Copyright © 2006 American Academy of Ophthalmology Published by Elsevier Inc.

Original Article

The International Classification of Retinoblastoma Predicts Chemoreduction Success

Carol L. Shields MD1, , Arman Mashayekhi MD1, Angela K. Au BS1, Craig Czyz MD1, Ann Leahey MD2, Anna T. Meadows MD2 and Jerry A. Shields MD1

1Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania.

2The Children’s 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 Reese–Ellsworth classification was created in the 1960s when external beam radiotherapy (EBRT) was the most popular conservative (nonenucleation) treatment.1 The Reese–Ellsworth 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 Reese–Ellsworth classification did not address the problem of subretinal seeding and did not differentiate between focal and diffuse vitreous seeding. For these reasons, the Reese–Ellsworth 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 Reese–Ellsworth 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 Children’s Hospital of Philadelphia, were identified. The eligibility criteria for treatment with CRD5 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 Reese–Ellsworth 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 Reese–Ellsworth classification and the ICRB were compared regarding their ability in predicting retinoblastoma success using CRD.

Table 1.

Reese–Ellsworth Classification for Conservative Treatment of Retinoblastoma

GroupLikelihood 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

GroupLikelihood 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

Group Subgroup Quick Reference Specific Features

D1  Subretinal seeds >3 mm from retinoblastoma

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, 1–10.6).

Table 3.

Success of Chemoreduction and Focal Treatments in 249 Consecutive Eyes Based on the Reese–Ellsworth Classification of Retinoblastoma

Reese–Ellsworth Group Major

Group*

Chemoreduction Success Number (%)

Reese–Ellsworth 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%)

Reese–Ellsworth Group Major

Group*

Chemoreduction Success Number (%)

Reese–Ellsworth Subgroup Major

Subgroup*

Chemoreduction Success Number (%)

IIIb (n = 6) 5 (83%)

IV (n = 37) 23 (62%) IVa (n = 22) 11 (50%)

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 Reese–Ellsworth classification (major groups) in 249 consecutive cases. B, Success rate based on the Reese–Ellsworth 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 Reese–Ellsworth 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 Reese–Ellsworth 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 Reese–Ellsworth classification as compared with our practical grouping system, which was intended to simplify retinoblastoma classification.12 We found the Reese–Ellsworth 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 Reese–Ellsworth 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 Children’s 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.

References

1 A.B. Reese and R.M. Ellsworth, The evaluation and current concept of retinoblastoma therapy, Trans Am Acad Ophthalmol Otolaryngol 67 (1963), pp. 164–172.2 J.E. Kingston, J.L. Hungerford, S.A. Madreperla and P.N. Plowman, Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma, Arch Ophthalmol 114 (1996), pp. 1339–1343. View Record in Scopus | Cited By in Scopus (135)3 B.L. Gallie, A. Budning and G. DeBoer et al., Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy, Arch Ophthalmol 114 (1996), pp. 1321–1328. View Record in Scopus | Cited By in Scopus (196)4 A.L. Murphree, J.G. Villablanca and W.F. Deegan III et al., Chemotherapy plus local treatment in the management of intraocular retinoblastoma, Arch Ophthalmol 114 (1996), pp. 1348–1356. View Record in Scopus | Cited By in Scopus (204)5 C.L. Shields, P. De Potter and B.P. Himelstein et al., Chemoreduction in the initial management of intraocular retinoblastoma, Arch Ophthalmol 114 (1996), pp. 1330–1338. View Record in Scopus | Cited By in Scopus (156)6 F.L. Ferris III and E.Y. Chew, A new era for the treatment of retinoblastoma, Arch Ophthalmol 114 (1996), p. 1412.7 C.L. Shields and J.A. Shields, Changing management of retinoblastoma, Clin Experiment Ophthalmol 32 (2004), pp. 345–346. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (3)8 C.L. Shields and J.A. Shields, Chemotherapy for retinoblastoma, Med Pediatr Oncol 38 (2002), pp. 377–378. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (8)9 C.L. Shields, A.T. Meadows, A.M. Leahey and J.A. Shields, Continuing challenges in the management of retinoblastoma with chemotherapy, Retina 24 (2004), pp. 849–862. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (42)10 C.L. Shields, S.G. Honavar and A.T. Meadows et al., Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation,

Am J Ophthalmol 133 (2002), pp. 657–664. Article | PDF (94 K) | View Record in Scopus | Cited By in Scopus (65)11 C.L. Shields, A. Mashayekhi and J. Cater et al., Chemoreduction for retinoblastoma: analysis of tumor control and risks for recurrence in 457 tumors, Am J Ophthalmol 138 (2004), pp. 329–337.

Article | PDF (119 K) | View Record in Scopus | Cited By in Scopus (19)12 C.L. Shields, A. Mashayekhi and H. Demirci et al., Practical approach to management of retinoblastoma, Arch Ophthalmol 122 (2004), pp. 729–735. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (17)13 A.L. Murphree, Intraocular retinoblastoma: the case for a new group classification, Ophthalmol Clin North Am 18 (2005), pp. 41–53 viii. View Record in Scopus | Cited By in Scopus (51)14 J.A. Shields and C.L. Shields, Intraocular Tumors: A Text and Atlas, Saunders, Philadelphia (1992), pp. 377–392.15 J.A. Shields and C.L. Shields, Atlas of Intraocular Tumors, Lippincott Williams & Wilkins, Philadelphia (1999), pp. 207–232. Full Text via CrossRef 16 J.A. Epstein, C.L. Shields and J.A. Shields, Trends in the management of retinoblastoma: evaluation of 1,196 consecutive eyes during 1974-2001, J Pediatr Ophthalmol Strabismus 40 (2003), pp. 196–203. View Record in Scopus | Cited By in Scopus (28)

17 J.A. Shields, C.L. Shields and A.T. Meadows, Chemoreduction in the management of

retinoblastoma, Am J Ophthalmol 140 (2005), pp. 505–506. Article | PDF (38 K) | View Record in Scopus | Cited By in Scopus (6)

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.