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Table 1. 
Chemoreduction Regimen and Doses for Intraocular Retinoblastoma
Chemoreduction Regimen and Doses for Intraocular Retinoblastoma
Table 2. 
Stratification of 30 Consecutive Patients Based on Reese-Ellsworth Group
Stratification of 30 Consecutive Patients Based on Reese-Ellsworth Group
Table 3. 
Baseline Tumor Features
Baseline Tumor Features
Table 4. 
Overview of Chemoreduction Failure and Need for External Beam Radiotherapy and/or Enucleation*
Overview of Chemoreduction Failure and Need for External Beam Radiotherapy and/or Enucleation*
Table 5. 
Reasons for External Beam Radiotherapy or Enucleation in 30 Consecutive Patients
Reasons for External Beam Radiotherapy or Enucleation in 30 Consecutive Patients
Table 6. 
Univariate Analysis of Clinical Factors Predictive of the Need for External Beam Radiotherapy or Enucleation*
Univariate Analysis of Clinical Factors Predictive of the Need for External Beam Radiotherapy or Enucleation*
Table 7. 
Final VA Related to RE Classification and Proximity of Tumor to Foveola at Initial Examination*
Final VA Related to RE Classification and Proximity of Tumor to Foveola at Initial Examination*
1.
Shields  JAShields  CL Management and prognosis of retinoblastoma. Intraocular Tumors: A Text and Atlas. Philadelphia, Pa WB Saunders Co1992;377- 391
2.
Shields  JAShields  CL Retinoblastoma. Atlas of Intraocular Tumors. Philadelphia, Pa Lippincott Williams & Wilkins1999;207- 232
3.
Shields  CLShields  JA Recent developments in the management of retinoblastoma. J Pediatr Ophthalmol Strabismus. 1999;368- 18
4.
Sanders  BMDraper  GJKingston  JE Retinoblastoma in Great Britain 1969-80: incidence, treatment, and survival. Br J Ophthalmol. 1988;72576- 583Article
5.
Shields  JAShields  CLSivalingam  V Decreasing frequency of enucleation in patients with retinoblastoma. Am J Ophthalmol. 1989;108185- 188
6.
Abramson  DHMarks  RFEllsworth  RMTretter  PKitchin  FD The management of unilateral retinoblastoma without primary enucleation. Arch Ophthalmol. 1982;1001249- 1252Article
7.
Kingston  JEHungerford  JLMadreperla  SAPlowman  PN Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol. 1996;1141339- 1343Article
8.
Gallie  BLBudning  ADeBoer  G  et al.  Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiation. Arch Ophthalmol. 1996;1141321- 1328Article
9.
Murphree  ALVillablanca  JGDeegan  WF  III  et al.  Chemotherapy plus local treatment in the managment of intraocular retinoblastoma. Arch Ophthalmol. 1996;1141348- 1356Article
10.
Shields  CLDePotter  PHimelstein  BShields  JAMeadows  ATMaris  JM Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol. 1996;1141330- 1338Article
11.
Shields  CLShields  JANeedle  M  et al.  Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma. Ophthalmology. 1997;1042101- 2111Article
12.
Friedman  DLHimelstein  BShields  CL  et al.  Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol. 2000;1812- 17
13.
Shields  CLSantos  CDiniz  W  et al.  Thermotherapy for retinoblastoma. Arch Ophthalmol. 1999;117885- 893Article
14.
Shields  CLHonavar  SGShields  JADemirci  HMeadows  ATNaduvilath  TJ Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol. 2002;120460- 464Article
15.
Abramson  DHServodidio  CA Retinoblastoma in the first year of life. Ophthalmic Paediatr Genet. 1992;13191- 203Article
16.
Shields  CLShields  JAMeadows  AT Chemoreduction for retinoblastoma may prevent trilateral retinoblastoma[letter]. J Clin Oncol. 2000;18236- 237
17.
Shields  CLMeadows  ATShields  JACarvalho  CSmith  AF Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol. 2001;1191269- 1272Article
18.
Abramson  DHServodidio  CADe Lillo  ARGamell  LSKruger  EFMcCormick  B Recurrence of unilateral retinoblastoma following radiation therapy. Ophthalmic Genet. 1994;15107- 113Article
Clinical Sciences
December 2002

Chemoreduction for Unilateral Retinoblastoma

Author Affiliations

From the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University (Drs C. L. Shields, Honavar, J. A. Shields, and Demirci), and the Division of Oncology, The Children's Hospital of Philadelphia (Dr Meadows), Philadelphia, Pa; and the Ocular Oncology Service, LV Prasad Eye Institute, Hyderabad, India (Dr Honavar and Mr Naduvilath).

Arch Ophthalmol. 2002;120(12):1653-1658. doi:10.1001/archopht.120.12.1653
Abstract

Objective  To evaluate conservative management of unilateral retinoblastoma using chemoreduction and focal treatment.

Design  Prospective nonrandomized single-center clinical trial.

Setting  Ocular Oncology Service at Wills Eye Hospital of Thomas Jefferson University, Philadelphia, Pa, in conjunction with the Division of Oncology at The Children's Hospital of Philadelphia.

Participants  Thirty eyes of 30 patients with unilateral retinoblastoma treated with chemoreduction between June 1, 1994, and August 31, 1999, that would otherwise have been managed with enucleation or external beam radiotherapy.

Intervention  All patients received treatment for retinoblastoma with a planned 6 cycles of chemoreduction using vincristine sulfate, etoposide, and carboplatin, combined with focal treatment (cryotherapy or thermotherapy) to each retinal tumor.

Main Outcome Measures  The main outcome measure was the postchemoreduction need for external beam radiotherapy or enucleation. The cumulative probability of each outcome was estimated using Kaplan-Meier survival analysis. A secondary outcome measure was final visual acuity in the affected eye. The clinical features at the time of patient presentation were analyzed for their impact on the main outcomes using a series of Fisher exact tests and Cox proportional hazards regressions.

Results  Eighteen eyes (60%) were classified as having Reese-Ellsworth (RE) groups I through IV retinoblastoma and 12 eyes (40%), group V retinoblastoma. By using Kaplan-Meier estimates, we found a need for either external beam radiotherapy or enucleation in 68% of eyes by 5 years. In fact, 38% of those in groups I through IV required either treatment, whereas all of those in group V required the additional use of either treatment. Specifically, the need for external beam radiotherapy occurred in 27% of eyes by 5 years. Eleven percent of those in groups I through IV and 50% of group V required external beam radiotherapy by 5 years. The factors predictive of the need for external beam radiotherapy included RE group V disease, tumor thickness greater than 5 mm, and presence of vitreous seeds. The need for enucleation occurred in 47% of eyes by 5 years using Kaplan-Meier analysis. Specifically, 29% of those in groups I through IV and 67% of group V required enucleation by 5 years. The factors predictive of the need for enucleation included age at diagnosis older than 12 months, RE group V disease, tumor base diameter greater than 15 mm, and tumor thickness greater than 5 mm.At a mean follow-up of 29 months, the final visual acuity was 20/200 or better in 6 eyes (20%) and worse than 20/200 in 14 (47%); enucleation was needed in 10 (33%). Of the 26 eyes with initial macular involvement of retinoblastoma, final visual acuity was 20/200 or better in 6 (23%). No patient developed retinoblastoma metastasis, pinealoblastoma, or second malignant neoplasms.

Conclusions  Chemoreduction is an option for selected eyes with unilateral retinoblastoma. Those with advanced RE group V retinoblastoma showed poorest results, while those with less advanced groups I through IV disease showed best results, maintaining the globe in 71% of eyes, sometimes with satisfactory functional visual acuity.

THE MANAGEMENT of retinoblastoma depends on many factors, including size and location of the tumor(s) and associated features such as vitreous or subretinal seeds, retinal detachment, and neovascular glaucoma.13 Additional features that affect ultimate therapeutic choice include patient age and tumor laterality. Retinoblastoma occurs as a unilateral condition in approximately 60% to 70% of cases.4 Historically, most patients with unilateral retinoblastoma have been treated with enucleation1,3,5 (also John Epstein, MD, unpublished data, March 2002). Previous attempts to salvage the eye with unilateral retinoblastoma by using conservative treatment (primarily radiotherapy) proved successful in only 13% of those with Reese-Ellsworth(RE) groups I through III and in none of those with groups IV and V retinoblastoma.6 More recently, chemoreduction has become an important therapeutic tool in the management of retinoblastoma.1,712 Chemoreduction is most commonly used for children with bilateral disease. However, its usefulness for children with unilateral disease has not been specifically explored. In this report, we analyze the results of chemoreduction and focal treatments for patients with unilateral retinoblastoma, most with advanced RE groups IV or V disease.

METHODS

All new patients with unilateral retinoblastoma who were treated with initial chemoreduction (Table 1)from June 1, 1994, to August 31, 1999, on the Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pa, in conjunction with the Division of Oncology at The Children's Hospital of Philadelphia were enrolled for this prospective clinical trial. The eligibility criteria for inclusion were children with intraocular retinoblastoma in whom either eye would ordinarily require enucleation or external beam radiotherapy for cure of the disease on the basis of published indications.1,3,10,11 Any patient whose tumor(s) could be controlled with conservative methods alone(cryotherapy, laser photocoagulation, thermotherapy, or plaque radiotherapy) was not eligible for inclusion in the chemotherapy protocol. Exclusion criteria for treatment with chemoreduction also included biomicroscopic evidence of iris neovascularization; neovascular glaucoma; tumor invasion into the anterior chamber, iris, optic nerve, choroid, or extraocular tissues as documented by clinical, ultrasonographic, and neuroimaging modalities; or any eye in which ultimate vision recovery was deemed hopeless. Patients with evidence of systemic metastasis, previous chemotherapy, previous treatment for retinoblastoma, or inadequate renal, hepatic, or auditory function were also excluded.

All data were collected in a prospective fashion. We performed photographic and ultrasonographic documentation of the eye with retinoblastoma and evaluated each patient for age at diagnosis, race, sex, and hereditary pattern. The eye was assessed for tumor growth pattern (endophytic, exophytic, intraretinal, or diffuse) and RE classification.1,3 We measured the retinoblastoma for greatest basal dimension by means of indirect ophthalmoscopic techniques and thickness by means of A-scan and B-scan ultrasonography. We recorded the proximity of the nearest tumor margin to the optic disc and foveola, and the tumor was classified as macular if a margin was within 3 mm of the foveola.

The chemoreduction protocol was approved by The Children's Hospital of Philadelphia Committee for the Protection of Human Subjects. We discussed the potential risks and benefits of chemoreduction with the patients' parents or guardians and obtained signed informed consent. The chemotherapeutic agents were used for a planned 6 cycles and included intravenous vincristine sulfate, etoposide, and carboplatin as given in Table 1. Ocular oncologic follow-up was provided at examination with the patient under anesthesia, every month after initiation of chemoreduction until complete control of the disease was achieved. Thereafter, we performed an examination every 2 to 4 months as needed. At each examination, we measured the base diameter and thickness of the retinoblastoma. We also noted the status of vitreous and subretinal seeds and the presence and extent of serous retinal detachment. When maximum tumor regression was achieved, usually at cycle 2 or 3, we applied focal treatment using thermotherapy or cryotherapy, coupled with chemoreduction,1,13 to each retinal tumor. Recurrent retinal tumor, vitreous seeds, and subretinal seeds were identified on follow-up and treated with methods that included cryotherapy, thermotherapy, laser photocoagulation, and plaque radiotherapy, to avoid external beam radiotherapy and enucleation. In general, we managed retinal tumor recurrence by using methods other than external beam radiotherapy or enucleation if the recurrent retinal tumor was less than 9 mm thick and 15 mm across the base, if the recurrent subretinal seeds numbered fewer than 20 and were scattered throughout the fundus, or if the recurrent subretinal or vitreous seed involved confluently no more than 1 quadrant of the fundus. On the other hand, external beam radiotherapy or enucleation was deemed necessary if the recurrent retinal tumor was larger than 9 mm thick and 15 mm across the base, if the recurrent subretinal seeds numbered more than 20 seeds and were scattered throughout the fundus, or if recurrent subretinal or vitreous seeds involved 2 or more confluent quadrants of the fundus. We considered the final ocular outcome to be a success if chemoreduction and focal treatment measures controlled the retinoblastoma, but to be a failure if external beam radiotherapy or enucleation were necessary.

The clinical data were analyzed with regard to the following 2 main outcome measures: (1) failure of chemoreduction plus focal therapy with the need for external beam radiotherapy, and (2) failure of chemoreduction plus focal therapy with the need for enucleation. We estimated the cumulative probability of surviving the outcome by using Kaplan-Meier survival analysis. We tested the equality of survival distribution between different levels of an independent factor by using the log-rank test. The effect of each individual clinical variable recorded at the time of patient presentation to the Ocular Oncology Service on the development of these outcomes was analyzed by comparing the incidences within different levels of a factor using Fisher exact and χ2 tests, wherever applicable. The risk of developing the outcome relative to the different levels of the independent factor, measured as relative risk, was estimated using univariable Cox regressions. The likelihood ratio test and the 95% confidence intervals derived from the Cox regression analysis denoted the statistical significance of the association of each factor. Because of the small sample size, we did not perform multivariable analyses, and inferences were considered significant at P≤.10.

RESULTS

Thirty patients with unilateral retinoblastoma were enrolled in this chemoreduction protocol. The mean patient age at presentation and induction of chemotherapy was 16 months (median, 11 months; range, 1-72 months). Twenty patients (67%) were male and 10 (33%) were female. Twenty-three patients (77%) were white; 4 (13%), African American; and 3 (10%), Hispanic. The disease was familial in 3 patients (10%) and sporadic in 27 (90%). The disease was unifocal in 26 eyes (87%) and multifocal in 4 (13%). Only 1 of the 4 eyes with multifocal disease had familial retinoblastoma. Each eye was grouped according to the RE classification1,3 as listed in Table 2. Of the 9 eyes classified as RE group II, chemoreduction was selected because of the macular or juxtapapillary location of the tumor as well as the presence of subretinal fluid and active subretinal seeds. Two of these patients had familial retinoblastoma, and chemoreduction was used for the additional benefit of chemoprevention of new tumors. Plaque radiotherapy was not an option in these 9 cases.

The clinical features of the tumors in each eye are listed in Table 3. The mean tumor base diameter was 14.5 mm (median, 14.0 mm; range, 8.0-25.0 mm) and mean tumor thickness was 7.2 mm (median, 7.1 mm; range, 3.5-13.4 mm). At the initial examination, retinoblastoma seeding was clinically apparent in the vitreous in 11 eyes (37%) and subretinal space in 21 (70%). The vitreous seeds involved a mean of 5 clock hours (median, 4 clock hours; range, 1-12 clock hours). The seeds were localized over the apex of the tumor in 6 eyes (55%) and were diffuse throughout the vitreous in 5 (45%). There were no eyes with vitreous seeds anterior to the ora serrata. Subretinal fluid was present in 21 eyes (70%), involved a mean of 43% of the retina (median, 40%), and extended for a mean of 7.2 clock hours. The subretinal fluid extended under half of the retina in 7 eyes and under the entire retina(total detachment) in 2. Subretinal seeds involved a mean of 5 clock hours(median, 5 clock hours; range, 1-12 clock hours).

The patients received chemoreduction, as detailed already, using vincristine, etoposide, and carboplatin for a mean of 6 cycles (median, 6 cycles; range, 2-6 cycles) and were subsequently followed up for a median of 23 months (mean, 29 months; range, 6-63 months). Of the 30 eyes, fewer than 6 cycles were given for reasons of poor tumor response in 5 eyes (17%), patient or family compliance difficulties in 1 (3%), and family preference owing to excellent control in 1 (3%).

Of the 30 eyes, 27% required external beam radiotherapy and 47% required enucleation by 5 years after treatment, using Kaplan-Meier analysis. External beam radiotherapy or enucleation was needed in 68% of patients by 5 years(Table 4 and Table 5). Of those eyes classified as RE groups I through III, external beam radiotherapy or enucleation was necessary in less than 11% by 5 years. External beam radiotherapy or enucleation was necessary in 60% of those classified as RE group IV and 100% of those classified as RE group V by 5 years.

Of the 18 eyes classified as RE groups I through IV, 11% required external beam radiotherapy and 29% required enucleation by 5 years using Kaplan-Meier analysis. Of those classified as RE group V, external beam radiotherapy was necessary in 50% and enucleation in 67% by 5 years (Table 4). The median time from chemoreduction initiation to external beam radiotherapy was 3 months (mean, 4 months; range, 2-7 months). The mean patient age at the time of external beam radiotherapy was 33 months (median, 21 months). Univariate risk factors for the need for treatment with external beam radiotherapy are listed in Table 6, as are univariate risk factors for the need for enucleation. The median time to enucleation was 15 months (mean, 9 months; range, 4-50 months). The mean patient age at the time of enucleation was 40.5 months (median, 35 months; range, 10-90 months).

The final visual acuity results are listed in Table 7. Overall, the final visual acuity was 20/200 or better in 6 eyes (20%) and worse than 20/200 in 14 (47%); enucleation was necessary in 10 eyes (33%). Of the 26 eyes with initial macular involvement of retinoblastoma, final visual acuity was 20/200 or better in 6 (23%). Of those 6 eyes with final visual acuity of 20/200 or better, the visual acuity was 20/100 in 1 eye, 20/60 in 1, 20/40 in 3, and 20/30 in 1.

No patient developed metastastic retinoblastoma or adverse effects caused by the chemotherapy, such as renal toxic effects, hearing loss, or second cancers. In addition, pinealoblastoma or intracranial neuroblastic malignancy did not occur in any patient. A systemic infection occurred in 1 patient (3%) and prolonged bone marrow suppression occurred in 2 (7%).

COMMENT

Enucleation is the most frequently used primary treatment for unilateral retinoblastoma13,5 (also John Epstein, MD, unpublished data, March 2002). With the advent of effective chemotherapeutic agents for intraocular disease, and the evidence that vision can be preserved in many eyes that would otherwise have been enucleated, the management of unilateral retinoblastoma has become complex. In a review of 461 children with unilateral retinoblastoma who were treated on the Ocular Oncology Service at Wills Eye Hospital, a trend toward decreasing frequency of enucleation was found during the past 3 decades5 (also John Epstein, MD, unpublished data, March 2002). In the 1970s, 96% of eyes with unilateral retinoblastoma were enucleated, whereas in the 1980s, 75% were enucleated. This trend stabilized in the 1990s, with 73% of such eyes enucleated5 (also John Epstein, MD, unpublished data, March 2002). This trend results partly from earlier diagnosis and partly from improved conservative (nonenucleation) treatment methods, such as chemoreduction and radiotherapy.

The decision regarding treatment strategy for unilateral retinoblastoma depends on the interaction of many factors, such as the location of the tumor(s), whether that be macular or extramacular; associated tumor seeding and subretinal fluid; the expected visual outcome; and, more important, anticipation of new tumors based on the family history and age of the patient. Today, most ophthalmologists will attempt to salvage an eye with extramacular unilateral retinoblastoma, especially if there is minimal subretinal fluid and seeding. Eyes with more extensive subretinal fluid and vitreous or subretinal seeds would more likely be treated with primary enucleation, since recurrence of seeds is anticipated following conservative methods.14 The management of unilateral macular retinoblastoma is more debatable. If minimal subretinal fluid and seeds are present, a conservative approach of chemoreduction might be used. In our series of 30 eyes, 26 (87%) of the tumors involved the macula. One might expect poor visual outcome in these patients, but, in fact, 6 (23%) displayed a final visual acuity of 20/200 or better. In 5 of these cases, the visual acuity was 20/30 to 20/60. Occasionally, macular retinoblastoma regresses after chemoreduction to a juxtamacular epicenter, allowing for functional foveal vision. This regression can often be predicted by observing the distribution of feeder vessels. The tumor generally will regress to an epicenter nearest the most dilated artery, whether that is the superotemporal or inferotemporal artery. Those eyes with macular retinoblastoma and equally dilated feeder vessels above and below the macula tend to regress to the center of the fovea and manifest reduced ultimate central vision. All children with treated unilateral retinoblastoma should be monitored for amblyopia, as this can also contribute to reduced posttreatment visual acuity.

The age of the patient at presentation is an important factor in the decision to use chemoreduction for unilateral retinoblastoma. In general, children with unilateral retinoblastoma who are younger than 3 to 6 months at presentation have a substantial risk to eventually manifest multifocal or bilateral disease.15 Therefore, chemoreduction might be considered in these young infants to minimize future tumors. Children with unilateral retinoblastoma at initial examination who are older than 12 months have less than a 5% chance for bilateral disease; hence, chemoreduction for tumor prevention is less applicable.15 A similar philosophy applies to those with a family history of retinoblastoma, as more than 1 tumor and bilateral involvement are anticipated. Children with familial retinoblastoma who have a unilateral tumor at first examination are more likely to be treated with chemoreduction to minimize future tumors and possibly minimize the risk for pinealoblastoma. Chemoreduction may prevent the often fatal, associated pinealoblastoma that is expected in approximately 8% to 10% of children with the genetic form of retinoblastoma.16,17

Before the advent of chemoreduction, attempts were made to salvage the eye with unilateral retinoblastoma.7,18 Conservative treatment, primarily with radiotherapy, failed in 13% to 20% of eyes classified as RE groups I through III and in 76% to 86% of eyes classified as RE groups IV and V retinoblastoma.7,18 A similar analysis of unilateral retinoblastoma from our department showed that primary enucleation was performed in 65% of 282 eyes in a 12-year period, while conservative therapy (external beam radiotherapy, laser photocoagulation, cryotherapy, plaque radiotherapy, and chemoreduction) was used in 35% (John Epstein, MD, unpublished data, March 2002). Of those treated conservatively, treatment failure requiring enucleation was noted in 17% of those eyes classified as RE groups I through III and in 44% of those classified as RE groups IV and V. In the present analysis, we specifically evaluated the results of chemoreduction for unilateral retinoblastoma and found that treatment failure requiring enucleation occurred in no patient in RE groups I through III and in 59% of those in groups IV and V, by Kaplan-Meier analysis. It appears that chemoreduction is a reasonable therapy for less advanced unilateral sporadic retinoblastoma. Its use for advanced unilateral sporadic retinoblastoma should be followed up cautiously and even reconsidered, as enucleation is anticipated in more than half of the cases.

The initial enthusiasm for chemoreduction has more recently been tempered by observations of tumor and seed recurrence.14 Despite dramatic tumor regression initially, some eyes are destined for failure and have been identified in this analysis. On the basis of these results, a perspective has been provided regarding the role of chemoreduction for unilateral retinoblastoma. These results support the use of chemoreduction for those patients with RE groups I through III disease who cannot be treated with local therapy alone. However, those patients with RE groups IV and V retinoblastoma might more appropriately be considered for primary enucleation. Important factors other than tumor staging, such as hereditary pattern, multifocality of tumors, tumor location and associated features, affect the therapeutic decision, as previously mentioned. Although more effective chemotherapy may allow improved globe salvage for advanced unilateral retinoblastoma in the future, it is necessary to carefully compare the benefits against the risks of subjecting children to drugs that have potential short- and long-term toxicity.

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Article Information

Submitted for publication March 26, 2002; final revision received July 1, 2002; accepted July 24, 2002.

This study was supported in part by the Paul Kayser International Award of Merit in Retina Research, Houston, Tex (Dr J. A. Shields); the Macula Foundation, New York, NY (Dr C. L. Shields); the Eye Tumor Research Foundation, Philadelphia(Dr C. L. Shields); Orbis International, New York (Dr Honavar); and the Hyderabad Eye Research Foundation, Hyderabad, India (Dr Honavar).

Corresponding author and reprints: Carol L. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, 840 Walnut St, Philadelphia, PA 19107 (e-mail: carol.shields@shieldsoncology.com).

References
1.
Shields  JAShields  CL Management and prognosis of retinoblastoma. Intraocular Tumors: A Text and Atlas. Philadelphia, Pa WB Saunders Co1992;377- 391
2.
Shields  JAShields  CL Retinoblastoma. Atlas of Intraocular Tumors. Philadelphia, Pa Lippincott Williams & Wilkins1999;207- 232
3.
Shields  CLShields  JA Recent developments in the management of retinoblastoma. J Pediatr Ophthalmol Strabismus. 1999;368- 18
4.
Sanders  BMDraper  GJKingston  JE Retinoblastoma in Great Britain 1969-80: incidence, treatment, and survival. Br J Ophthalmol. 1988;72576- 583Article
5.
Shields  JAShields  CLSivalingam  V Decreasing frequency of enucleation in patients with retinoblastoma. Am J Ophthalmol. 1989;108185- 188
6.
Abramson  DHMarks  RFEllsworth  RMTretter  PKitchin  FD The management of unilateral retinoblastoma without primary enucleation. Arch Ophthalmol. 1982;1001249- 1252Article
7.
Kingston  JEHungerford  JLMadreperla  SAPlowman  PN Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol. 1996;1141339- 1343Article
8.
Gallie  BLBudning  ADeBoer  G  et al.  Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiation. Arch Ophthalmol. 1996;1141321- 1328Article
9.
Murphree  ALVillablanca  JGDeegan  WF  III  et al.  Chemotherapy plus local treatment in the managment of intraocular retinoblastoma. Arch Ophthalmol. 1996;1141348- 1356Article
10.
Shields  CLDePotter  PHimelstein  BShields  JAMeadows  ATMaris  JM Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol. 1996;1141330- 1338Article
11.
Shields  CLShields  JANeedle  M  et al.  Combined chemoreduction and adjuvant treatment for intraocular retinoblastoma. Ophthalmology. 1997;1042101- 2111Article
12.
Friedman  DLHimelstein  BShields  CL  et al.  Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol. 2000;1812- 17
13.
Shields  CLSantos  CDiniz  W  et al.  Thermotherapy for retinoblastoma. Arch Ophthalmol. 1999;117885- 893Article
14.
Shields  CLHonavar  SGShields  JADemirci  HMeadows  ATNaduvilath  TJ Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol. 2002;120460- 464Article
15.
Abramson  DHServodidio  CA Retinoblastoma in the first year of life. Ophthalmic Paediatr Genet. 1992;13191- 203Article
16.
Shields  CLShields  JAMeadows  AT Chemoreduction for retinoblastoma may prevent trilateral retinoblastoma[letter]. J Clin Oncol. 2000;18236- 237
17.
Shields  CLMeadows  ATShields  JACarvalho  CSmith  AF Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol. 2001;1191269- 1272Article
18.
Abramson  DHServodidio  CADe Lillo  ARGamell  LSKruger  EFMcCormick  B Recurrence of unilateral retinoblastoma following radiation therapy. Ophthalmic Genet. 1994;15107- 113Article
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