Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information

Intraocular Extraocular Reese-Ellsworth Classification for Intraocular Tumors

Treatment Option Overview
Intraocular Retinoblastoma

Unilateral Disease         Standard treatment options         Treatment options under clinical evaluation Bilateral Disease         Standard treatment options Future Directions         Treatment options under clinical evaluation Current Clinical Trials

Extraocular Retinoblastoma

Standard Treatment Options Treatment Options Under Clinical Evaluation Current Clinical Trials

Recurrent Retinoblastoma

Current Clinical Trials

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Changes to This Summary (11/05/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of retinoblastoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Incidence.
• Cellular classification.
• Stage information.
• Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system ² in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version ³, which is written in less-technical language, and in Spanish ⁴.

General Information

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, an ophthalmologist with extensive experience in the treatment of children with retinoblastoma, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive Care ⁵ summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site. ⁶

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ Late Effects of Treatment for Childhood Cancer ⁷ summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Retinoblastoma is a relatively uncommon tumor of childhood that arises in the retina and accounts for about 3% of the cancers occurring in children younger than 15 years. The estimated annual incidence in the United States is approximately 10 to 14 per million children aged 0 to 4 years. Although retinoblastoma may occur at any age, it most often occurs in younger children, usually before age 2 years. Ninety-five percent of cases are diagnosed before age 5 years. Retinoblastoma diagnosed in patients older than 5 years has a poorer prognosis. This is likely due to the low incidence of retinoblastoma in this age group, resulting in a low level of suspicion, which may ultimately cause a delay in diagnosis.[2] Retinoblastoma is a tumor that occurs in heritable (40%) and nonheritable (60%) forms. Heritable disease includes those patients with a positive family history (10%) and who have sustained a new germline mutation at the time of conception (30%).

Retinoblastoma is usually confined to the eye, and as a result, more than 90% of children with intraocular retinoblastoma will be cured. The present challenge for those who treat retinoblastoma is to prevent loss of an eye, blindness, and other serious effects of treatment that reduce the life span or the quality of life.

The heritable form of retinoblastoma may manifest as unilateral or bilateral disease. Most unilateral diseases are not heritable, whereas children with bilateral diseases are all presumed to have the heritable form. In heritable retinoblastoma, tumors tend to occur at a younger age than in the nonheritable form of the disease. Unilateral tumors in infants are more likely to be the heritable form, whereas older children with unilateral tumors are more likely to have the nonheritable form of the disease.[3,4] Unilateral tumors in younger children have fewer genetic abnormalities than those in older children.[5] Children with the heritable form who have a normal examination in at least one eye on initial presentation need to be examined frequently for the development of new retinoblastoma tumors. It is recommended that they be examined every 2 to 4 months for at least 28 months.[6] Following treatment, patients require careful surveillance until age 5 years.[7]

Trilateral retinoblastoma is a well-recognized syndrome that consists of unilateral or bilateral heritable retinoblastoma associated with an intracranial neuroblastic tumor. It has been observed that 5% to 15% of children with either familial, multifocal, or bilateral retinoblastoma may develop an intracranial neuroblastic tumor as well.[8] Children with heritable retinoblastoma have an increased risk of trilateral retinoblastoma, which is associated with a poor prognosis,[9] although intensive therapies being developed for extraocular retinoblastoma may offer some promise.[10] It also has been found that patients who are asymptomatic at the time of diagnosis with an intracranial tumor have a better overall survival than patients who are symptomatic.[8] Screening by neuroimaging may improve the cure rate. It has been recommended that children with heritable retinoblastoma should be screened using magnetic resonance neuroimaging or computerized tomography (CT) scan every 6 months after diagnosis until age 5 years, since these tumors are not likely to occur after this time.[9] The current practice of using chemotherapy to reduce the extent of intraocular tumor in bilateral cases may prevent the development of pineal tumors.[11]

Patients with the heritable type of retinoblastoma have a markedly increased frequency of second malignant neoplasms (SMN).[12] The cumulative incidence is about 26% (± 10%) in nonirradiated patients and 58% (± 10%) in irradiated patients by 50 years after diagnosis of retinoblastoma—a rate of about 1% per year.[13] Most of the SMN are osteosarcomas, soft tissue sarcomas, or melanomas. There is also an increased incidence of acute myelogenous leukemia in children receiving chemotherapy, which may be related to usage of topoisomerase II inhibitors.[14][Level of evidence: 3iiiA]

A cohort study of 963 patients, who were at least 1-year survivors of hereditary retinoblastoma diagnosed at two United States institutions from 1914 through 1984, evaluated risk for soft tissue sarcoma overall and by histological subtype. Risks were elevated for soft tissue sarcoma overall and leiomyosarcoma was the most frequent subtype, with 78% of leiomyosarcomas diagnosed 30 or more years after the retinoblastoma diagnosis. Risks were elevated in patients treated with or without radiation therapy, and, in those treated with radiation therapy, sarcomas were seen both within and outside the field of radiation. These data suggest a genetic predisposition to soft tissue sarcoma, similar to what has been seen for osteosarcomas.[15]

A markedly increased mortality from lung, bladder, and other epithelial cancers occurs in patients with heritable retinoblastoma who were spared radiation. Tobacco use is associated with these cancers in this uniquely susceptible population.[16] The carcinogenic effect of radiation increases with dose, particularly for secondary sarcomas where a stepwise increase is apparent at all dose categories.[13] In irradiated patients, two-thirds of the second cancers occur within irradiated tissue and one-third outside the radiation field.[13] The risk for SMN in the field of radiation is heavily dependent on the patient’s age at the time the external-beam radiation therapy is given, and the histopathologic type of SMN may be influenced by the attained age.[17] This risk may be less for patients older than 12 months.[7,18]

A study from the United Kingdom following patients treated with high doses of radiation therapy from 1873 until 1950 found that among 144 survivors, 58 subsequent cancers developed between age 25 and 84 years, for a cumulative cancer incidence of 68.8%. Of note, only eight of those cancers were of bone and soft tissue, and epithelial cancers were more common, with survival from same being quite poor.[16]

Survival from second malignancies is certainly suboptimal and varies widely across studies.[16,19-21] However, with advances in therapy, it is essential that all second malignancies be treated with curative intent.[22] Those who survive SMN are at increased risk for developing additional malignancies at a rate of about 2% per year.[23] There is no clear increase in second malignancies in patients with sporadic retinoblastoma beyond that associated with the treatment.[13,21]

All siblings of patients with retinoblastoma should have regular ophthalmic examinations, and studies suggest that DNA polymorphism analysis may help predict which persons are at risk and warrant close follow-up. Cytogenetic abnormalities (e.g., deletion on the long arm of chromosome 13) are sometimes observed.[24]

Genetic counseling should be an integral part of the therapy for a patient with retinoblastoma, whether unilateral or bilateral.[25] Genetic counseling, however, is not always straightforward. Families with retinoblastoma may have a founder with embryonic mutagenesis causing genetic mosaicism of gametes.[26] A significant proportion (10%–18%) of children with retinoblastoma have somatic genetic mosaicism,[27,28] making the genetic story more complex and contributing to the difficulty of genetic counseling.[29]

Clinical laboratory service is now becoming more available in some centers for performing genetic testing of relatives of retinoblastoma patients to determine risk of hereditary susceptibility to the disease. Exon by exon sequencing of the RB1 gene demonstrates germline mutation in 90% of patients with heritable retinoblastoma.[30,31] Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out.[29] The multistep assay includes DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions, Southern blot analysis to characterize genomic rearrangements, and transcript analysis to characterize potential splicing mutations buried within introns. This expanded analysis has shown promise in better defining the functional significance of apparently novel mutations in pilot investigations performed at the University of Pennsylvania. Such testing should be performed only at institutions with expertise in RB1 gene mutation analysis. The RB1 gene is located within the q14 band of chromosome 13.[32] The absence of detectable RB1 mutations in some patients may suggest that alternative genetic mechanisms may underlie the development of retinoblastoma.[33]

The type of treatment required depends on both the extent of the disease within the eye and whether the disease has spread beyond the eye, either to the brain or to the rest of the body.[34] Risk of extraocular recurrence may be increased in the presence of pathologic scleral invasion and in patients that require bilateral enucleation.[35][Level of evidence: 3iiDi] Routine bone marrow biopsy and lumbar puncture are not indicated, except when there is a high level of suspicion that the tumor has spread beyond the globe.[36,37] Examples include patients with an abnormal complete blood count or those whose tumors extend beyond the lamina cribrosa on pathologic examination of the enucleated specimen.

It is not uncommon for patients with retinoblastoma to have extensive disease within one eye at diagnosis, with either massive tumors involving more than one half of the retina, multiple tumors diffusely involving the retina, or obvious seeding of the vitreous. For those with bilateral disease, systemic therapy should be targeted to treat the more severe eye.[38,39] The goals of therapy are threefold: eradicate the disease, preserve as much vision as possible, and decrease risk of late sequelae from treatment, particularly SMN.

Patients with retinoblastoma demonstrate a variety of long-term visual field defects after treatment for their intraocular disease. These defects are related to tumor size, location, and treatment method.[40] One study of visual acuity following treatment with systemic chemotherapy and focal ophthalmic therapy was conducted in 54 eyes in 40 children. After a mean follow-up of 68 months, 27 eyes (50%) had a final visual acuity of 20/40 or better, and 36 eyes (67%) had final visual acuity of 20/200 or better. The clinical factors that predicted visual acuity of 20/40 or better were a tumor margin at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.[41]

Since systemic carboplatin is now commonly used in the treatment of retinoblastoma (Refer to Intraocular Retinoblastoma ⁸ and Extraocular Retinoblastoma ⁹ sections of this summary), concern has been raised about hearing loss related to therapy. However, a recent analysis of 164 children treated with six cycles of carboplatin containing therapy (18.6mg/kg per cycle) showed no loss of hearing among children who had a normal initial audiogram.[42]

References

1. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.  [PUBMED Abstract]
   
   
2. de Aguirre Neto JC, Antoneli CB, Ribeiro KB, et al.: Retinoblastoma in children older than 5 years of age. Pediatr Blood Cancer 48 (3): 292-5, 2007.  [PUBMED Abstract]
   
   
3. Zajaczek S, Jakubowska A, Kurzawski G, et al.: Age at diagnosis to discriminate those patients for whom constitutional DNA sequencing is appropriate in sporadic unilateral retinoblastoma. Eur J Cancer 34 (12): 1919-21, 1998.  [PUBMED Abstract]
   
   
4. Murphree L, Singh A: Heritable retinoblastoma: the RBI cancer predisposition syndrome. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 428-33. 
   
   
5. Herzog S, Lohmann DR, Buiting K, et al.: Marked differences in unilateral isolated retinoblastomas from young and older children studied by comparative genomic hybridization. Hum Genet 108 (2): 98-104, 2001.  [PUBMED Abstract]
   
   
6. Abramson DH, Mendelsohn ME, Servodidio CA, et al.: Familial retinoblastoma: where and when? Acta Ophthalmol Scand 76 (3): 334-8, 1998.  [PUBMED Abstract]
   
   
7. Abramson DH, Frank CM: Second nonocular tumors in survivors of bilateral retinoblastoma: a possible age effect on radiation-related risk. Ophthalmology 105 (4): 573-9; discussion 579-80, 1998.  [PUBMED Abstract]
   
   
8. Paulino AC: Trilateral retinoblastoma: is the location of the intracranial tumor important? Cancer 86 (1): 135-41, 1999.  [PUBMED Abstract]
   
   
9. Kivelä T: Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. J Clin Oncol 17 (6): 1829-37, 1999.  [PUBMED Abstract]
   
   
10. Jubran RF, Erdreich-Epstein A, Butturini A, et al.: Approaches to treatment for extraocular retinoblastoma: Children's Hospital Los Angeles experience. J Pediatr Hematol Oncol 26 (1): 31-4, 2004.  [PUBMED Abstract]
    
    
11. Shields CL, Meadows AT, Shields JA, et al.: Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol 119 (9): 1269-72, 2001.  [PUBMED Abstract]
    
    
12. Gallie BL, Dunn JM, Chan HS, et al.: The genetics of retinoblastoma. Relevance to the patient. Pediatr Clin North Am 38 (2): 299-315, 1991.  [PUBMED Abstract]
    
    
13. Wong FL, Boice JD Jr, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278 (15): 1262-7, 1997.  [PUBMED Abstract]
    
    
14. Gombos DS, Hungerford J, Abramson DH, et al.: Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology 114 (7): 1378-83, 2007.  [PUBMED Abstract]
    
    
15. Kleinerman RA, Tucker MA, Abramson DH, et al.: Risk of soft tissue sarcomas by individual subtype in survivors of hereditary retinoblastoma. J Natl Cancer Inst 99 (1): 24-31, 2007.  [PUBMED Abstract]
    
    
16. Fletcher O, Easton D, Anderson K, et al.: Lifetime risks of common cancers among retinoblastoma survivors. J Natl Cancer Inst 96 (5): 357-63, 2004.  [PUBMED Abstract]
    
    
17. Kleinerman RA, Tucker MA, Tarone RE, et al.: Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 23 (10): 2272-9, 2005.  [PUBMED Abstract]
    
    
18. Moll AC, Imhof SM, Schouten-Van Meeteren AY, et al.: Second primary tumors in hereditary retinoblastoma: a register-based study, 1945-1997: is there an age effect on radiation-related risk? Ophthalmology 108 (6): 1109-14, 2001.  [PUBMED Abstract]
    
    
19. Aerts I, Pacquement H, Doz F, et al.: Outcome of second malignancies after retinoblastoma: a retrospective analysis of 25 patients treated at the Institut Curie. Eur J Cancer 40 (10): 1522-9, 2004.  [PUBMED Abstract]
    
    
20. Eng C, Li FP, Abramson DH, et al.: Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 85 (14): 1121-8, 1993.  [PUBMED Abstract]
    
    
21. Dunkel IJ, Gerald WL, Rosenfield NS, et al.: Outcome of patients with a history of bilateral retinoblastoma treated for a second malignancy: the Memorial Sloan-Kettering experience. Med Pediatr Oncol 30 (1): 59-62, 1998.  [PUBMED Abstract]
    
    
22. Moll AC, Imhof SM, Bouter LM, et al.: Second primary tumors in patients with retinoblastoma. A review of the literature. Ophthalmic Genet 18 (1): 27-34, 1997.  [PUBMED Abstract]
    
    
23. Abramson DH, Melson MR, Dunkel IJ, et al.: Third (fourth and fifth) nonocular tumors in survivors of retinoblastoma. Ophthalmology 108 (10): 1868-76, 2001.  [PUBMED Abstract]
    
    
24. Wiggs J, Nordenskjöld M, Yandell D, et al.: Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene. N Engl J Med 318 (3): 151-7, 1988.  [PUBMED Abstract]
    
    
25. Musarella MA, Gallie BL: A simplified scheme for genetic counseling in retinoblastoma. J Pediatr Ophthalmol Strabismus 24 (3): 124-5, 1987 May-Jun.  [PUBMED Abstract]
    
    
26. Munier FL, Thonney F, Girardet A, et al.: Evidence of somatic and germinal mosaicism in pseudo-low-penetrant hereditary retinoblastoma, by constitutional and single-sperm mutation analysis. Am J Hum Genet 63 (6): 1903-8, 1998.  [PUBMED Abstract]
    
    
27. Sippel KC, Fraioli RE, Smith GD, et al.: Frequency of somatic and germ-line mosaicism in retinoblastoma: implications for genetic counseling. Am J Hum Genet 62 (3): 610-9, 1998.  [PUBMED Abstract]
    
    
28. Munier F, Pescia G, Jotterand-Bellomo M, et al.: Constitutional karyotype in retinoblastoma. Case report and review of literature. Ophthalmic Paediatr Genet 10 (2): 129-50, 1989.  [PUBMED Abstract]
    
    
29. Clark R: Retinoblastoma: genetic testing and counseling. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 441-6. 
    
    
30. Noorani HZ, Khan HN, Gallie BL, et al.: Cost comparison of molecular versus conventional screening of relatives at risk for retinoblastoma. Am J Hum Genet 59 (2): 301-7, 1996.  [PUBMED Abstract]
    
    
31. Lohmann DR, Gerick M, Brandt B, et al.: Constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma. Am J Hum Genet 61 (2): 282-94, 1997.  [PUBMED Abstract]
    
    
32. Bunin G, Orjuela M: Geographic and environmental factors. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 410-6. 
    
    
33. Nichols KE, Houseknecht MD, Godmilow L, et al.: Sensitive multistep clinical molecular screening of 180 unrelated individuals with retinoblastoma detects 36 novel mutations in the RB1 gene. Hum Mutat 25 (6): 566-74, 2005.  [PUBMED Abstract]
    
    
34. Kopelman JE, McLean IW, Rosenberg SH: Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmology 94 (4): 371-7, 1987.  [PUBMED Abstract]
    
    
35. Chantada GL, Dunkel IJ, Antoneli CB, et al.: Risk factors for extraocular relapse following enucleation after failure of chemoreduction in retinoblastoma. Pediatr Blood Cancer 49 (3): 256-60, 2007.  [PUBMED Abstract]
    
    
36. Moscinski LC, Pendergrass TW, Weiss A, et al.: Recommendations for the use of routine bone marrow aspiration and lumbar punctures in the follow-up of patients with retinoblastoma. J Pediatr Hematol Oncol 18 (2): 130-4, 1996.  [PUBMED Abstract]
    
    
37. Pratt CB, Meyer D, Chenaille P, et al.: The use of bone marrow aspirations and lumbar punctures at the time of diagnosis of retinoblastoma. J Clin Oncol 7 (1): 140-3, 1989.  [PUBMED Abstract]
    
    
38. Abramson DH, Beaverson K, Sangani P, et al.: Screening for retinoblastoma: presenting signs as prognosticators of patient and ocular survival. Pediatrics 112 (6 Pt 1): 1248-55, 2003.  [PUBMED Abstract]
    
    
39. Shields CL, Mashayekhi A, Demirci H, et al.: Practical approach to management of retinoblastoma. Arch Ophthalmol 122 (5): 729-35, 2004.  [PUBMED Abstract]
    
    
40. Abramson DH, Melson MR, Servodidio C: Visual fields in retinoblastoma survivors. Arch Ophthalmol 122 (9): 1324-30, 2004.  [PUBMED Abstract]
    
    
41. Demirci H, Shields CL, Meadows AT, et al.: Long-term visual outcome following chemoreduction for retinoblastoma. Arch Ophthalmol 123 (11): 1525-30, 2005.  [PUBMED Abstract]
    
    
42. Lambert MP, Shields C, Meadows AT: A retrospective review of hearing in children with retinoblastoma treated with carboplatin-based chemotherapy. Pediatr Blood Cancer 50 (2): 223-6, 2008.  [PUBMED Abstract]
    
    

Cellular Classification

The tumor is composed mainly of undifferentiated anaplastic cells that arise from the nuclear layers of the retina. Histology shows similarity to neuroblastoma and medulloblastoma, including aggregation around blood vessels, necrosis, calcification, and Flexner-Wintersteiner rosettes. Retinoblastomas are characterized by marked cell proliferation as evidenced by high mitosis counts and extremely high MIB-1 labeling indices.[1]

References

1. Schwimer CJ, Prayson RA: Clinicopathologic study of retinoblastoma including MIB-1, p53, and CD99 immunohistochemistry. Ann Diagn Pathol 5 (3): 148-54, 2001.  [PUBMED Abstract]
   
   

Stage Information

Although there are several staging systems currently available for retinoblastoma, for the purpose of treatment, retinoblastoma is categorized into intraocular and extraocular disease.

5-year disease-free survival: >90%

Intraocular retinoblastoma is localized to the eye and may be confined to the retina or may extend to involve the globe; however, it does not extend beyond the eye into the tissues around the eye or to other parts of the body.

5-year disease-free survival: <10%

Extraocular retinoblastoma has extended beyond the eye. It may be confined to the tissues around the eye, or it may have spread, typically to the central nervous system or most commonly to the bone marrow or lymph nodes.

Reese and Ellsworth have developed a generally adopted classification system for intraocular retinoblastoma that has been shown to have prognostic significance for maintenance of sight and control of local disease at a time when surgery and external-beam radiation therapy (EBRT) were the only treatment options. The Reese-Ellsworth system is relevant to decisions regarding the use of local treatment modalities and chemoreduction, but another system has since evolved which may offer greater precision in stratifying risk for newer therapies. (See International Classification System in the Future Directions ¹⁰ section of this summary.)

Group I: very favorable for maintenance of sight

1. Solitary tumor, smaller than 4 disc diameters (DD), at or behind the equator.
2. Multiple tumors, none larger than 4 DD, all at or behind the equator.

Group II: favorable for maintenance of sight

1. Solitary tumor, 4 to 10 DD at or behind the equator.
2. Multiple tumors, 4 to 10 DD behind the equator.

Group III: possible for maintenance of sight

1. Any lesion anterior to the equator.
2. Solitary tumor, larger than 10 DD behind the equator.

Group IV: unfavorable for maintenance of sight

1. Multiple tumors, some larger than 10 DD.
2. Any lesion extending anteriorly to the ora serrata.

Group V: very unfavorable for maintenance of sight

1. Massive tumors involving more than one half the retina.
2. Vitreous seeding.

There is now a new classification system for retinoblastoma. The International Classification for Intraocular Retinoblastoma that is used in the current Children’s Oncology Group treatment studies, as well in some institutional studies, has been shown to assist in predicting those who are likely to be cured without the need for enucleation or EBRT.[1-3]

International Classification System for Intraocular Retinoblastoma

• Group A: Small intraretinal tumors away from foveola and disc.
  • All tumors are 3 mm or smaller in greatest dimension, confined to the retina and
  • All tumors are located further than 3 mm from the foveola and 1.5 mm from the optic disc.



• Group B: All remaining discrete tumors confined to the retina.
  • All other tumors confined to the retina not in Group A.
  • Tumor-associated subretinal fluid less than 3 mm from the tumor with no subretinal seeding.



• Group C: Discrete local disease with minimal subretinal or vitreous seeding.
  • Tumor(s) are discrete.
  • Subretinal fluid, present or past, without seeding involving up to one-fourth of the retina.
  • Local fine vitreous seeding may be present close to discrete tumor.
  • Local subretinal seeding less than 3 mm (2 DD) from the tumor.



• Group D: Diffuse disease with significant vitreous or subretinal seeding.
  • Tumor(s) may be massive or diffuse.
  • Subretinal fluid present or past without seeding, involving up to total retinal detachment.
  • Diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses.
  • Diffuse subretinal seeding may include subretinal plaques or tumor nodules.



• Group E: Presence of any one or more of these poor prognosis features.
  • Tumor touching the lens.
  • Tumor anterior to anterior vitreous face involving ciliary body or anterior segment.
  • Diffuse infiltrating retinoblastoma.
  • Neovascular glaucoma.
  • Opaque media from hemorrhage.
  • Tumor necrosis with aseptic orbital cellulites.
  • Phthisis bulbi.

References

1. Murphree L: Staging and grouping of retinoblastoma. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 422-7. 
   
   
2. Zage PE, Reitman AJ, Seshadri R, et al.: Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma. Pediatr Blood Cancer 50 (3): 567-72, 2008.  [PUBMED Abstract]
   
   
3. Shields CL, Mashayekhi A, Au AK, et al.: The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113 (12): 2276-80, 2006.  [PUBMED Abstract]
   
   

Treatment Option Overview

Treatment planning by a multidisciplinary team of cancer specialists who have experience treating ocular tumors of childhood is required to determine and implement optimum treatment. Because of the complexity of therapy, expertise in pediatric radiation therapy and ophthalmology should be available.[1]

References

1. Chintagumpala M, Chevez-Barrios P, Paysse EA, et al.: Retinoblastoma: review of current management. Oncologist 12 (10): 1237-46, 2007.  [PUBMED Abstract]
   
   

Intraocular Retinoblastoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

Treatment of retinoblastoma should be planned after the extent of the tumor within and outside the eye is known. Treatment options consider both cure and preservation of sight.[1-4]

Treatment options for the involved eye include the following:

1. Enucleation, if the tumor is massive or if there is little expectation for useful vision.



2. External-beam radiation therapy (EBRT) with doses ranging from 35 Gy to 46 Gy. Because of the need to sedate young children and the intricacies of field planning, special expertise in pediatric radiation therapy is important. Newer methods of delivering EBRT are being used at many centers in an attempt to reduce adverse long-term effects. This includes intensity-modulated radiation therapy (IMRT), stereotactic radiation therapy, and proton-beam radiation therapy.[5-7] The Children's Oncology Group (COG) is conducting a clinical trial in which reduced-dose (26 Gy) IMRT is being used in combination with chemoreduction.



3. Cryotherapy, used in addition to radiation or in place of photocoagulation for lesions smaller than 4 disc diameters (DD) in the anterior portion of the retina.



4. Light coagulation (photocoagulation), occasionally used alone with small tumors. In patients with early-stage disease, light coagulation is usually used in addition to radiation therapy or when there is limited recurrence following radiation therapy. Photocoagulation is used for posteriorly located tumors that are smaller than 4 DD, distinct from the optic nerve head and macula, and without involvement of large nutrient vessels or choroid involvement. Thermotherapy delivered via infrared radiation is an alternative to laser photocoagulation.[8]



5. Brachytherapy with radioactive plaques for either focal unilateral presentations or recurrent disease following previous EBRT.[9-11]



6. Systemic chemotherapy: During the past 10 years, systemic chemotherapy to reduce tumor volume (chemoreduction) and to avoid the long-term effects of radiation therapy for patients with intraocular tumors has succeeded in rendering many eyes amenable to treatment with cryotherapy or photocoagulation.[1,2,12] Chemotherapy may also be continued or initiated with concurrent local control interventions.[13] Factors such as tumor location (macula), patient age (patient older than 2 months), and tumor size correlate with responsiveness to chemotherapy.[13,14] Multiagent chemotherapy is generally used although carboplatin as a single agent causes shrinkage of retinoblastoma tumors.[15,16][Level of evidence: 3iiiDiii] Most tumors treated with vincristine and carboplatin require additional local therapy;[1,2,12,17,18] the addition of etoposide to the chemotherapy regimen may improve outcome.[14,19] One study utilized carboplatin and etoposide with focal therapy, without vincristine and found acceptable vision salvage rates for Reese-Ellsworth (R-E) Groups I through IV and International Classification Groups A and B retinoblastoma.[20] The success rate of these trials varies from center to center, but overall, the rate is highest for tumors that are unilateral or unifocal and without vitreous seeding (see below). There are emerging data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma.[21] Local tumor recurrence is not uncommon in the first few years after treatment,[22] and can often be successfully treated with focal therapy.[11] Among patients with heritable disease, younger patients and those with a positive family history are more likely to form new tumors. Chemotherapy may treat small previously undetected lesions by slowing their growth and this may improve overall salvage with focal therapy.[23]



7. Subtenon (subconjunctival) chemotherapy: Carboplatin is administered by the treating ophthalmologist into the subconjunctival space. This modality is undergoing testing in phase I and II trials and is generally used in conjunction with systemic chemotherapy and local ophthalmic therapies for retinoblastoma with vitreous seeding. This approach offers some promise in this group of patients.[24,25]

Because unilateral disease is usually massive and there is often no expectation that useful vision can be preserved, surgery (enucleation) is usually undertaken and radiation therapy is not given to the tumor bed. Even this is being tested, however, as patients with unilateral disease have been treated with chemotherapy in an attempt to preserve vision in the affected eye.[2,26,27] One study revealed that children with retinoblastoma who present with obvious external findings of leukocoria, strabismus, or red eye detectable by their family or pediatrician most often require enucleation. Children who manifest no obvious external findings can often avoid enucleation.[28]

When there is potential for preservation of sight because the tumors are smaller, treatment with other modalities (radiation therapy, photocoagulation, cryotherapy, thermotherapy, chemoreduction, and brachytherapy) instead of surgery should be considered. In selected children with unilateral disease, chemoreduction reduced the need for enucleation or EBRT to 68% within 5 years of treatment. R-E Group correlated with successful chemoreduction: 11% of children classified as having R-E Group II or III disease, 60% of children having R-E Group IV disease, and 100% of children having R-E Group V disease required enucleation or EBRT within 5 years of treatment.[29]

Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, it is very important that children with unilateral retinoblastoma receive periodic examinations of the unaffected eye. Asynchronous bilateral disease occurs most frequently in families with affected parents.

Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These include anterior chamber seeding, choroidal involvement, tumor beyond the lamina cribrosa, intraocular hemorrhage, or scleral and extrascleral extension.[30] Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide, or vincristine, carboplatin, and etoposide, has been used in patients with certain high-risk features assessed by pathologic review after enucleation to prevent the development of metastatic disease.[31-33]

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site ¹¹.

• The COG is currently conducting a study of unilateral retinoblastoma with high-risk features using a standard regimen of six cycles of carboplatin, etoposide and vincristine.

The management of bilateral disease depends on the extent of the disease in each eye. Systemic therapy should be chosen based on the eye with more extensive disease.

Usually the disease is more advanced in one eye, with less involvement in the other eye. The standard of care in the past has been to enucleate the more involved eye; however, if there is potential for vision in both eyes, bilateral irradiation or chemoreduction with close follow-up for response and focal treatment (e.g., cryotherapy or laser therapy) is indicated.

A number of large centers in Europe and North America have published trial results using systemic chemotherapy for patients whose intraocular tumors are not initially amenable to local management.[2,18,20,22,23,27,28,34-42] Examples of such tumors are those that are too large to be treated with either cryotherapy, laser photocoagulation, or plaque radiation therapy (brachytherapy). Another example is the newborn with a tumor over the optic nerve head. All these situations share the likelihood that local therapy would limit vision as to offer little improvement over enucleation. Most centers have limited this approach to patients with bilateral disease, reasoning that for patients with unilateral disease, the morbidity of enucleation is modest. When disease is massive and there is no expectation that useful vision can be preserved, surgery is usually undertaken and radiation therapy is not given.

In all cases, the goal of chemotherapy is the reduction (hence the term chemoreduction) of tumor volume, making possible the use of local therapy (cryotherapy, photocoagulation, thermotherapy, plaque radiation therapy).[2,30] All centers reporting to date have demonstrated the short-term goal is achievable, especially for tumors that are R-E group IV or lower, reporting responses in nearly 75% of eyes. Group V tumors, particularly those with vitreous seeding, have proven problematic. Subretinal seeds have a recurrence rate of 5% following chemotherapy.[20,23,43]

The backbone of the chemoreduction protocols has generally been carboplatin, etoposide, and vincristine (CEV). Studies from The Children’s Hospital of Philadelphia and Wills Eye Hospital reported complete success in the avoidance of enucleation or EBRT in R-E Group I, II, and III eyes when patients were treated for six cycles.[1,2,19] Other available data have been published in abstract form, and larger studies with more mature data are still required to make definitive conclusions. A similar study at Children’s Hospital of Los Angeles reported 13 Group B (R-E Groups I–IV) eyes treated with only three courses of this chemotherapy with 6 of 11 patients successfully treated. Three patients were salvaged with further chemotherapy only, for a total of 9 of 11 (82%) patients who did not require enucleation and/or EBRT.[36] However, local control was often transient in patients with vitreous seeding or very large tumors (R-E Group V), and fewer than half of patients were treated successfully without requiring EBRT and/or enucleation.[1,2] Several strategies have been used in an attempt to overcome this problem. Researchers reported the use of nine courses of CEV with the addition of high-dose cyclosporine A as a modulator of the p-glycoprotein for eight R-E Group V eyes with an 88% (7/8 eyes) success rate without the use of EBRT or enucleation.[37,38] However, researchers using the Gallie regimen in ten R-E Group V eyes, reported only a 20% (2/10 eyes) success rate.[39]

Using the International Classification system for intraocular retinoblastoma applied to these data retrospectively, approximately 30% of Group Cs' and 70% of Group Ds' eyes failed systemic chemotherapy alone and achieved responses in pilot studies. (Refer to the Future Directions ¹⁰ section of this summary for a more complete description of the International Classification system.)

This has led to newer adjuvant therapies, including subtenon (subconjunctival) carboplatin in pilot studies that also use higher doses of carboplatin or etoposide.[24,25]

Two studies using the International Classification have found somewhat discrepant results, perhaps in part due to differences in approaches to systemic chemotherapy and focal therapy. One study using carboplatin and etoposide, found that vision salvage rate without EBRT for eyes with Group A and B tumors was 77.3% but was only 26.9% for eyes with Group C and D tumors.[20][Level of evidence: 3iiDiv] In contrast, the other study using protocols containing carboplatin, etoposide, and vincristine, with some Group C and D patients treated with higher doses of carboplatin, found treatment success in 100% of Group A, 93% of Group B, 90% of Group C, and 47% of Group D eyes.[44]

The unresolved issues are long-term tumor control and the consequences of chemotherapy. Most of these patients are exposed to etoposide, which has been associated with secondary leukemia in patients without predisposition to cancer, but at modest rates when compared to the risk of EBRT in heritable retinoblastoma. In a retrospective database and literature review, ocular and pediatric oncologists at referral centers in Europe and the Americas and the Retinoblastoma databases at the National Institutes of Health and the Ophthalmic Oncology Service at Memorial Sloan-Kettering Cancer Center conducted a study of secondary acute myeloid leukemia among patients treated for retinoblastoma. Fifteen patients were identified, 12 patients (79%) had received chemotherapy with a topoisomerase II inhibitor, and eight (43%) had received chemotherapy with an epipodophyllotoxin. Ten children died of their leukemia. [45]

Whether patients with heritable retinoblastoma will have greater susceptibility to chemotherapy-induced second tumors is not known. Some patients will progress, and the risk of exposure both to chemotherapy and irradiation in this population has not been determined.

Studies are planned for a variety of patient groups. The International Classification system is being utilized for these trials. This classification schema is based on the extent and location of intraocular retinoblastoma and is being used in the upcoming series of protocols from the COG. The preliminary version of this system was verified to be reproducible with preliminary data from five centers that staged their patients on an Internet site in August 2000. Experience with a closely related grouping system has been published.[3] Data have been published using this system in a study of chemotherapy for intraocular retinoblastoma, where stage appeared to assist in prognosis for successful treatment without enucleation or EBRT.[44]

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site ¹¹.

• For patients Group B disease, COG is investigating the use of vincristine and carboplatin chemoreduction combined with local ophthalmic therapies, without the use of etoposide.



• For patients with Group C or D disease, COG is investigating use of higher doses of systemic carboplatin, combined with subconjunctival carboplatin and lower doses of EBRT, using intensity-modulated approaches.



• Also under investigation is the use of adenovirus-mediated gene therapy for treatment of vitreous tumor seeding.[46]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with intraocular retinoblastoma ¹². The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹¹.

References

1. Friedman DL, Himelstein B, Shields CL, et al.: Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol 18 (1): 12-7, 2000.  [PUBMED Abstract]
   
   
2. Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol 133 (5): 657-64, 2002.  [PUBMED Abstract]
   
   
3. Shields CL, Mashayekhi A, Demirci H, et al.: Practical approach to management of retinoblastoma. Arch Ophthalmol 122 (5): 729-35, 2004.  [PUBMED Abstract]
   
   
4. Shields CL, Meadows AT, Leahey AM, et al.: Continuing challenges in the management of retinoblastoma with chemotherapy. Retina 24 (6): 849-62, 2004.  [PUBMED Abstract]
   
   
5. Krasin MJ, Crawford BT, Zhu Y, et al.: Intensity-modulated radiation therapy for children with intraocular retinoblastoma: potential sparing of the bony orbit. Clin Oncol (R Coll Radiol) 16 (3): 215-22, 2004.  [PUBMED Abstract]
   
   
6. Reisner ML, Viégas CM, Grazziotin RZ, et al.: Retinoblastoma--comparative analysis of external radiotherapy techniques, including an IMRT technique. Int J Radiat Oncol Biol Phys 67 (3): 933-41, 2007.  [PUBMED Abstract]
   
   
7. Lee CT, Bilton SD, Famiglietti RM, et al.: Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: how do protons compare with other conformal techniques? Int J Radiat Oncol Biol Phys 63 (2): 362-72, 2005.  [PUBMED Abstract]
   
   
8. Shields CL, Santos MC, Diniz W, et al.: Thermotherapy for retinoblastoma. Arch Ophthalmol 117 (7): 885-93, 1999.  [PUBMED Abstract]
   
   
9. Shields CL, Shields JA, Cater J, et al.: Plaque radiotherapy for retinoblastoma: long-term tumor control and treatment complications in 208 tumors. Ophthalmology 108 (11): 2116-21, 2001.  [PUBMED Abstract]
   
   
10. Merchant TE, Gould CJ, Wilson MW, et al.: Episcleral plaque brachytherapy for retinoblastoma. Pediatr Blood Cancer 43 (2): 134-9, 2004.  [PUBMED Abstract]
    
    
11. Shields CL, Mashayekhi A, Sun H, et al.: Iodine 125 plaque radiotherapy as salvage treatment for retinoblastoma recurrence after chemoreduction in 84 tumors. Ophthalmology 113 (11): 2087-92, 2006.  [PUBMED Abstract]
    
    
12. Gündüz K, Shields CL, Shields JA, et al.: The outcome of chemoreduction treatment in patients with Reese-Ellsworth group V retinoblastoma. Arch Ophthalmol 116 (12): 1613-7, 1998.  [PUBMED Abstract]
    
    
13. Lumbroso L, Doz F, Urbieta M, et al.: Chemothermotherapy in the management of retinoblastoma. Ophthalmology 109 (6): 1130-6, 2002.  [PUBMED Abstract]
    
    
14. Gombos DS, Kelly A, Coen PG, et al.: Retinoblastoma treated with primary chemotherapy alone: the significance of tumour size, location, and age. Br J Ophthalmol 86 (1): 80-3, 2002.  [PUBMED Abstract]
    
    
15. Abramson DH, Lawrence SD, Beaverson KL, et al.: Systemic carboplatin for retinoblastoma: change in tumour size over time. Br J Ophthalmol 89 (12): 1616-9, 2005.  [PUBMED Abstract]
    
    
16. Dunkel IJ, Lee TC, Shi W, et al.: A phase II trial of carboplatin for intraocular retinoblastoma. Pediatr Blood Cancer 49 (5): 643-8, 2007.  [PUBMED Abstract]
    
    
17. Wilson MW, Rodriguez-Galindo C, Haik BG, et al.: Multiagent chemotherapy as neoadjuvant treatment for multifocal intraocular retinoblastoma. Ophthalmology 108 (11): 2106-14; discussion 2114-5, 2001.  [PUBMED Abstract]
    
    
18. Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of intraocular retinoblastoma with vincristine and carboplatin. J Clin Oncol 21 (10): 2019-25, 2003.  [PUBMED Abstract]
    
    
19. Kingston JE, Hungerford JL, Madreperla SA, et al.: Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Arch Ophthalmol 114 (11): 1339-43, 1996.  [PUBMED Abstract]
    
    
20. Zage PE, Reitman AJ, Seshadri R, et al.: Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma. Pediatr Blood Cancer 50 (3): 567-72, 2008.  [PUBMED Abstract]
    
    
21. Shields CL, Meadows AT, Shields JA, et al.: Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol 119 (9): 1269-72, 2001.  [PUBMED Abstract]
    
    
22. Shields CL, Mashayekhi A, Cater J, et al.: Chemoreduction for retinoblastoma. Analysis of tumor control and risks for recurrence in 457 tumors. Am J Ophthalmol 138 (3): 329-37, 2004.  [PUBMED Abstract]
    
    
23. Wilson MW, Haik BG, Billups CA, et al.: Incidence of new tumor formation in patients with hereditary retinoblastoma treated with primary systemic chemotherapy: is there a preventive effect? Ophthalmology 114 (11): 2077-82, 2007.  [PUBMED Abstract]
    
    
24. Abramson DH, Frank CM, Dunkel IJ: A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 106 (10): 1947-50, 1999.  [PUBMED Abstract]
    
    
25. Villablanca JG, Jubran R, Murphree AL: Phase I study of subtenon carboplatin I with systemic high dose carboplatin/etoposide/vincristine (CEV) for eyes with disseminated intraocular retinoblastoma (RB). [Abstract] Proceedings of the XIII Biannual Meeting of ISGED and the X International Symposium on Retinoblastoma, May 4, 2001, Fort Lauderdale, Fla. USA . 
    
    
26. Shields CL, Shields JA: Editorial: chemotherapy for retinoblastoma. Med Pediatr Oncol 38 (6): 377-8, 2002.  [PUBMED Abstract]
    
    
27. Schouten-Van Meeteren AY, Moll AC, Imhof SM, et al.: Overview: chemotherapy for retinoblastoma: an expanding area of clinical research. Med Pediatr Oncol 38 (6): 428-38, 2002.  [PUBMED Abstract]
    
    
28. Shields CL, Gorry T, Shields JA: Outcome of eyes with unilateral sporadic retinoblastoma based on the initial external findings by the family and the pediatrician. J Pediatr Ophthalmol Strabismus 41 (3): 143-9; quiz 172-3, 2004 May-Jun.  [PUBMED Abstract]
    
    
29. Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol 120 (12): 1653-8, 2002.  [PUBMED Abstract]
    
    
30. Levy C, Doz F, Quintana E, et al.: Role of chemotherapy alone or in combination with hyperthermia in the primary treatment of intraocular retinoblastoma: preliminary results. Br J Ophthalmol 82 (10): 1154-8, 1998.  [PUBMED Abstract]
    
    
31. 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 (1): 41-8, 2001.  [PUBMED Abstract]
    
    
32. Honavar SG, Singh AD, Shields CL, et al.: Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol 120 (7): 923-31, 2002.  [PUBMED Abstract]
    
    
33. Chantada GL, Dunkel IJ, de Dávila MT, et al.: Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol 88 (8): 1069-73, 2004.  [PUBMED Abstract]
    
    
34. Beck MN, Balmer A, Dessing C, et al.: First-line chemotherapy with local treatment can prevent external-beam irradiation and enucleation in low-stage intraocular retinoblastoma. J Clin Oncol 18 (15): 2881-7, 2000.  [PUBMED Abstract]
    
    
35. Murphree AL, Villablanca JG, Deegan WF 3rd, et al.: Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 114 (11): 1348-56, 1996.  [PUBMED Abstract]
    
    
36. Jubran RF, Murphree AL, Villablanca JG: Low dose carboplatin/etoposide/vincristine (CEV) and local therapy (LT) for intraocular retinoblastoma group II-IV eyes. [Abstract] Proceedings of the XIII Biannual Meeting of ISGED and the X International Symposium on Retinoblastoma, May 4, 2001, Fort Lauderdale, Fla. USA . 
    
    
37. Gallie BL, Budning A, DeBoer G, et al.: Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 114 (11): 1321-8, 1996.  [PUBMED Abstract]
    
    
38. Chan HSL, Heon E, Budning A, et al.: Improvement of the cure rate of intraocular retinoblastoma without significantly increasing toxicity with higher dose carboplatin-teniposide in a cyclosporine multidrug resistance-reversal regimen. [Abstract] Proceedings of the XIII Biannual Meeting of ISGED and the X International Symposium on Retinoblastoma, May 4, 2001, Fort Lauderdale, Fla. USA . 
    
    
39. Villablanca JG, Atchaneeyasakul L, Murphree AL: Clinical outcome of group V eyes treated with cyclosporin A (CSA)/carboplatin/etoposide/vincristine (CEV). [Abstract] Proceedings of the XIII Biannual Meeting of ISGED and the X International Symposium on Retinoblastoma, May 4, 2001, Fort Lauderdale, Fla. USA . 
    
    
40. Chan HS, Gallie BL, Munier FL, et al.: Chemotherapy for retinoblastoma. Ophthalmol Clin North Am 18 (1): 55-63, viii, 2005.  [PUBMED Abstract]
    
    
41. Rodriguez-Galindo C, Chantada GL, Haik BG, et al.: Treatment of Retinoblastoma: Current Status and Future Perspectives. Curr Treat Options Neurol 9 (4): 294-307, 2007.  [PUBMED Abstract]
    
    
42. Shields CL, Mashayekhi A, Cater J, et al.: Macular retinoblastoma managed with chemoreduction: analysis of tumor control with or without adjuvant thermotherapy in 68 tumors. Arch Ophthalmol 123 (6): 765-73, 2005.  [PUBMED Abstract]
    
    
43. Shields CL, Honavar SG, Shields JA, et al.: Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol 120 (4): 460-4, 2002.  [PUBMED Abstract]
    
    
44. Shields CL, Mashayekhi A, Au AK, et al.: The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113 (12): 2276-80, 2006.  [PUBMED Abstract]
    
    
45. Gombos DS, Hungerford J, Abramson DH, et al.: Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology 114 (7): 1378-83, 2007.  [PUBMED Abstract]
    
    
46. Chévez-Barrios P, Chintagumpala M, Mieler W, et al.: Response of retinoblastoma with vitreous tumor seeding to adenovirus-mediated delivery of thymidine kinase followed by ganciclovir. J Clin Oncol 23 (31): 7927-35, 2005.  [PUBMED Abstract]
    
    

Extraocular Retinoblastoma

Few patients with retinoblastoma present with extraocular disease. Extraocular disease may be localized to the soft tissues surrounding the eye or to the optic nerve beyond the margin of resection. However, further extension may occur into the brain and meninges with subsequent seeding of the spinal fluid, as well as distant metastatic disease involving the lungs, bones, and bone marrow. In patients with the genetic form of retinoblastoma, central nervous system (CNS) disease is less likely the result of metastatic or regional spread than a primary intracranial focus, such as a pineal tumor. Early diagnosis may be helpful; it has been recommended that cranial computerized tomography or magnetic resonance imaging be done twice a year until age 5 years for those who carry the gene (bilateral and unilateral heritable cases).

There is no clearly proven effective or standard therapy for the treatment of extraocular retinoblastoma, although orbital irradiation and chemotherapy have been used. In the past, palliative therapy with radiation (including craniospinal irradiation when there is meningeal involvement) and/or intrathecal chemotherapy with methotrexate, cytarabine, and hydrocortisone, plus supportive care has been used.[1]

With emerging dose-intensive chemotherapy regimens and the use of high-dose chemotherapy with autologous stem cell rescue, clinical trials are ongoing to improve the dismal outcome for this relatively small group of patients. The agents used in the past included vincristine, cyclophosphamide, and doxorubicin; although they produce an initial response, overall survival has been less than optimal. Carboplatin, ifosfamide, and etoposide have shown more promise for remission and may be used in conjunction with high-dose chemotherapy followed by stem cell rescue.[2-5] Patients presenting with extensive non-CNS metastases have been treated successfully with myeloablative chemotherapy with stem cell rescue.[4,6-8] Information about ongoing clinical trials is available from the NCI Web site ¹¹.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with extraocular retinoblastoma ¹³. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹¹.

References

1. Rootman J, Hofbauer J, Ellsworth RM, et al.: Invasion of the optic nerve by retinoblastoma: a clinicopathological study. Can J Ophthalmol 11 (2): 106-14, 1976.  [PUBMED Abstract]
   
   
2. Namouni F, Doz F, Tanguy ML, et al.: High-dose 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 (14): 2368-75, 1997.  [PUBMED Abstract]
   
   
3. Kremens B, Wieland R, Reinhard H, et al.: High-dose chemotherapy with autologous stem cell rescue in children with retinoblastoma. Bone Marrow Transplant 31 (4): 281-4, 2003.  [PUBMED Abstract]
   
   
4. Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of metastatic retinoblastoma. Ophthalmology 110 (6): 1237-40, 2003.  [PUBMED Abstract]
   
   
5. Antoneli CB, Ribeiro KB, Rodriguez-Galindo C, et al.: The addition of ifosfamide/etoposide to cisplatin/teniposide improves the survival of children with retinoblastoma and orbital involvement. J Pediatr Hematol Oncol 29 (10): 700-4, 2007.  [PUBMED Abstract]
   
   
6. Dunkel IJ, Aledo A, Kernan NA, et al.: Successful treatment of metastatic retinoblastoma. Cancer 89 (10): 2117-21, 2000.  [PUBMED Abstract]
   
   
7. Matsubara H, Makimoto A, Higa T, et al.: A multidisciplinary treatment strategy that includes high-dose chemotherapy for metastatic retinoblastoma without CNS involvement. Bone Marrow Transplant 35 (8): 763-6, 2005.  [PUBMED Abstract]
   
   
8. Jubran RF, Erdreich-Epstein A, Butturini A, et al.: Approaches to treatment for extraocular retinoblastoma: Children's Hospital Los Angeles experience. J Pediatr Hematol Oncol 26 (1): 31-4, 2004.  [PUBMED Abstract]
   
   

Recurrent Retinoblastoma

The prognosis for a patient with recurrent or progressive retinoblastoma depends on the site and extent of the recurrence or progression. With the use of systemic chemotherapy, without radiation therapy or enucleation, recurrence is not uncommon and generally occurs in the first 6 months following therapy. Risk factors for recurrence include larger tumor size or thickness at original diagnosis, Reese-Ellsworth Group V disease, younger age at diagnosis, and family history of retinoblastoma.[1-5] When the recurrence or progression of retinoblastoma is confined to the eye and is small, the prognosis for sight and survival may be excellent with local therapy only. If the recurrence or progression is confined to the eye but is extensive, the prognosis for sight is poor; however, the survival remains excellent. If the recurrence or progression is extraocular, the chance of survival is probably less than 50%. In this circumstance, the treatment depends on many factors and individual patient considerations; clinical trials may be appropriate and should be considered.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent retinoblastoma ¹⁴. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹¹.

References

1. Shields CL, Honavar SG, Shields JA, et al.: Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol 120 (4): 460-4, 2002.  [PUBMED Abstract]
   
   
2. Gombos DS, Kelly A, Coen PG, et al.: Retinoblastoma treated with primary chemotherapy alone: the significance of tumour size, location, and age. Br J Ophthalmol 86 (1): 80-3, 2002.  [PUBMED Abstract]
   
   
3. Shields CL, Shelil A, Cater J, et al.: Development of new retinoblastomas after 6 cycles of chemoreduction for retinoblastoma in 162 eyes of 106 consecutive patients. Arch Ophthalmol 121 (11): 1571-6, 2003.  [PUBMED Abstract]
   
   
4. Lee TC, Hayashi NI, Dunkel IJ, et al.: New retinoblastoma tumor formation in children initially treated with systemic carboplatin. Ophthalmology 110 (10): 1989-94; discussion 1994-5, 2003.  [PUBMED Abstract]
   
   
5. Wilson MW, Haik BG, Billups CA, et al.: Incidence of new tumor formation in patients with hereditary retinoblastoma treated with primary systemic chemotherapy: is there a preventive effect? Ophthalmology 114 (11): 2077-82, 2007.  [PUBMED Abstract]
   
   

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Changes to This Summary (11/05/2008)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Intraocular Retinoblastoma ⁸

Added text ¹⁸ about treatment options under clinical evaluation and cited a Children's Oncology Group (COG) study of unilateral retinoblastoma with high-risk features.

Added Zage et al. as reference 20 ¹⁹ and level of evidence 3iiDiv.

Added text ²⁰ about treatment options under clinical evaluation and cited two COG studies and a third trial studying the use of adenovirus-mediated gene therapy.

Extraocular Retinoblastoma ⁹

Added text ²¹ to update the status of treatment options under clinical evaluation.

More Information

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• PDQ® - NCI's Comprehensive Cancer Database ²².

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Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment ²³

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment ²⁴

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care ⁵

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer) ²⁵

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention ²⁶

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics ²⁷

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine ²⁸

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Glossary Terms

Consecutive case series (not population-based) with event-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Consecutive case series (not population-based) with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with progression-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.