The Oncologist, Vol. 2, No. 1, 1–5,
February 1997
© 1997 AlphaMed Press
Proposal for a New Staging Scheme for Intraocular and Extraocular Retinoblastoma Based on an Analysis of 103 Globes
Charles B. Pratta,
James Fontanesib,,
Xiaolong Luc,,
David M. Parhamd,,
Jon Elfervige,
David Meyere
a Departments of Hematology/Oncology,
b Radiation Oncology,
c Biostatistics, and
d Pathology and
Laboratory Medicine, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA and
c Departments of Pediatrics,
b Radiation Oncology, and
d Pathology, University of Tennessee, Memphis School of Medicine, Memphis, Tennessee, USA and
c Vitreoretinal Foundation, Memphis, Tennessee, USA
Correspondence:
Charles B. Pratt, M.D., St. Jude Children’s Research Hospital, P.O. Box 318, Memphis, TN 38101-0318, USA. Telephone: 901-495-3300; Fax: 901-521-9005.
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ABSTRACT
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Management of retinoblastoma is highly individualized and depends heavily on grouping or staging. In view of evolving methods of imaging and treating retinoblastoma, we have developed and evaluated a revised staging scheme. We analyzed the survival data of 73 patients treated at St. Jude Children’s Research Hospital to compare the ability of the Reese-Ellsworth grouping system, the original St. Jude, and the modified St. Jude staging schemes to predict progression-free survival. None of the staging schemes significantly correlated with progression-free survival. This modified staging scheme provides an instrument for assessing the natural history of retinoblastoma based on ophthalmologic, other clinical, and imaging findings. Because it can identify patients at higher risk, the modified St. Jude scheme may be useful in selecting appropriate therapy regimens for children with retinoblastoma.
Key Words. Retinoblastoma • Reese-Ellsworth groupings • Staging • Outcome
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INTRODUCTION
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Dr. Algernon Reese and Dr. Robert Ellsworth, while they were at the Harkness Eye Institute in New York City, conceived a clinical groupings list for unilateral or bilateral retinoblastoma, describing their suitability for treatment with radiation therapy [1,2]. Most retinal specialists and radiation oncologists have accepted these groupings as the standard predictors of salvage of the vision and globes following radiation therapy.
In an early treatment protocol, St. Jude Children’s Research Hospital oncologists, pathologists, retinal surgeons and radiation oncologists developed a retinoblastoma staging scheme that considered both the ophthalmologic and histopathologic evidences of disease extent [3]. This scheme was applied to the treatment of more than 40 patients, as reported in 1980 [3]. Other reported staging schemes have been similar in content but have reflected diverse perceptions of the natural history of retinoblastoma, which extends from the retinal surface to involve extraretinal, orbital, and distant metastatic sites [4, 5]. An "international" staging system has also been utilized by various working groups (Stannard, personal communication).
Management of retinoblastoma is highly individualized, and depends heavily on staging or grouping. In light of the various modes of treatment that have evolved since 1970 and the improved diagnostic imaging detection of extraretinal disease, we have developed and evaluated a modified staging scheme, based on our previously reported scheme [3].
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SUBJECTS AND METHODS
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The medical records of 73 patients admitted to St. Jude Children’s Research Hospital between October, 1977 and January, 1992 were reviewed and patients were staged using a modified staging scheme, the original St. Jude scheme [3], and the Reese-Ellsworth groupings [1, 2] (Tables 1A, 1B, 1C
). Progression-free survival was defined from diagnosis to disease progression or death. For each staging system, patients were also grouped based on whether or not at least one eye with stage II or higher was involved. Progression-free survival was estimated by the method of Kaplan and Meier. The log rank test was used to compare survival curves between groups for each staging system. Staging was based on the initial fundus drawings made by a retinal surgeon, the pathology report of resected globe(s), and any other information related to the presence of metastatic disease, as determined by diagnostic imaging, physical examination, and funduscopic examinations. The original and modified staging schemes are shown in Table 1 for comparison with the Reese-Ellsworth groupings (for suitability of treatment of retinoblastoma with radiation therapy).
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RESULTS
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The various staging schemes were evaluated in 43 patients with unilateral disease and 30 patients with bilateral disease. Thus, a total of 103 globes were evaluated. Thirty-four of the patients were boys, and 39 were girls. The median age at diagnosis was 1 year, with a range of 0 to 7.8 years. The median follow-up was 12.5 years with a range of 3 to 18.3 years. Table 2 lists the demographics of the patient group and the median duration of follow-up. Table 3 indicates the distribution of the 73 patients in the modified St. Jude staging scheme and the Reese-Ellsworth groupings.
Sixty-six of 73 patients continue to survive progression-free (Fig. 1). There were nine failures among the 73 patients. Among the three patients with unilateral disease who died, one with stage IIA disease (modified system) was not treated for pneumonia, at his parent’s request; his disease was associated with constitutional abnormalities related to the 13q syndrome. Another patient, who also died of pneumonia and multiple congenital abnormalities, had gross motor and mental retardation and survived to the age of 8 years prior to the diagnosis of unilateral retinoblastoma which extended into the orbit (modified stage IIIC). Another patient had unilateral stage IID (modified St. Jude scheme) disease at diagnosis, followed by the development of metastatic disease. Twenty-six of 30 patients with bilateral disease survive. Two patients, with modified stage IIB-IB and IVB-IE retinoblastoma (right and left eyes, respectively), died of metastatic disease; two others died of second malignant neoplasms (osteosarcoma of the maxilla and Ewing sarcoma of the calcaneus, respectively).
The correlations between progression-free survival of patients and the three staging schemes, the Reese-Ellsworth groupings [1], the original St. Jude staging system [3], and the St. Jude modified staging scheme, were separately calculated. This data did not support a significant correlation between progression-free survival with any of the three systems (p = 0.17, p = 0.86, p = 0.26), respectively (Figs. 2, 3, 4).
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Figure 2. Progression-free survival of 73 patients using modified staging scheme, comparing patients with at least one eye with Stages II or higher and both eyes with Stage I or a healthy eye (p = 0.26).
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Figure 3. Progression-free survival of 73 patients using Reese-Ellsworth grouping system, comparing patients with Groups II, III, IV, V disease with patients with Stage I disease or a healthy eye (p = 0.17).
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Figure 4. Progression-free survival of 73 patients comparing Stage I or a healthy eye with Stage II-IV, using original St. Jude staging system (p = 0.86).
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DISCUSSION
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Retinoblastoma can have a rapid growth rate, which makes efficient diagnosis and treatment a matter of great importance. To date, few standard staging systems have categorized disease extending beyond the globe. Our modified staging system for retinoblastoma considers both intraocular and extraocular disease. This scheme provides a logical ophthalmologic as well as histopathologic description of unifocal, unilateral, multifocal, and bilateral retinoblastoma, reflecting the natural progression and the malignant nature of this disease by synthesizing clinical funduscopic findings, diagnostic imaging data, and overall clinical physical examination [6-14]. Additionally, its use will provide information regarding stages and sites of disease which may be used for communication among investigators.
Although the modified staging system presented here is complicated because it is subdivided into 16 categories, the extent of disease may be thought of in its four major categories. These are: tumor confined to the retina, extraretinal tumor confined to the globe, extrachoroidal tumor (which would include tumor in the emissaries-optic nerve-orbit), and distant metastatic disease. It is important to define these specific sites of disease because of the requirement for differing treatment modalities in relation to these various sites, and extent of tumor. For example, tumors confined to the retina (stage I) may require enucleation, cryotherapy, laser, or radiation. The extent of tumors confined to extraretinal areas of the globe (stage II) can only be diagnosed with certainty by the pathologist and may require chemotherapy following enucleation. Extrachoroidal tumor (stage III) should be treated with chemotherapy, and, in most instances, also with radiation therapy. For individuals presenting with distant disease (metastatic, stage IV) or who develop distant metastases after earlier treatment, chemotherapy and irradiation will become the most useful modalities of treatment. Presently, chemotherapy is being used as initial treatment at our institution and elsewhere for unilateral or bilateral retinoblastoma with Reese-Ellsworth groupings I-V, provided there is no evidence of disease involving the optic nerve or extraocular structures.
The Reese-Ellsworth groupings best predicted progression-free rather than overall survival in patients with retinoblastoma, yet it is fair to note that over half of the events had nothing to do with the presenting disease status of these patients. For patients with unilateral disease, only one of three events was disease-related (two patients died of pneumonia secondary to underlying conditions). For patients with bilateral disease, two deaths were due to second malignant neoplasms, probably related to the genetic abnormality and independent of the initial tumor stage. Evaluation of greater numbers of patients might lead to greater correlation of extent of presenting disease with progression-free survival.
Although the modified staging scheme is not superior statistically to the Reese-Ellsworth groupings [1,2] and the original St. Jude staging scheme [3] in predicting progression-free survival, this modified staging scheme should provide better information for assigning appropriate treatment and should lead to possible improvement in prognosis, treatment outcome, and progression-free survival.
Staging of retinoblastoma, just as that of other childhood and adult cancers, continues to change with greater emphasis on diagnostic imaging and pathology [15]. Thus, the staging schemes of today may be antiquated or obsolete in the near future and replaced by molecular markers more appropriate to changing clinical findings.
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ACKNOWLEDGMENT
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This work was supported by Cancer Center Grant (CORE) Grant CA-21765 and Solid Tumor Program Project Grant CA-23099 from the National Cancer Institute, and the American Lebanese Syrian Associated Charities (ALSAC).
The authors thank Jan Kelley and Peggy Vandiveer for typing of the manuscript, Sharon Naron for editorial assistance, and Katherine Poquette for technical assistance.
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REFERENCES
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accepted for publication December 4, 1996.
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Abstract
Introduction
