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NCI/PDQ^® Health professionals: Retinoblastoma Treatment (PDQ®)

National Cancer Institute
Last Modified: October 5, 2012

TABLE OF CONTENTS

• General Information
  • Incidence
  • Hereditary and Nonhereditary Forms of Retinoblastoma
    • Screening
  • Factors Influencing Mortality
    • Trilateral retinoblastoma
    • Subsequent neoplasms
  • Late Effects from Retinoblastoma Therapy

• Cellular Classification

• Stage Information
  • Intraocular
  • Extraocular
  • Reese-Ellsworth Classification for Intraocular Tumors
  • International Classification System for Intraocular Retinoblastoma

• Treatment Option Overview

• Intraocular Retinoblastoma Treatment
  • Unilateral Disease
    • Standard treatment options
  • Bilateral Disease
    • Standard treatment options
  • Treatment Options Under Clinical Evaluation
    • Current Clinical Trials

• Extraocular Retinoblastoma Treatment
  • Standard Treatment Options
    • Orbital and loco-regional retinoblastoma
    • Central nervous system disease
    • Trilateral retinoblastoma
    • Extracranial metastatic retinoblastoma
  • Treatment Options Under Clinical Evaluation
    • Current Clinical Trials

• Recurrent Retinoblastoma Treatment
  • Current Clinical Trials

• Changes to This Summary (10/05/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 1 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 and Palliative Care 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. 2 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.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. 1 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 summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Incidence

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 4 per 1 million children younger than 15 years. Although retinoblastoma may occur at any age, it most often occurs in younger children; the annual incidence is 10 to 14 per 1 million in children aged 0 to 4 years. Ninety-five percent of cases are diagnosed before age 5 years, and two-thirds of these cases occur before age 2 years. Older age is usually associated with more advanced disease and a poorer prognosis. 3

Hereditary and Nonhereditary Forms of Retinoblastoma

Retinoblastoma is a tumor that occurs in heritable (25% to 30%) and nonheritable (70% to 75%) forms. Hereditary disease is defined by the presence of a positive family history, multifocal retinoblastoma, or an identified germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25%) or may have occurred in utero at the time of conception, in patients with sporadic disease (75%). Hereditary retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4. 4 5 Approximately 85% of patients with unilateral retinoblastoma do not have the hereditary form of the disease, whereas all children with bilateral disease are presumed to have the hereditary form, even though only 20% have an affected parent. In hereditary retinoblastoma, tumors tend to occur at a younger age than in the nonhereditary form of the disease. Unilateral retinoblastoma in children younger than 1 year should raise concern for the hereditary disease, whereas older children with a unilateral tumor are more likely to have the nonhereditary form of the disease. 6 7

Screening

Children with the hereditary form of retinoblastoma may continue to develop new tumors for a few years after diagnosis. For this reason, children with hereditary retinoblastoma need to be examined frequently for the development of new tumors. It is recommended that they be examined every 2 to 4 months for at least 28 months. 8 Following treatment, patients require careful surveillance until age 5 years. 9 The interval between exams is based on both the age of the child (more frequent visits as the child ages) and the stability of the disease.

Early-in-life screening by fundus exams under general anesthesia at regular intervals, according to a schedule based on the absolute estimated risk, can improve prognosis in terms of globe sparing in children with positive family histories of retinoblastoma. Intensive screening decreased the need for enucleation and external-beam radiation therapy in a retrospective review of groups of nonscreened versus differently screened children with positive family histories of retinoblastoma. 10

The parents and siblings of patients with retinoblastoma should have screening ophthalmic examinations to exclude an unknown familial disease. Siblings should continue to be screened until age 3 to 5 years or until it is confirmed that they do not have a genetic mutation.

Blood and/or tumor samples can be screened to determine if a retinoblastoma patient has a mutation in the RB1 gene. Once the patient's genetic mutation has been identified, other family members can be screened directly for the mutation. The RB1 gene is located within the q14 band of chromosome 13. Exon by exon sequencing of the RB1 gene demonstrates germline mutation in 90% of patients with hereditary retinoblastoma. 11 12 13 Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out. 14 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 is showing 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. 14 In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected and more exhaustive techniques such as karyotyping, multiplex ligation-dependent probe amplification, and fluorescence in situ hybridization may be needed. The absence of detectable RB1 mutations in some patients may suggest that alternative genetic mechanisms may underlie the development of retinoblastoma. 15

Genetic counseling should be an integral part of the management of patients with retinoblastoma and their families, whether unilateral or bilateral. 16 It is of utmost importance to assist parents in understanding the genetic consequences of each form of retinoblastoma and to estimate risk of disease in family members. 13 16 Genetic counseling, however, is not always straightforward. Families with retinoblastoma may have a founder mutation with embryonic mutagenesis causing genetic mosaicism of gametes. 17 A significant proportion (10%18%) of children with retinoblastoma have somatic genetic mosaicism, 18 19 making the genetic story more complex and contributing to the difficulty of genetic counseling. 14

Factors Influencing Mortality

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. With improvements in the diagnosis and management of retinoblastoma over the past several decades, metastatic retinoblastoma is observed less frequently in the United States and other developed nations. As a result, other causes of retinoblastoma-related mortality in the first decade of life, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality. In the United States, before the advent of chemoreduction as a means of treating bilateral (hereditary) disease, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis. 20 21

Trilateral retinoblastoma

Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with hereditary retinoblastoma and is defined by the development of an intracranial midline neuroblastic tumor, which typically develops more than 20 months after the diagnosis of retinoblastoma. 22 23 Patients who are asymptomatic at the time of diagnosis with an intracranial tumor have a better outcome than patients who are symptomatic. 22

Given the poor prognosis of trilateral retinoblastoma and the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral disease, routine neuroimaging could potentially detect the majority of cases within 2 years of first diagnosis. 22 While it is not clear whether early diagnosis can impact survival, the frequency of screening with magnetic resonance imaging for those suspected of having hereditary disease or those with unilateral disease and a positive family history has been recommended as often as every 6 months for 5 years. It is unclear if this will have an impact on outcome or survival. 23 Computed tomography scans should be avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.

Subsequent neoplasms

Patients with hereditary retinoblastoma have a markedly increased frequency of subsequent neoplasms (SNs). 24 25 The cumulative incidence was reported to be 26% ( 10%) in nonirradiated patients and 58% ( 10%) in irradiated patients by 50 years after diagnosis of retinoblastomaa rate of about 1% per year. 26 However, more recent studies analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients. 27 The most common SNs are osteosarcomas, soft tissue sarcomas, or melanomas. There is no evidence of an increased incidence of acute myeloid leukemia in children with hereditary retinoblastoma. 28[Level of evidence: 3iiiA]

A cohort study of 963 patients, who were at least 1-year survivors of hereditary retinoblastoma diagnosed at two U.S. institutions from 1914 through 1984, evaluated risk for soft tissue sarcoma overall and by histologic subtype. Leiomyosarcoma was the most frequent subtype, with 78% being 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. The carcinogenic effect of radiation increased with dose, particularly for secondary sarcomas where a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of the SNs occur within irradiated tissue and one-third occur outside the radiation field. 26 The risk for SNs is heavily dependent on the patient's age at the time the external-beam radiation therapy is given, especially in children younger than 12 months, and the histopathologic types of SNs may be influenced by age. 27 9 29 These data support a genetic predisposition to soft tissue sarcoma, in addition to the risk of osteosarcoma. 30

It has become apparent that patients with hereditary retinoblastoma are also at risk of developing epithelial cancers late in adulthood. A marked increase in mortality from lung, bladder, and other epithelial cancers has been described. 31 32

Survival from SNs is certainly suboptimal and varies widely across studies. 25 31 33 34 35 36 However, with advances in therapy, it is essential that all SNs be treated with curative intent. 37 Those who survive SNs are at a sevenfold increased risk for developing an SN. 38 The risk further increases threefold when patients are treated with radiation therapy for their retinoblastoma. 39 There is no clear increase in SNs in patients with sporadic retinoblastoma beyond that associated with the treatment. 26 36

Late Effects from Retinoblastoma Therapy

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 and Extraocular Retinoblastoma sections of this summary for more information), concern has been raised about hearing loss related to therapy. However, an analysis of 164 children treated with six cycles of carboplatin-containing therapy (18.6 mg/kg per cycle) showed no loss of hearing among children who had a normal initial audiogram. 42

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
2. 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]
3. 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]
4. Castéra L, Sabbagh A, Dehainault C, et al.: MDM2 as a modifier gene in retinoblastoma. J Natl Cancer Inst 102 (23): 1805-8, 2010. [PUBMED Abstract]
5. de Oliveira Reis AH, de Carvalho IN, de Sousa Damasceno PB, et al.: Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma. Pediatr Blood Cancer 59 (1): 39-43, 2012. [PUBMED Abstract]
6. 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]
7. 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. [PUBMED Abstract]
8. Abramson DH, Mendelsohn ME, Servodidio CA, et al.: Familial retinoblastoma: where and when? Acta Ophthalmol Scand 76 (3): 334-8, 1998. [PUBMED Abstract]
9. 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]
10. Rothschild PR, Lévy D, Savignoni A, et al.: Familial retinoblastoma: fundus screening schedule impact and guideline proposal. A retrospective study. Eye (Lond) 25 (12): 1555-61, 2011. [PUBMED Abstract]
11. 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]
12. 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]
13. Richter S, Vandezande K, Chen N, et al.: Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet 72 (2): 253-69, 2003. [PUBMED Abstract]
14. Clark R: Retinoblastoma: genetic testing and counseling. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 441-6. [PUBMED Abstract]
15. 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]
16. 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]
17. 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]
18. 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]
19. 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]
20. Blach LE, McCormick B, Abramson DH, et al.: Trilateral retinoblastoma--incidence and outcome: a decade of experience. Int J Radiat Oncol Biol Phys 29 (4): 729-33, 1994. [PUBMED Abstract]
21. Broaddus E, Topham A, Singh AD: Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93 (1): 24-7, 2009. [PUBMED Abstract]
22. Paulino AC: Trilateral retinoblastoma: is the location of the intracranial tumor important? Cancer 86 (1): 135-41, 1999. [PUBMED Abstract]
23. Kivelí 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]
24. 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]
25. Marees T, Moll AC, Imhof SM, et al.: Risk of second malignancies in survivors of retinoblastoma: more than 40 years of follow-up. J Natl Cancer Inst 100 (24): 1771-9, 2008. [PUBMED Abstract]
26. 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]
27. 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]
28. 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]
29. 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]
30. 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]
31. 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]
32. Marees T, van Leeuwen FE, de Boer MR, et al.: Cancer mortality in long-term survivors of retinoblastoma. Eur J Cancer 45 (18): 3245-53, 2009. [PUBMED Abstract]
33. Yu CL, Tucker MA, Abramson DH, et al.: Cause-specific mortality in long-term survivors of retinoblastoma. J Natl Cancer Inst 101 (8): 581-91, 2009. [PUBMED Abstract]
34. 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]
35. 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]
36. 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]
37. 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]
38. 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]
39. Marees T, van Leeuwen FE, Schaapveld M, et al.: Risk of third malignancies and death after a second malignancy in retinoblastoma survivors. Eur J Cancer 46 (11): 2052-8, 2010. [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

Retinoblastoma is composed mainly of undifferentiated anaplastic cells that arise from 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 available for retinoblastoma, for the purpose of treatment, retinoblastoma is categorized into intraocular and extraocular disease.

Intraocular

Intraocular retinoblastoma is localized to the eye and may be confined to the retina or may extend to involve other structures such as the choroid, ciliary body, anterior chamber, and optic nerve head. Intraocular retinoblastoma, however, does not extend beyond the eye into the tissues around the eye or to other parts of the body.

Extraocular

Extraocular (metastatic) retinoblastoma has extended beyond the eye. It may be confined to the tissues around the eye (orbital retinoblastoma), or it may have spread to the central nervous system, bone marrow, or lymph nodes (metastatic retinoblastoma).

Reese-Ellsworth Classification for Intraocular Tumors

Reese and Ellsworth developed a 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 primary treatment options.

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 of the retina.
2. Vitreous seeding.

International Classification System for Intraocular Retinoblastoma

There is a new classification system for retinoblastoma, which may offer greater precision in stratifying risk for newer therapies. 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 2 3 4

• 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 the following 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. [PUBMED Abstract]
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]
4. Novetsky DE, Abramson DH, Kim JW, et al.: Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies--an analysis of impact. Ophthalmic Genet 30 (1): 40-4, 2009. [PUBMED Abstract]

Treatment Option Overview

Treatment planning by a multidisciplinary team of cancer specialists, including a pediatric oncologist, ophthalmologist, and radiation oncologist, who have experience treating ocular tumors of childhood is required to optimize treatment planning. 1

The goals of therapy are threefold:

1. Eradicate the disease to save the patient's life.
2. Preserve as much vision as possible.
3. Decrease risk of late sequelae from treatment, particularly subsequent neoplasms.

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. 2 Eyes with glaucoma and those in which glaucoma resulted in buphthalmia are significantly associated with high-risk pathology risk factors and the occurrence of microscopically residual tumor. 3 Enucleation is reserved for patients with advanced unilateral intraocular disease with no hope for useful vision in the affected eye. Subsequent risk of extraocular recurrence may be increased in the presence of high-risk histopathologic features such as massive choroid invasion, scleral invasion, and optic nerve invasion. 4 5; 6[Level of evidence: 3iiDi] Clinical features predictive of these histological findings include eyes with glaucoma, especially those that have become buphthalmic. 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. 7 8 Examples include patients with an abnormal complete blood count or those whose tumors show massive choroidal involvement and which 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 may be used to treat the more severe eye. 9 10 There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma. 11

References:

1. Chintagumpala M, Chevez-Barrios P, Paysse EA, et al.: Retinoblastoma: review of current management. Oncologist 12 (10): 1237-46, 2007. [PUBMED Abstract]
2. 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]
3. Chantada GL, Gonzalez A, Fandino A, et al.: Some clinical findings at presentation can predict high-risk pathology features in unilateral retinoblastoma. J Pediatr Hematol Oncol 31 (5): 325-9, 2009. [PUBMED Abstract]
4. Cuenca A, Giron F, Castro D, et al.: Microscopic scleral invasion in retinoblastoma: clinicopathological features and outcome. Arch Ophthalmol 127 (8): 1006-10, 2009. [PUBMED Abstract]
5. Gupta R, Vemuganti GK, Reddy VA, et al.: Histopathologic risk factors in retinoblastoma in India. Arch Pathol Lab Med 133 (8): 1210-4, 2009. [PUBMED Abstract]
6. 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]
7. 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]
8. 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]
9. 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]
10. Shields CL, Mashayekhi A, Demirci H, et al.: Practical approach to management of retinoblastoma. Arch Ophthalmol 122 (5): 729-35, 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]

Intraocular Retinoblastoma Treatment

Treatment of retinoblastoma is individualized and considers the age of the patient, laterality, potential for vision, and intraocular tumor burden. Treatment options consider both cure of the disease and preservation of sight. 1 2 3 Different combinations of the following approaches may be applied to the individual patient, considering the two main scenarios, unilateral and bilateral disease.

Treatment options for the involved eye include the following:

1. Enucleation: If the tumor is massive and there is little expectation for useful vision in the affected eye, up-front enucleation may be indicated, depending on laterality. Patients must be monitored closely for orbital recurrence of disease, particularly in the first 2 years after enucleation. 4[Level of evidence: 3iiA] Recurrence in the orbit is often associated with systemic disease (85%) and should be treated with aggressive therapy.
2. Radiation therapy:
   • External-beam radiation therapy (EBRT): Retinoblastoma is a very radiosensitive malignancy; EBRT doses ranging from 35 Gy to 46 Gy usually result in long-term remissions. 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, stereotactic radiation therapy, and proton-beam radiation therapy (charged-particle radiation therapy). 5 6 7 EBRT in infants causes growth failure of the orbital bones and results in cosmetic deformity. It also increases the risk of subsequent neoplasms in children with hereditary retinoblastoma.
   • Brachytherapy: Brachytherapy with radioactive plaques is very effective in the treatment of localized retinal tumors that are not amenable to other means of local therapy. 8 9 10

3. Local treatments: For patients undergoing eye salvage treatment, aggressive local therapy is required.
   • Cryotherapy: Cryotherapy is based on the application of a cryoprobe to the sclera in the immediate vicinity of the retinal tumor. It is used as primary therapy or with chemotherapy for tumors smaller than 4 disc diameters (DD) in the anterior portion of the retina.
   • Laser therapy (thermotherapy): Laser therapy may be used as primary therapy for small tumors or in combination with chemotherapy for larger tumors. Traditional photocoagulation, in which the laser was applied around the tumor, has given way to thermotherapy. Thermotherapy is delivered directly to the tumor surface via infrared wavelengths of light. 11

4. Systemic chemotherapy: Systemic chemotherapy plays a role both in the adjuvant setting for patients with high-risk pathology, and in the eye-salvage regimens, where it is used in conjunction with aggressive focal treatments. During the past 15 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 laser therapy. 1 12 13; 14[Level of evidence: 3iiDiii] Chemotherapy may also be continued or initiated with concurrent local control interventions. 15 Factors such as tumor location (macula), patient age (patient older than 2 months), and tumor size correlate with responsiveness to chemotherapy. 15 16

   Multiagent chemotherapy is generally used, although carboplatin as a single agent causes shrinkage of retinoblastoma tumors. 17; ; 18[[Level of evidence: 3iiiDiiiLevel of evidence: 3iiiDiii] Most standard regimens incorporate vincristine, carboplatin, and etoposide, although a two-drug regimen without etoposide may also be effective for early intraocular stages.] Most standard regimens incorporate vincristine, carboplatin, and etoposide, although a two-drug regimen without etoposide may also be effective for early intraocular stages. 1 12 13 16 19 20 21 22 The success rate of these trials varies from center to center, but overall, the rate is highest for discrete tumors without vitreous seeding. Local tumor recurrence is not uncommon in the first few years after treatment The success rate of these trials varies from center to center, but overall, the rate is highest for discrete tumors without vitreous seeding. Local tumor recurrence is not uncommon in the first few years after treatment 23 and can often be successfully treated with focal therapy. and can often be successfully treated with focal therapy. 10 Among patients with hereditary disease, younger patients and those with positive family histories 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. Among patients with hereditary disease, younger patients and those with positive family histories 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. 24

   There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma. 25

5. Subtenon (subconjunctival) chemotherapy: Periocular delivery of carboplatin results in high intraocular concentrations of the agent, and this approach is often used in ocular salvage approaches, particularly when there is a high intravitreous tumor burden. Carboplatin is administered by the treating ophthalmologist into the subtenon space, and it is generally used in conjunction with systemic chemotherapy and local ophthalmic therapies. 26 27 28 Responses have also been noted with subtenon topotecan. 29
6. Ophthalmic artery infusion of chemotherapy: Direct delivery of chemotherapy into the eye globe via cannulation of the ophthalmic artery is a feasible and effective method for ocular salvage. Melphalan was the chemotherapeutic agent used in the first studies, although it can be associated with significant local side effects, including third cranial nerve palsy, orbital edema, permanent retinal detachment, vitreous hemorrhage, and retinal pigment epithelium changes. 30 Other agents such as topotecan and carboplatin are also being tested. Ocular salvage rates are greater than 70% when ophthalmic artery infusion of chemotherapy is used as primary treatment, although success rates are inferior when this approach is used after failure of systemic chemotherapy or radiation. 31 32 33 Retinal and choroidal vasculopathy may occur in 10% to 20% of patients. 34 This modality continues to undergo study at very specialized retinoblastoma treatment centers, but preliminary data appear to indicate that this treatment modality results in satisfactory ocular salvage rates in patients with intraocular unilateral retinoblastoma. 31 33 34 35 36 37 38

   This treatment is not without complications in some cases. 31 37 39

Unilateral Disease

Standard treatment options

Because unilateral disease is usually massive and there is often no expectation that useful vision can be preserved, up-front surgery (enucleation) is usually recommended. Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These features include anterior chamber seeding, choroidal involvement, tumor beyond the lamina cribrosa, or scleral and extrascleral extension. 40 41 42 Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide or with 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, 43 44 45 46; 47[Level of evidence: 2A] with the suggestion of success compared with historical controls. 48[Level of evidence: 3iiDiii]

Patients with unilateral disease may also be offered chemotherapy and aggressive focal treatments in an attempt to save the eye and preserve vision. 1 49 50 Ocular salvage rates correlate with intraocular stage. 51 In selected children with unilateral disease, 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. 52 Caution must be exerted with extended chemotherapy and delayed enucleation when tumor control does not appear to be possible. Pre-enucleation chemotherapy for eyes with advanced intraocular disease may result in downstaging and underestimate the pathological evidence of extraretinal and extraocular disease, thus, increasing the risk of dissemination. 53

Pilot studies have evaluated the delivery of chemotherapy via ophthalmic artery cannulation as initial treatment for advanced unilateral and bilateral intraocular retinoblastoma. In the setting of a multidisciplinary, state-of-the-art center, intra-arterial chemotherapy may result in ocular salvage rates in excess of 80% for patients with advanced intraocular unilateral retinoblastoma. 31 35[Level of evidence: 3iiiDii]; 32[Level of evidence: 3iiiDiv]

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, regardless of the treatment they received. Asynchronous bilateral disease occurs most frequently in patients with affected parents and in children diagnosed during the first months of life. Pre-enucleation magnetic resonance imaging has low sensitivity and specificity for the detection of high-risk pathology. 54 As discussed, genetic counseling and testing at the time of diagnosis is the key to defining risk and planning follow-up.

Bilateral Disease

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. Treatment modality options described for unilateral disease may be applied to one or both affected eyes in patients with bilateral disease.

Standard treatment options

Usually the disease is more advanced in one eye, with less involvement in the other eye. Overall treatment management is dictated by the most advanced eye. While up-front enucleation of an advanced eye and risk-adapted adjuvant chemotherapy may be required, a more conservative approach using primary chemoreduction with close follow-up for response and focal treatment (e.g., cryotherapy or laser therapy) may be indicated. EBRT is now reserved for patients whose eyes do not respond adequately to primary systemic chemotherapy and focal consolidation.

A number of large centers in Europe and North America have published trial results using systemic chemotherapy in conjunction with aggressive focal consolidation for patients with bilateral disease. 1 20 23 24 50 51 55 56 57 58 59 60 61 62 63; 22[Level of evidence: 3iiDiv] Chemotherapy may shrink the tumors (chemoreduction), allowing greater efficacy of subsequent focal therapy. 1 40 Treatment strategies often differ in terms of chemotherapy regimens and local control measures.

Centers using the R-E classification have demonstrated that the goal to save eyes may be achievable for tumors that are R-E Group IV or lower. 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 that enucleation or EBRT may be avoided in R-E Group I, II, and III eyes when patients were treated with six cycles. 1 12 21 Tumors associated with massive vitreous or subretinal seeds have proven problematic. 64 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 12

Other researchers reported the use of nine courses of CEV with the addition of high-dose cyclosporine A (a modulator of the p-glycoprotein) for eight R-E Group V eyes with an 88% (7 out of 8 eyes) success rate without the use of EBRT or enucleation. 58 59 However, conflicting results were seen in another study using the cyclosporine regimen in ten R-E Group V eyes, which reported only a 20% (2 out of 10 eyes) success rate. 60

The International Classification