry A. Shields MD
1

1
Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia,
Pennsylvania.
2
The Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania.

Received 9 November 2005;
accepted 20 June 2006.
Available online 25 September 2006.

Purpose
To evaluate the reliability of the International Classification of Retinoblastoma (ICRB) for predicting
treatment success with chemoreduction (CRD).
Design
Noncomparative interventional case series.
Participants
Two hundred forty-nine consecutive eyes.
Methods
All eyes were treated with CRD and were classified according to the ICRB: group A included those
eyes with retinoblastoma 3 mm; group B included those eyes with retinoblastoma >3 mm, macular
location, or minor subretinal fluid; group C included those eyes with retinoblastoma with localized
seeds; group D included those eyes with retinoblastoma with diffuse seeds; group E included those
eyes with massive retinoblastoma necessitating enucleation. The CRD regimen included vincristine,
etoposide, and carboplatin for 6 cycles plus local consolidation with thermotherapy or cryotherapy.
Main Outcome Measure
Chemoreduction success, defined as avoidance of external beam radiotherapy or enucleation.
Results
Of the 249 eyes, 23 (9%) were in group A, 96 (39%) were in group B, 21 (8%) were in group C, and
109 (44%) were in group D. In this series, group E eyes were managed with enucleation. Treatment
success was achieved in 100% of group A, 93% of group B, 90% of group C, and 47% of group D
eyes.
Conclusions
The ICRB can be of assistance in predicting CRD success for retinoblastoma. Additional treatment
methods are necessary to salvage more group D eyes.
Article Outline
Patients and Methods
Results
Discussion
References
In Paris in April, 2003, a new retinoblastoma classification was finalized by a group of retinoblastoma
experts. The primary goal for development of this new classification was to create a simpler, more
user-friendly classification that would be quick to recall and more applicable to current therapies such
as chemoreduction (CRD). The previously used ReeseEllsworth classification was created in the
1960s when external beam radiotherapy (EBRT) was the most popular conservative (nonenucleation)
treatment.
1
The ReeseEllsworth classification was based on location, multifocality, and size of the
tumor(s). At that time, peripheral retinoblastomas at the ora serrata, multifocal tumors, and larger
tumors were more difficult to treat than smaller, single macular tumors. Hence, peripheral, multifocal,
and large tumors were assumed to be more aggressive and earned a higher ranking in the Reese
Ellsworth classification, implying a worse ocular prognosis.
In the mid 1990s, there was a gradual shift in conservative treatment methods for retinoblastoma from
EBRT to CRD (combined with focal therapies).
[2], [3], [4] and [5]
This new treatment paradigm brought
solutions to old problems but also created new problems.
6
No longer were peripheral, multifocal, or
large tumors considered to have a worse prognosis than small, solitary macular tumors. In fact, it
became apparent that tumor location, multifocality, and size were not of major concern because CRD
was effective despite these variables. The limiting variables for retinoblastoma control in the CRD era
were different than in the EBRT era and related predominantly to the management of associated
vitreous and subretinal seeds.
[7], [8], [9], [10] and [11]
The ReeseEllsworth classification did not address the
problem of subretinal seeding and did not differentiate between focal and diffuse vitreous seeding. For
these reasons, the ReeseEllsworth classification was found to be a poor predictor of CRD success.
12

Therefore, a new classification for retinoblastoma was designed.
[12] and [13]
The new classification, the
International Classification of Retinoblastoma (ICRB), was based mainly on extent of tumor seeding in
the vitreous cavity and subretinal space with minor consideration of tumor size and location.
In previous reports, we explored CRD success based on the ReeseEllsworth classification. In this
analysis, we evaluated CRD success based on the new ICRB.
Patients and Methods
All new patients with retinoblastoma who were treated with initial CRD (Institutional Review Board
approved CHP no. 582) on the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson
University, in conjunction with the Division of Oncology at The Childrens Hospital of Philadelphia,
were identified. The eligibility criteria for treatment with CRD
5
were children with retinoblastoma in
whom either eye ordinarily would require enucleation or EBRT for cure of the disease based on
published indications.
[14] and [15]
Any patient whose tumor(s) could be controlled properly with focal
methods alone (cryotherapy, laser photocoagulation, thermotherapy, plaque radiotherapy) was not
eligible for inclusion in this study. An exception to this rule were bilateral cases in which the more
advanced eye necessitated CRD so the less advanced eye, which otherwise might have been treated
without CRD, was included in the CRD protocol.
Exclusion criteria for treatment with CRD, as documented by clinical, ultrasonographic, and
neuroimaging methods, included evidence of iris neovascularization, neovascular glaucoma, extensive
hyphema, extensive vitreous hemorrhage, or tumor invasion into the anterior chamber, iris, optic nerve,
choroid, or extraocular tissues. Exclusion criteria from a systemic standpoint included evidence of
systemic metastasis, prior chemotherapy, failure to thrive, or inadequate organ function of the kidney,
liver, or ear. Patients who received prior treatment for retinoblastoma were not included in this study.
The protocol chemotherapeutic agents included intravenous vincristine, etoposide, and carboplatin.
[5]
and [10]
Chemoreduction cycles were provided every 28 days for a total of 6 cycles. The potential risks
and benefits of the CRD protocol were discussed with the patient and his or her family, at which time
informed consent was obtained.
Each study eye was classified according to the ReeseEllsworth classification (Table 1) and the ICRB
(Table 2). Ocular oncology follow-up was provided with examination under anesthesia every 1 to 2
months after initiation of CRD until tumor control was achieved. Thereafter, examinations were
performed every 2 to 4 months as needed. Adjuvant treatment to the regressed retinoblastomas with
thermotherapy, cryotherapy, or both was provided under the guidelines of the CRD protocol. Minor
tumor recurrences were treated with thermotherapy, cryotherapy, or plaque radiotherapy. Major tumor
recurrences required EBRT or enucleation. The final ocular outcome of success (complete tumor
control without the need for additional EBRT or enucleation) or failure (need for EBRT or enucleation)
was recorded at the most recent examination. The ReeseEllsworth classification and the ICRB were
compared regarding their ability in predicting retinoblastoma success using CRD.
Table 1.
ReeseEllsworth Classification for Conservative Treatment of Retinoblastoma
Group
Likelihood of Globe Salvage

Features
I Very favorable
a) Solitary tumor, less than 4 disc diameters in size, at or behind
the equator

b) Multiple tumors, none more than 4 disc diameters in size, all at
or behind the equator
II Favorable
a) Solitary tumor, 4 to 10 disc diameters in size, at or behind the
equator
Group
Likelihood of Globe Salvage

Features

b) Multiple tumors, 4 to 10 disc diameters in size, behind the
equator
III Doubtful a) Any lesion anterior to the equator

b) Solitary tumors larger than 10 disc diameters behind the
equator
IV Unfavorable a) Multiple tumors, some larger than 10 disc diameters

b) Any lesion extending anteriorly to the ora serrata
V Very unfavorable a) Massive tumors involving over half the retina

b) Vitreous seeding
Refers to chances of salvaging the affected eye and not systemic prognosis.


Table 2.
International Classification of Retinoblastoma
Group Subgroup Quick Reference Specific Features
A A Small tumor
Retinoblastoma 3 mm in size
B B Larger tumor
Retinoblastoma >3 mm in size or

Macula Macular retinoblastoma location (3 mm to foveola)

Juxtapapillary Juxtapapillary retinoblastoma location (1.5 mm to disc)

Subretinal fluid Clear subretinal fluid 3 mm from margin
C

Focal seeds Retinoblastoma with

C1

Subretinal seeds 3 mm from retinoblastoma

C2

Vitreous seeds 3 mm from retinoblastoma

C3

Both subretinal and vitreous seeds 3 mm from
retinoblastoma
D

Diffuse seeds Retinoblastoma with

D1

Subretinal seeds >3 mm from retinoblastoma
Group Subgroup Quick Reference Specific Features

D2

Vitreous seeds >3 mm from retinoblastoma

D3

Both subretinal and vitreous seeds >3 mm from
retinoblastoma
E E
Extensive
retinoblastoma
Extensive retinoblastoma occupying >50% globe or

Neovascular glaucoma

Opaque media from hemorrhage in anterior chamber,
vitreous, or subretinal space

Invasion of postlaminar optic nerve, choroid (>2 mm),
sclera, orbit, anterior chamber
Refers to 3 mm in basal dimension or thickness.


Results
Between July, 1994, and June, 2004, 249 eyes of 163 patients were treated with the CRD protocol
[5] and
[10]
and were included in this study. The percent success for each group and subgroup of the Reese
Ellsworth (Table 1) and ICRB (Table 2) classifications are listed in Table 3 and Table 4, respectively
(Figure 1 and Figure 2). The mean patient follow-up was 6.2 years (median, 6.2; range, 110.6).
Table 3.
Success of Chemoreduction and Focal Treatments in 249 Consecutive Eyes Based on the Reese
Ellsworth Classification of Retinoblastoma
ReeseEllsworth
Group Major
Group*
Chemoreduction
Success Number (%)
ReeseEllsworth
Subgroup Major
Subgroup*
Chemoreduction
Success Number (%)
I (n = 27) 25 (93%) Ia (n = 14) 14 (100%)

Ib (n = 13) 11 (85%)
II (n = 53) 46 (88%) IIa (n = 37) 31 (84%)

IIb (n = 16) 15 (94%)
III (n = 78) 65 (83%) IIIa (n = 72) 60 (83%)

IIIb (n = 6) 5 (83%)
IV (n = 37) 23 (62%) IVa (n = 22) 11 (50%)
ReeseEllsworth
Group Major
Group*
Chemoreduction
Success Number (%)
ReeseEllsworth
Subgroup Major
Subgroup*
Chemoreduction
Success Number (%)

IVb (n = 15) 12 (80%)
V (n = 54) 23 (43%) Va (n = 9) 3 (33%)

Vb (n = 45) 20 (44%)



Table 4.
Success of Chemoreduction and Focal Treatment in 249 Consecutive Eyes Based on the International
Classification of Retinoblastoma
International
Classification of
Retinoblastoma Major
Group
Chemoreduction
Success Number (%)
International
Classification of
Retinoblastoma Minor
Subgroup
Chemoreduction
Success Number (%)
A (n = 23) 23 (100%) A (n = 23) 23 (100%)
B (n = 96) 89 (93%) B (n = 96) 89 (93%)
C (n = 21) 19 (90%) C1 (n = 6) 6 (100%)

C2 (n = 14) 13 (93%)

C3 (n = 1) 0 (0%)
D (n = 109) 51 (47%) D1 (n = 82) 47 (57%)

D2 (n = 10) 3 (30%)

D3 (n = 17) 1 (6%)
Group E eyes were not included in this analysis because all were managed with enucleation.



Full-size image (56K)
Figure 1. A, Success rate of chemoreduction for retinoblastoma based on the ReeseEllsworth
classification (major groups) in 249 consecutive cases. B, Success rate based on the ReeseEllsworth
classification (minor subgroups) in 249 consecutive cases.



Full-size image (102K)
Figure 2. A, Success rate of chemoreduction for retinoblastoma based on the International
Classification of Retinoblastoma (major groups) in 249 consecutive cases. B, Success rate based on the
International Classification of Retinoblastoma (minor subgroups) in 249 consecutive cases. There was
only one eye in group C3, and that eye failed.


When assessing the eyes using the 5 major ReeseEllsworth groups, success was achieved in 93% of
group I, 88% of group II, 83% of group III, 62% of group IV, and 43% of group V (Table 3, Fig 1).
When assessing the 10 subcategory groups of the ReeseEllsworth classification, there was anomalous
correlation, and the success for each group is listed in Table 3. Group IIb fared slightly better than
groups Ib and IIa, group IVb fared better than group IVa, and group Vb fared better than group Va.
Groups Ib, IIa, IIIa, IIIb, and IVb showed approximately the same success rate, minimizing the
predictive properties of each group.
The 5 major groups in the ICRB showed a progressive decrease in success rate from group A to group
D as follows: 100% success for group A, 93% for group B, 90% for group C, and 47% success for
group D (Table 4, Fig 2). Group E eyes were not eligible for CRD and usually were managed by
primary enucleation. When assessing the subcategory groups of the ICRB, there was a decreasing trend
for success with each group as listed in Table 4 (Fig 2). Group C3 contained only 1 patient and this
caused an obvious aberration in Figure 2; however, other subgroups, such as groups D1, D2, and D3,
showed reliable correlation because patient numbers were greater.
There was no incidence of chemotherapy-related toxicities of kidney or auditory function. There was
no case of chemotherapy-related second cancer during the period of this study.
Discussion
The ICRB was designed to simplify retinoblastoma classification and to predict treatment success with
current methods, specifically CRD.
[12], [13] and [16]
This classification was not intended to predict life
prognosis or visual outcome. It was intended to predict globe outcome, specifically, avoidance
probability of enucleation and EBRT after CRD. In this study, we have shown that the ICRB is
predictive of globe outcome after CRD. Patients within groups A, B, and C had a considerable chance
for globe salvage and avoidance of EBRT. Patients within group D had a much lower chance of
success, with approximately one half requiring EBRT or enucleation.
In 2003, we published an analysis of the success of CRD using the ReeseEllsworth classification as
compared with our practical grouping system, which was intended to simplify retinoblastoma
classification.
12
We found the ReeseEllsworth classification to be relatively reliable in predicting
globe outcome using the major classification categories, but less reliable when using the subcategories.
Based on that classification, several more advanced eyes fared better than less advanced eyes. Our
practical grouping system showed reliable predictability for treatment success in both the major
categories and subcategories. In this current analysis, with a larger study group, the ReeseEllsworth
classification produced similar results as previous studies, displaying reliability within the major
categories and unreliability within the subcategories. The ICRB showed consistent predictability for
CRD success within the major categories and fairly consistent reliability within the subcategories.
The clinical judgment of tumor seeds and subretinal fluid is important. Eyes with extensive subretinal
fluid typically show subretinal seeds, whether the seeds are coarse or fine. Increasing amount of
subretinal fluid correlates with increasing risk for subretinal seeds (Mashayekhi A, Shields CL, Czyz C,
Shields JA. Subretinal fluid in retinoblastoma: correlation with clinical findings and outcome of
treatment using chemoreduction. Paper presented at: AAO Annual Meeting, October 18, 2005;
Chicago, Illinois). In this analysis, eyes with subretinal fluid more than 3 mm from the tumor, with or
without visible subretinal seeds, were graded as group D1.
The difference between group C and D eyes depends on the distance of subretinal or vitreous seeds, or
both, being 3 mm or less from the tumor (group C) versus more than 3 mm from the tumor (group D).
During the development of the ICRB, there was discussion regarding whether the cutoff variable
should be 3 mm or 6 mm. In this analysis, we evaluated the 249 eyes using the 3-mm parameter. Out of
interest, we also investigated the 6-mm cutoff parameter and found similar results, with success in
100% of group A (23/23 eyes), 93% of group B (89/96 eyes), 88% of group C (29/33 eyes), and 42%
of group D (41/97 eyes). For the subgroups, the 6-mm cutoff results were similar to the 3-mm results,
because success was achieved in 100% of group A (23/23 eyes), 93% of group B (89/96 eyes), 89% of
C1 (16/18 eyes), 93% of C2 (13/14 eyes), 0% of C3 (0/1 eye), 53% of D1 (37/70 eyes), 30% of D2
(3/10 eyes), and 6% of D3 (1/17 eyes).
A national collaborative retinoblastoma study is planned for the near future in the United States. This
study, funded by the Childrens Oncology Group, will assess 3 major outcomes of chemotherapy for
retinoblastoma, based on the ICRB. These studies include: (1) a single-arm trial of systemic
chemotherapy (vincristine, etoposide, carboplatin) for high-risk retinoblastoma showing
histopathologic features of invasion of the choroid, optic nerve, or orbit after enucleation; (2) a single-
arm trial of systemic CRD (vincristine and carboplatin) for group B retinoblastoma; (3) a single-arm
trial of systemic CRD (vincristine, etoposide, carboplatin) and sub-Tenon chemotherapy (carboplatin)
for groups C and D retinoblastoma. Our understanding of the role of CRD in the management of
retinoblastoma,
17
particularly in group D eyes, will improve with this collaborative effort.
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Manuscript no. 2005-1095.Supported by a donation from Michael, Bruce, and Ellen Ratner, New York,
New York (JAS, CLS); the Paul Kayser International Award of Merit in Retina Research, Houston,
Texas (JAS); the National Institutes of Health, Bethesda, Maryland (NIH R25 training grant [AKA]);
Mellon Charitable Giving from the Martha W. Rogers Charitable Trust, Philadelphia, Pennsylvania
(CLS); the Macula Foundation, New York, New York (CLS); and the Eye Tumor Research
Foundation, Philadelphia, Pennsylvania (CLS, JAS).
Reprint requests to Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Hospital,
840 Walnut Street, Philadelphia, PA 19107.