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Retinoblastoma Treatment (PDQ®)

Health Professional Version
Last Modified: 12/06/2013
Table of Contents

General Information

Cellular Classification

Stage Information

Treatment Option Overview

Intraocular Retinoblastoma Treatment

Extraocular Retinoblastoma Treatment

Recurrent Intraocular Retinoblastoma Treatment

Changes to This Summary (12/06/2013)

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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 following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

  • 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.

(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.[1,3,4] Between 1975 and 2010, childhood cancer mortality has decreased by more than 50%.[1,3,4] 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 summary on Late Effects of Treatment for Childhood Cancer 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 cases 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 cases 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.[5]

Heritable and Nonheritable Forms of Retinoblastoma

Retinoblastoma is a tumor that occurs in heritable (25% to 30%) and nonheritable (70% to 75%) forms. Heritable 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%). Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4.[6,7] Approximately 85% of patients with unilateral retinoblastoma do not have the heritable form of the disease, whereas all children with bilateral disease are presumed to have the heritable form, even though only 25% have an affected parent. In heritable retinoblastoma, tumors tend to be diagnosed at a younger age than in the nonheritable form of the disease. Unilateral retinoblastoma in children younger than 1 year raises concern for heritable disease, whereas older children with a unilateral tumor are more likely to have the nonheritable form of the disease.[8,9]

Screening

Children with the heritable form of retinoblastoma may continue to develop new tumors for a few years after diagnosis and treatment; for this reason, they 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.[10] The interval between exams is based on the age of the child (less 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 and use of less-intensive, ocular-salvage treatments in children with a positive family history of retinoblastoma.[11] Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, periodic examinations of the unaffected eye are performed until the germline status of the RB1 gene is determined.

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 patient with retinoblastoma 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 heritable retinoblastoma.[12-14] Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out.[15] A multistep assay including 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 may need to be performed for a complete genetic evaluation of the RB1 gene.[15] 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, fluorescence in situ hybridization, and methylation analysis of the RB1 promoter may be needed. The absence of detectable RB1 mutations in some patients may suggest that alternative genetic mechanisms may underlie the development of retinoblastoma.[16] In a report of 29 patients with clinical retinoblastoma and no evidence of a RB1 mutation, 15 demonstrated high levels of MYCN amplification. These patients had distinct, aggressive, histologic features and a median age at diagnosis of 4 months.[17]

Genetic counseling is an integral part of the management of patients with retinoblastoma and their families, regardless of clinical presentation;[18] counseling assists parents in understanding the genetic consequences of each form of retinoblastoma and in estimating the risk of disease in family members.[14,18] Genetic counseling, however, is not always straightforward. Families with retinoblastoma may have a founder mutation with embryonic mutagenesis causing genetic mosaicism of gametes.[19] A significant proportion (10%–18%) of children with retinoblastoma have somatic genetic mosaicism,[20,21] making the genetic story more complex and contributing to the difficulty of genetic counseling.[15]

(Refer to the PDQ summaries on Cancer Genetics Risk Assessment and Counseling and Cancer Genetics Overview for more information.)

Factors Influencing Mortality

The present challenge for those who treat retinoblastoma is to preserve life and to prevent the 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 (heritable) disease, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis.[22]

Trilateral retinoblastoma

Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with heritable 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.[23] Patients who are asymptomatic at the time of diagnosis with an intracranial tumor have a better outcome than patients who are symptomatic.

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. Although it is not clear whether early diagnosis can impact survival, screening with magnetic resonance imaging has been recommended as often as every 6 months for 5 years for those suspected of having heritable disease or those with unilateral disease and a positive family history.[23] Computed tomography scans are generally avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.

Subsequent neoplasms (SNs)

Patients with heritable retinoblastoma have a markedly increased frequency of SNs.[24,25] There may be an association between type of RB1 mutation and incidence of SNs, with complete loss of RB1 activity having a higher incidence of SNs.[26] The cumulative incidence was reported to be 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.[27] 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.[28] The most common SN is osteosarcoma, followed by soft tissue sarcoma and melanoma; these malignancies may occur inside or outside of the radiation field, although most are radiation-induced. The carcinogenic effect of radiation therapy is associated with the dose delivered, particularly for subsequent sarcomas, where a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of SNs occur within irradiated tissue, and one-third occur outside the radiation field.[27-29]

The risk of SNs also appears to be 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.[28,30,31] These data support a genetic predisposition to soft tissue sarcomas, in addition to the risk of osteosarcoma.[29]

There is no evidence of an increased incidence of acute myeloid leukemia in children with heritable retinoblastoma.[32]; [33][Level of evidence: 3iiiA] Of 245 patients, all of whom received etoposide, only one patient had acute promyelocytic leukemia after 79 months.[32]

With the increase in survival of patients with heritable retinoblastoma, it has become apparent that they 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.[34,35]

Survival from SNs is certainly suboptimal and varies widely across studies.[25,34,36-39] However, with advances in therapy, it is essential that all SNs be treated with curative intent.[40] Those who survive SNs are at a sevenfold increased risk for developing another SN.[41] The risk further increases threefold when patients are treated with radiation therapy for their retinoblastoma.[42] Retinoblastoma survivors with bilateral disease and an inherited germline mutation are at a slightly higher risk of a SN than those without an inherited mutation; this increase appears to be most significant for melanoma.[43]

There is no clear increase in SNs in patients without a germline retinoblastoma mutation beyond that associated with the treatment.[27,39]

Late Effects from Retinoblastoma Therapy

Orbital growth is somewhat diminished after enucleation; however, the impact of enucleation on orbital volume may be less after placement of an orbital implant.[44]

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.[45] One study of visual acuity after 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.[46]

Because systemic carboplatin is now commonly used in the treatment of retinoblastoma (refer to the Intraocular Retinoblastoma and Extraocular Retinoblastoma sections of this summary for more information), concern has been raised about hearing loss related to therapy. While 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,[47] another series documented hearing loss in 17% of patients.[48] Age younger than 6 months at the time of treatment and higher carboplatin systemic exposures appear to correlate with an increased risk of ototoxicity.[48,49]

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. Childhood cancer. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, based on November 2012 SEER data submission, posted to the SEER web site, April 2013, Section 28. Also available online. Last accessed April 04, 2014. 

  4. Childhood cancer by the ICCC. In: Howlader N, Noone AM, Krapcho M, et al., eds.: SEER Cancer Statistics Review, 1975-2010. Bethesda, Md: National Cancer Institute, based on November 2012 SEER data submission, posted to the SEER web site, April 2013, Section 29. Also available online. Last accessed June 26, 2014. 

  5. 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]

  6. 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]

  7. 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]

  8. 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]

  9. 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. 

  10. Abramson DH, Mendelsohn ME, Servodidio CA, et al.: Familial retinoblastoma: where and when? Acta Ophthalmol Scand 76 (3): 334-8, 1998.  [PUBMED Abstract]

  11. 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]

  12. 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]

  13. 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]

  14. 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]

  15. Clark R: Retinoblastoma: genetic testing and counseling. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 441-6. 

  16. 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]

  17. Rushlow DE, Mol BM, Kennett JY, et al.: Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol 14 (4): 327-34, 2013.  [PUBMED Abstract]

  18. 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]

  19. 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]

  20. 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]

  21. 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]

  22. Broaddus E, Topham A, Singh AD: Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93 (1): 24-7, 2009.  [PUBMED Abstract]

  23. 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]

  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. Dommering CJ, Marees T, van der Hout AH, et al.: RB1 mutations and second primary malignancies after hereditary retinoblastoma. Fam Cancer 11 (2): 225-33, 2012.  [PUBMED Abstract]

  27. 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]

  28. 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]

  29. 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]

  30. 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]

  31. 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]

  32. Turaka K, Shields CL, Meadows AT, et al.: Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma. Pediatr Blood Cancer 59 (1): 121-5, 2012.  [PUBMED Abstract]

  33. 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]

  34. 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]

  35. 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]

  36. 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]

  37. 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]

  38. 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]

  39. 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]

  40. 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]

  41. 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]

  42. 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]

  43. Kleinerman RA, Yu CL, Little MP, et al.: Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol 30 (9): 950-7, 2012.  [PUBMED Abstract]

  44. Chojniak MM, Chojniak R, Testa ML, et al.: Abnormal orbital growth in children submitted to enucleation for retinoblastoma treatment. J Pediatr Hematol Oncol 34 (3): e102-5, 2012.  [PUBMED Abstract]

  45. Abramson DH, Melson MR, Servodidio C: Visual fields in retinoblastoma survivors. Arch Ophthalmol 122 (9): 1324-30, 2004.  [PUBMED Abstract]

  46. 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]

  47. 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]

  48. Qaddoumi I, Bass JK, Wu J, et al.: Carboplatin-associated ototoxicity in children with retinoblastoma. J Clin Oncol 30 (10): 1034-41, 2012.  [PUBMED Abstract]

  49. Leahey A: A cautionary tale: dosing chemotherapy in infants with retinoblastoma. J Clin Oncol 30 (10): 1023-4, 2012.  [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, extremely high MIB-1 labeling indices, and strong diffuse nuclear immunoreactivity for CRX, a useful marker to discriminate retinoblastoma from other malignant small round cell tumors.[1,2]

Cavitary Retinoblastoma

Cavitary retinoblastoma, a rare variant of retinoblastoma, has ophthalmoscopically visible lucent cavities within the tumor. The cavitary spaces appear hollow on ultrasonography and hypofluorescent on angiography. Histopathologically, the cavitary spaces have been shown to represent areas of photoreceptor differentiation.[3] These tumors have been associated with minimal visible tumor response to chemotherapy, which is thought to be a sign of tumor differentiation.[4]

References
  1. Terry J, Calicchio ML, Rodriguez-Galindo C, et al.: Immunohistochemical expression of CRX in extracranial malignant small round cell tumors. Am J Surg Pathol 36 (8): 1165-9, 2012.  [PUBMED Abstract]

  2. 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]

  3. Palamar M, Pirondini C, Shields CL, et al.: Cavitary retinoblastoma: ultrasonographic and fluorescein angiographic findings in 3 cases. Arch Ophthalmol 126 (11): 1598-600, 2008.  [PUBMED Abstract]

  4. Mashayekhi A, Shields CL, Eagle RC Jr, et al.: Cavitary changes in retinoblastoma: relationship to chemoresistance. Ophthalmology 112 (6): 1145-50, 2005.  [PUBMED Abstract]

Stage Information

Although there are several staging systems available for retinoblastoma,[1] for the purpose of treatment, retinoblastoma is categorized into intraocular and extraocular disease. Overall assessment of retinoblastoma extension is documented by staging systems; the intraocular extension, which is relevant for ocular salvage, is documented by grouping systems.

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).

Staging Systems

AJCC Staging System

Several staging systems have been proposed over the years. The AJCC clinical and pathological classifications represent a consensus opinion around which a common language is used.

Clinical classification system

Table 1. Primary Tumor (T)a
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
TXPrimary tumor cannot be assessed.
T0No evidence of primary tumor.
T1Tumors no more than 2/3 the volume of the eye with no vitreous or subretinal seeding.
T1aNo tumor in the either eye is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea.
T1bAt least one tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea. No retinal detachment or subretinal fluid beyond 5 mm from above the base of the tumor.
T1cAt least one tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea, with retinal detachment or subretinal fluid beyond 5 mm from the base of the tumor.
T2Tumors no more than 2/3 the volume of the eye with vitreous or subretinal seeding. Can have retinal detachment.
T2aFocal vitreous and/or subretinal seeding of fine aggregates of tumor cells is present, but no large clumps or "snowballs" of tumor cells.
T2bMassive vitreous and/or subretinal seeding is present, defined as diffuse clumps or "snowballs" of tumor cells.
T3Severe intraocular disease.
T3aTumor fills more than 2/3 of the eye.
T3bOne or more complications present, which may include tumor-associated neovascular or angle closure glaucoma, tumor extension into the anterior segment, hyphema, vitreous hemorrhage, or orbital cellulitis.
T4Extraocular disease detected by imaging studies.
T4aInvasion of optic nerve.
T4bInvasion of the orbit.
T4cIntracranial extension not past chiasm.
T4dIntracranial extension past chiasm.

Table 2. Regional Lymph Nodes (N)a
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
NXRegional lymph nodes cannot be assessed.
N0No regional lymph node involvement.
N1Regional lymph node involvement (preauricular, cervical, submandibular).
N2Distant lymph node involvement.

Table 3. Metastasis (M)a
M0No metastasis.
M1Systemic metastasis.
M1aSingle lesion to sites other than CNS.
M1bMultiple lesions to sites other than CNS.
M1cPrechiasmatic CNS lesion(s).
M1dPostchiasmatic CNS lesion(s).
M1eLeptomeningeal and/or CSF involvement.

CNS = central nervous system; CSF = cerebrospinal fluid.
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.

Pathologic classification system

Table 4. Primary Tumor (pT)a
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
pTxPrimary tumor cannot be assessed.
pT0No evidence of primary tumor.
pT1Tumor confined to eye with no optic nerve or choroidal invasion.
pT2Tumor with minimal optic nerve and/or choroidal invasion.
pT2aTumor superficially invades optic nerve head but does not extend past lamina cribrosa or tumor exhibits focal choroidal invasion.
pT2bTumor superficially invades optic nerve head but does not extend past lamina cribrosa and exhibits focal choroidal invasion.
pT3Tumor with significant optic nerve and/or choroidal invasion.
pT3aTumor invades optic nerve past lamina cribrosa but not to surgical resection line or tumor exhibits massive choroidal invasion.
pT3bTumor invades optic nerve past lamina cribrosa but not to surgical resection line and exhibits massive choroidal invasion.
pT4Tumor invades optic nerve to resection line or exhibits extra-ocular extension elsewhere.
pT4aTumor invades optic nerve to resection line but no extra-ocular extension identified.
pT4bTumor invades optic nerve to resection line and extra-ocular extension identified.

Table 5. Regional Lymph Nodes (pN)a
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.
pNXRegional lymph nodes cannot be assessed.
pN0No regional lymph node involvement.
pN1Regional lymph node involvement (preauricular, cervical).
N2Distant lymph node involvement.

Table 6. Metastasis (pM)a
cM0No metastasis.
pM1Metastasis to sites other than CNS.
pM1aSingle lesion.
pM1bMultiple lesions.
pM1cCNS metastasis.
pM1dDiscrete mass(es) without leptomeningeal and/or CSF involvement.
pM1eLeptomeningeal and/or CSF involvement.

CNS = central nervous system; CSF = cerebrospinal fluid.
aReprinted with permission from AJCC: Retinoblastoma. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 562–63.

International Retinoblastoma Staging System

A simplified staging system, the International Retinoblastoma Staging System, has been proposed by an international consortium of ophthalmologists and pediatric oncologists.[2]

Table 7. International Retinoblastoma Staging System
Stage Description 
CNS = central nervous system; CSF = cerebrospinal fluid.
Stage 0Eye has not been enucleated and no dissemination of disease (refer to the International Classification of Retinoblastoma section of this summary for more information).
Stage IEye enucleated, completely resected histologically
Stage IIEye enucleated, microscopic residual tumor
Stage IIIRegional extensiona. Overt orbital disease
b. Preauricular or cervical lymph node extension
Stage IVMetastatic diseasea. Hematogenous metastasis (without CNS involvement)
1. Single lesion
2. Multiple lesions
b. CNS extension (with or without any other site of regional or metastatic disease)
1. Prechiasmatic lesion
2. CNS mass
3. Leptomeningeal and CSF disease

Grouping Systems

Grouping systems are relevant for assessment of intraocular disease extension and are helpful predictors of ocular salvage.

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 of Retinoblastoma

There is a new grouping system for retinoblastoma, which may offer greater precision in stratifying risk for newer therapies. The International Classification of Retinoblastoma that is used in the current Children’s Oncology Group treatment studies and 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.[3-6] The International Classification of Retinoblastoma was able to predict high-risk histopathology in a study of over 500 patients with retinoblastoma. Histopathologic evidence of high-risk disease was noted in 17% of Group D and 24% of Group E eyes in this study. Such predication can be helpful in counseling parents regarding the need for postoperative systemic therapy.[7]

  • 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. Chantada GL, Sampor C, Bosaleh A, et al.: Comparison of staging systems for extraocular retinoblastoma: analysis of 533 patients. JAMA Ophthalmol 131 (9): 1127-34, 2013.  [PUBMED Abstract]

  2. Chantada G, Doz F, Antoneli CB, et al.: A proposal for an international retinoblastoma staging system. Pediatr Blood Cancer 47 (6): 801-5, 2006.  [PUBMED Abstract]

  3. Murphree L: Staging and grouping of retinoblastoma. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 422-7. 

  4. 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]

  5. Shields CL, Mashayekhi A, Au AK, et al.: The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113 (12): 2276-80, 2006.  [PUBMED Abstract]

  6. 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]

  7. Kaliki S, Shields CL, Rojanaporn D, et al.: High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology 120 (5): 997-1003, 2013.  [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 outcomes.[1] Evaluation at specialized treatment centers is highly suggested before the initiation of treatment in order to improve the likelihood of ocular salvage.

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 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.[4-6]; [7][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.[8-10]

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.[11,12]

Metastasis from retinoblastoma generally develops within 1 year of diagnosis. If there is no metastatic disease by 5 years after treatment, the patient is generally considered cured.[13]

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. Sastre X, Chantada GL, Doz F, et al.: Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Arch Pathol Lab Med 133 (8): 1199-202, 2009.  [PUBMED Abstract]

  7. 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]

  8. 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]

  9. 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]

  10. Zacharoulis S, Abramson DH, Dunkel IJ: More aggressive bone marrow screening in retinoblastoma patients is not indicated: the memorial Sloan-Kettering cancer center experience. Pediatr Blood Cancer 46 (1): 56-61, 2006.  [PUBMED Abstract]

  11. 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]

  12. Shields CL, Mashayekhi A, Demirci H, et al.: Practical approach to management of retinoblastoma. Arch Ophthalmol 122 (5): 729-35, 2004.  [PUBMED Abstract]

  13. Broaddus E, Topham A, Singh AD: Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93 (1): 24-7, 2009.  [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. When selecting a treatment option, cure of the disease, preservation of sight, and prevention of late effects should be considered.[1]

Different combinations of the following approaches may be applied to the individual patient depending on whether the patient has unilateral or 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.[2][Level of evidence: 3iiA] Recurrence in the orbit is often associated with systemic disease (85%) and warrants treatment 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).[3-5] 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 heritable 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.[6-8]

  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.[9,10]

  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.[1,11]; [12][Level of evidence: 3iiDiii] 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 standard regimens incorporate vincristine, carboplatin, and etoposide, although a two-drug regimen without etoposide may also be effective for early intraocular stages.[1,11,14,17-19] 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 [20] and can often be successfully treated with focal therapy.[8] 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.[21]

    There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma.[22]

  5. Ophthalmic artery infusion of chemotherapy: Direct delivery of chemotherapy into the eye via cannulation of the ophthalmic artery is a feasible and effective method for ocular salvage. Melphalan is the most commonly used chemotherapeutic agent.[23] Other agents such as topotecan and carboplatin are also being tested, given as single agents or in combination.[24] Ocular salvage rates are higher 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.[23,25-27] This modality continues to undergo study at very specialized retinoblastoma treatment centers, but preliminary data appear to indicate that this treatment approach results in satisfactory ocular salvage rates as first-line therapy in patients with intraocular unilateral retinoblastoma and as a salvage treatment in patients who have failed other conservative approaches.[23,26-32]; [24,33][Level of evidence: 3iiDiii]; [34,35][Level of evidence: 3iiDiv]

    Small body and ocular size may pose technical limitations to its use in very young patients. Intravenous chemotherapy has been used in neonates and young infants to postpone intra-arterial chemotherapy. One or several cycles of single-agent carboplatin have been used to bridge the time until the child is aged 3 months and weighs 6 kg.[36][Level of evidence: 3iiiDi]

    In a recent report of 81 patients with heritable retinoblastoma, intra-arterial chemotherapy was able to eliminate ophthalmoscopically undetectable tumors present at diagnosis in the majority of patients.[37][Level of evidence: 3iiDi]

    This treatment is not without complications in some cases.[23,30,38,39] Retinal and choroidal vasculopathy may occur in 10% to 20% of patients.[32,40]

  6. Intravitreal chemotherapy: Pilot studies suggest that direct intravitreal injection of melphalan may be effective in controlling active vitreous seeds.[33][Level of evidence: 3iiDi]; [41][Level of evidence: 3iiiDiii] While concerns of the potential for tumor dissemination have limited its use, a recent review calculated that the proportion of patients with extraocular tumor spread potentially due to intravitreal injection was 0.007 (95% CI, 0.0008–0.0236).[42]

  7. 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 for patients with vitreous disease.[43,44] Responses have also been noted with subtenon topotecan.[45] With the advent of intra-arterial and intravitreal delivery of chemotherapy, periocular administration is now seldomly used.

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.[19,46-48] 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,[19,49-52]; [53][Level of evidence: 2A] with the suggestion of success compared with historical controls.[54][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] Ocular salvage rates correlate with intraocular stage. In selected children with unilateral disease, Reese-Ellsworth (R-E) Group correlated with successful systemic 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.[55] Caution must be exerted with extended systemic 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.[56]

The delivery of chemotherapy via ophthalmic artery cannulation as initial treatment for advanced unilateral retinoblastoma appears to be more effective than systemic chemoreduction. 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.[27]; [23,28][Level of evidence: 3iiiDii]; [25][Level of evidence: 3iiiDiv]

Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, these children are candidates for genetic counseling and testing and 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.[57] 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 is generally 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. Chemoreduction (systemic or intra-arterial) coupled with aggressive focal treatments and very close monitoring is usually the treatment of choice, with the goal of ocular and vision preservation and the delay or avoidance of EBRT and enucleation.

Standard treatment options

Intraocular tumor burden is usually asymmetric. Treatment 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 or intra-arterial chemotherapy and focal consolidation.

A number of large centers in Europe and North America have published trial results that used systemic chemotherapy in conjunction with aggressive focal consolidation for patients with bilateral disease.[1,18,20,21,58-63] Chemotherapy may shrink the tumors (chemoreduction), allowing greater efficacy of subsequent focal therapy.[1] Treatment strategies often differ in terms of chemotherapy regimens and local control measures.

Centers using the R-E Classification for Intraocular Tumors 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); using this regimen in combination with aggressive focal treatments, enucleation or EBRT may be avoided in R-E Groups I, II, and III eyes.[1,11] Tumors associated with massive vitreous or subretinal seeds have proven problematic.[64] Local control is often transient in patients with vitreous seeding or very large tumors (R-E Group V), and more than one-half of patients may eventually need EBRT and/or enucleation.[1,11] In one study, the addition of high-dose cyclosporine A (a modulator of p-glycoprotein) to the CEV regimen resulted in improved ocular salvage rates.[60]

The International Classification of Retinoblastoma grouping system may be better than the R-E Classification for Intraocular Tumors at predicting success of treatment with systemic chemotherapy in combination with local control. The combinations of carboplatin and etoposide (CE) [65] or CEV [66,67] in conjunction with local control have resulted in ocular salvage rates above 90% for early intraocular disease (Groups A and B eyes), 70% to 90% for Group C eyes, and 40% to 50% for Group D eyes.[65,67,68]; [65][Level of evidence: 3iiDiv] However, for patients with advanced intraocular disease (typically Group D eyes), EBRT is frequently required for ocular salvage.[65]; [66][Level of evidence: 3iiDiii]

For patients with large intraocular tumor burden or with subretinal or vitreous seeds (Groups C and D eyes), the use of periocular chemotherapy, usually in combination with systemic therapy, has been explored.[43,69] In one study, systemic chemoreduction, subtenon carboplatin, and local consolidation resulted in ocular salvage of 47% of Group D eyes. An additional 35% of eyes were salvaged with intensity-modulated radiation therapy.[70][Level of evidence: 2Div] The impact of this approach on ocular salvage is not well defined.

The treatment recommendation for Group E eyes is up-front enucleation. The use of prolonged systemic chemotherapy for Group E eyes to avoid or delay enucleation has been associated with lower disease-specific survival (P < .001).[56][Level of evidence: 3iiiB]

Delivery of chemotherapy via ophthalmic artery cannulation has also been shown to be feasible and effective in patients with bilateral disease, in both the up-front and salvage settings.[23,28,35][Level of evidence: 3iiDii] However, this treatment should only be performed in an experienced center with a state-of-the-art treatment infrastructure and a dedicated multidisciplinary team.

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 with the risks associated with EBRT in heritable retinoblastoma.

Cavitary Retinoblastoma

In patients with cavitary retinoblastoma, minimal visual response is seen after intravenous chemotherapy and/or intra-arterial chemotherapy. Despite the blunted clinical response, cavitary retinoblastoma has a favorable long-term outcome with stable tumor regression and globe salvage. Aggressive or prolonged chemotherapy or adjunctive therapies are generally not necessary. In a retrospective series of 26 cavitary retinoblastomas that were treated with intravenous chemoreduction and/or intra-arterial chemotherapy, the mean reduction in tumor base was 22% and mean reduction in tumor thickness was 29%. Despite minimal reduction, tumor recurrence was noted in only one eye, globe salvage was achieved in 22 eyes, and there were no cases of metastasis or death during 49 months (range, 6–189 months) of follow-up.[71]

Treatment Options Under Clinical Evaluation

Studies are planned for a variety of patient groups. The International Classification of Retinoblastoma is being utilized for these trials.

Information about ongoing clinical trials is available from the NCI Web site.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with intraocular retinoblastoma. 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.

References
  1. 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]

  2. Kim JW, Kathpalia V, Dunkel IJ, et al.: Orbital recurrence of retinoblastoma following enucleation. Br J Ophthalmol 93 (4): 463-7, 2009.  [PUBMED Abstract]

  3. 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]

  4. 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]

  5. 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]

  6. 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]

  7. Merchant TE, Gould CJ, Wilson MW, et al.: Episcleral plaque brachytherapy for retinoblastoma. Pediatr Blood Cancer 43 (2): 134-9, 2004.  [PUBMED Abstract]

  8. 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]

  9. Shields CL, Santos MC, Diniz W, et al.: Thermotherapy for retinoblastoma. Arch Ophthalmol 117 (7): 885-93, 1999.  [PUBMED Abstract]

  10. Francis JH, Abramson DH, Brodie SE, et al.: Indocyanine green enhanced transpupillary thermotherapy in combination with ophthalmic artery chemosurgery for retinoblastoma. Br J Ophthalmol 97 (2): 164-8, 2013.  [PUBMED Abstract]

  11. 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]

  12. Shields CL, Palamar M, Sharma P, et al.: Retinoblastoma regression patterns following chemoreduction and adjuvant therapy in 557 tumors. Arch Ophthalmol 127 (3): 282-90, 2009.  [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. Aerts I, Sastre-Garau X, Savignoni A, et al.: Results of a multicenter prospective study on the postoperative treatment of unilateral retinoblastoma after primary enucleation. J Clin Oncol 31 (11): 1458-63, 2013.  [PUBMED Abstract]

  20. 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]

  21. 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]

  22. 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]

  23. Gobin YP, Dunkel IJ, Marr BP, et al.: Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol 129 (6): 732-7, 2011.  [PUBMED Abstract]

  24. Marr BP, Brodie SE, Dunkel IJ, et al.: Three-drug intra-arterial chemotherapy using simultaneous carboplatin, topotecan and melphalan for intraocular retinoblastoma: preliminary results. Br J Ophthalmol 96 (10): 1300-3, 2012.  [PUBMED Abstract]

  25. Peterson EC, Elhammady MS, Quintero-Wolfe S, et al.: Selective ophthalmic artery infusion of chemotherapy for advanced intraocular retinoblastoma: initial experience with 17 tumors. J Neurosurg 114 (6): 1603-8, 2011.  [PUBMED Abstract]

  26. Abramson DH, Marr BP, Dunkel IJ, et al.: Intra-arterial chemotherapy for retinoblastoma in eyes with vitreous and/or subretinal seeding: 2-year results. Br J Ophthalmol 96 (4): 499-502, 2012.  [PUBMED Abstract]

  27. Abramson DH, Marr BP, Brodie SE, et al.: Ophthalmic artery chemosurgery for less advanced intraocular retinoblastoma: five year review. PLoS One 7 (4): e34120, 2012.  [PUBMED Abstract]

  28. Abramson DH, Dunkel IJ, Brodie SE, et al.: Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology 117 (8): 1623-9, 2010.  [PUBMED Abstract]

  29. Shields CL, Bianciotto CG, Jabbour P, et al.: Intra-arterial chemotherapy for retinoblastoma: report No. 1, control of retinal tumors, subretinal seeds, and vitreous seeds. Arch Ophthalmol 129 (11): 1399-406, 2011.  [PUBMED Abstract]

  30. Shields CL, Bianciotto CG, Jabbour P, et al.: Intra-arterial chemotherapy for retinoblastoma: report No. 2, treatment complications. Arch Ophthalmol 129 (11): 1407-15, 2011.  [PUBMED Abstract]

  31. Shields CL, Kaliki S, Shah SU, et al.: Minimal exposure (one or two cycles) of intra-arterial chemotherapy in the management of retinoblastoma. Ophthalmology 119 (1): 188-92, 2012.  [PUBMED Abstract]

  32. Bianciotto C, Shields CL, Iturralde JC, et al.: Fluorescein angiographic findings after intra-arterial chemotherapy for retinoblastoma. Ophthalmology 119 (4): 843-9, 2012.  [PUBMED Abstract]

  33. Ghassemi F, Shields CL: Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol 130 (10): 1268-71, 2012.  [PUBMED Abstract]

  34. Schaiquevich P, Ceciliano A, Millan N, et al.: Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma. Pediatr Blood Cancer 60 (5): 766-70, 2013.  [PUBMED Abstract]

  35. Palioura S, Gobin YP, Brodie SE, et al.: Ophthalmic artery chemosurgery for the management of retinoblastoma in eyes with extensive (>50%) retinal detachment. Pediatr Blood Cancer 59 (5): 859-64, 2012.  [PUBMED Abstract]

  36. Gobin YP, Dunkel IJ, Marr BP, et al.: Combined, sequential intravenous and intra-arterial chemotherapy (bridge chemotherapy) for young infants with retinoblastoma. PLoS One 7 (9): e44322, 2012.  [PUBMED Abstract]

  37. Abramson DH, Francis JH, Dunkel IJ, et al.: Ophthalmic artery chemosurgery for retinoblastoma prevents new intraocular tumors. Ophthalmology 120 (3): 560-5, 2013.  [PUBMED Abstract]

  38. Suzuki S, Yamane T, Mohri M, et al.: Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology 118 (10): 2081-7, 2011.  [PUBMED Abstract]

  39. Munier FL, Beck-Popovic M, Balmer A, et al.: Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma. Retina 31 (3): 566-73, 2011.  [PUBMED Abstract]

  40. Muen WJ, Kingston JE, Robertson F, et al.: Efficacy and complications of super-selective intra-ophthalmic artery melphalan for the treatment of refractory retinoblastoma. Ophthalmology 119 (3): 611-6, 2012.  [PUBMED Abstract]

  41. Munier FL, Gaillard MC, Balmer A, et al.: Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol 96 (8): 1078-83, 2012.  [PUBMED Abstract]

  42. Smith SJ, Smith BD: Evaluating the risk of extraocular tumour spread following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol 97 (10): 1231-6, 2013.  [PUBMED Abstract]

  43. 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]

  44. Marr BP, Dunkel IJ, Linker A, et al.: Periocular carboplatin for retinoblastoma: long-term report (12 years) on efficacy and toxicity. Br J Ophthalmol 96 (6): 881-3, 2012.  [PUBMED Abstract]

  45. Mallipatna AC, Dimaras H, Chan HS, et al.: Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol 129 (6): 738-45, 2011.  [PUBMED Abstract]

  46. Chantada GL, Guitter MR, Fandiño AC, et al.: Treatment results in patients with retinoblastoma and invasion to the cut end of the optic nerve. Pediatr Blood Cancer 52 (2): 218-22, 2009.  [PUBMED Abstract]

  47. Eagle RC Jr: High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med 133 (8): 1203-9, 2009.  [PUBMED Abstract]

  48. Kaliki S, Shields CL, Rojanaporn D, et al.: High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology 120 (5): 997-1003, 2013.  [PUBMED Abstract]

  49. 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]

  50. Honavar SG, Singh AD, Shields CL, et al.: Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol 120 (7): 923-31, 2002.  [PUBMED Abstract]

  51. 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]

  52. 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]

  53. Chantada GL, Fandiño AC, Guitter MR, et al.: Results of a prospective study for the treatment of unilateral retinoblastoma. Pediatr Blood Cancer 55 (1): 60-6, 2010.  [PUBMED Abstract]

  54. Kaliki S, Shields CL, Shah SU, et al.: Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma. Arch Ophthalmol 129 (11): 1422-7, 2011.  [PUBMED Abstract]

  55. Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol 120 (12): 1653-8, 2002.  [PUBMED Abstract]

  56. Zhao J, Dimaras H, Massey C, et al.: Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis. J Clin Oncol 29 (7): 845-51, 2011.  [PUBMED Abstract]

  57. Chawla B, Sharma S, Sen S, et al.: Correlation between clinical features, magnetic resonance imaging, and histopathologic findings in retinoblastoma: a prospective study. Ophthalmology 119 (4): 850-6, 2012.  [PUBMED Abstract]

  58. 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]

  59. 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]

  60. 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]

  61. 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]

  62. 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]

  63. Qaddoumi I, Billups CA, Tagen M, et al.: Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity. Cancer 118 (22): 5663-70, 2012.  [PUBMED Abstract]

  64. 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]

  65. Lumbroso-Le Rouic L, Aerts I, Lévy-Gabriel C, et al.: Conservative treatments of intraocular retinoblastoma. Ophthalmology 115 (8): 1405-10, 1410.e1-2, 2008.  [PUBMED Abstract]

  66. Cohen VM, Kingston J, Hungerford JL: The success of primary chemotherapy for group D heritable retinoblastoma. Br J Ophthalmol 93 (7): 887-90, 2009.  [PUBMED Abstract]

  67. Shields CL, Mashayekhi A, Au AK, et al.: The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113 (12): 2276-80, 2006.  [PUBMED Abstract]

  68. 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]

  69. Chantada GL, Fandino AC, Carcaboso AM, et al.: A phase I study of periocular topotecan in children with intraocular retinoblastoma. Invest Ophthalmol Vis Sci 50 (4): 1492-6, 2009.  [PUBMED Abstract]

  70. Berry JL, Jubran R, Kim JW, et al.: Long-term outcomes of Group D eyes in bilateral retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage. Pediatr Blood Cancer 60 (4): 688-93, 2013.  [PUBMED Abstract]

  71. Rojanaporn D, Kaliki S, Bianciotto CG, et al.: Intravenous chemoreduction or intra-arterial chemotherapy for cavitary retinoblastoma: long-term results. Arch Ophthalmol 130 (5): 585-90, 2012.  [PUBMED Abstract]

Extraocular Retinoblastoma Treatment

In developed countries, 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, and as distant metastatic disease involving the lungs, bones, and bone marrow.

Standard Treatment Options

Orbital and locoregional retinoblastoma

Orbital retinoblastoma occurs as a result of progression of the tumor through the emissary vessels and sclera. For this reason, transscleral disease is considered to be extraocular and should be treated as such. Orbital retinoblastoma is isolated in 60% to 70% of cases. Treatment includes systemic chemotherapy and radiation therapy; with this approach, 60% to 85% of patients can be cured. Because most recurrences occur in the central nervous system (CNS), regimens using drugs with well-documented CNS penetration are recommended. Different chemotherapy regimens have proven to be effective, including vincristine, cyclophosphamide, and doxorubicin and platinum- and epipodophyllotoxin-based regimens, or a combination of both.[1-3] For patients with macroscopic orbital disease, it is recommended that surgery be delayed until response to chemotherapy is achieved (usually two or three courses of treatment). Patients then undergo enucleation and receive an additional four to six courses of chemotherapy. Next, local control is consolidated with orbital irradiation (40 Gy to 45 Gy). Using this approach, orbital exenteration is not indicated.[3] Patients with isolated involvement of the optic nerve at the transsection level receive similar systemic treatment, and irradiation includes the entire orbit (36 Gy) with 10 Gy boost to the chiasm (total 46 Gy).[2]

Central nervous system disease

Intracranial dissemination occurs by direct extension through the optic nerve and its prognosis is dismal. Treatment for these patients includes platinum-based intensive systemic chemotherapy and CNS-directed therapy. Although intrathecal chemotherapy has been traditionally used, there is no preclinical or clinical evidence to support its use. Although the use of irradiation in these patients is controversial, responses have been observed with craniospinal irradiation using 25 Gy to 35 Gy to the entire craniospinal axis and a boost (10 Gy) to sites of measurable disease. Therapeutic intensification with high-dose, marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue has been explored, but its role is not yet clear.[4][Level of evidence: 3iiA]

Trilateral retinoblastoma

Trilateral retinoblastoma is usually associated with a pineal lesion with a cystic appearance that can be misleading or, less commonly, as a suprasellar lesion.[5] In patients with the heritable form of retinoblastoma, CNS disease is less likely the result of metastatic or regional spread than a primary intracranial focus, such as a pineal tumor. The prognosis for patients with trilateral retinoblastoma is very poor; most patients die of disseminated neuraxis disease in less than 9 months. While pineoblastomas occurring in older patients are sensitive to radiation therapy, current strategies are directed towards avoiding irradiation by using intensive chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue, an approach similar to those being used in the treatment of brain tumors in infants.[6]

Because of the poor prognosis of trilateral retinoblastoma, screening neuroimaging is a common practice. Routine baseline brain magnetic resonance imaging (MRI) is recommended at diagnosis because it may detect trilateral retinoblastoma at a subclinical stage. In a small series of patients, the 5-year overall survival was 67% for those detected at baseline, compared with 11% for the group with a delayed diagnosis.[5] The value of screening with MRI for those suspected of having heritable disease or those with unilateral disease and a positive family history is under discussion. It has been recommended as often as every 6 months for up to 5 years. Given the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral retinoblastoma, routine screening might detect the majority of cases within 2 years. However, it is not clear whether screening by neuroimaging improves survival.[7] Computed tomography scans should be avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.

Extracranial metastatic retinoblastoma

Hematogenous metastases may develop in the bones, bone marrow, and less frequently, in the liver. Although long-term survivors have been reported with conventional chemotherapy, these reports should be considered anecdotal; metastatic retinoblastoma is not curable with conventional chemotherapy. In recent years, however, studies of small series of patients have shown that metastatic retinoblastoma can be cured using high-dose, marrow-ablative chemotherapy and autologous hematopoietic stem cell rescue.[8-14]; [15][Level of evidence: 3iiA]

Two reports suggest that there may be a role for intensive multimodality therapy with autologous stem cell rescue for patients with metastatic retinoblastoma.[4,15][Level of evidence: 3iiA] A few responses were noted in CNS (including trilateral) and systemic metastases.

Treatment Options Under Clinical Evaluation

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

  • COG-ARET0321 (Combination Chemotherapy, Autologous Stem Cell Transplant [SCT], and/or Radiation Therapy in Treating Young Patients With Extraocular Retinoblastoma): Patients with metastatic or recurrent retinoblastoma that is beyond the globe are eligible for treatment with combined conventional chemotherapy, high-dose chemotherapy, and SCT with conventional radiation.
Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with extraocular retinoblastoma. 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.

References
  1. 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]

  2. Aerts I, Sastre-Garau X, Savignoni A, et al.: Results of a multicenter prospective study on the postoperative treatment of unilateral retinoblastoma after primary enucleation. J Clin Oncol 31 (11): 1458-63, 2013.  [PUBMED Abstract]

  3. Radhakrishnan V, Kashyap S, Pushker N, et al.: Outcome, pathologic findings, and compliance in orbital retinoblastoma (International Retinoblastoma Staging System stage III) treated with neoadjuvant chemotherapy: a prospective study. Ophthalmology 119 (7): 1470-7, 2012.  [PUBMED Abstract]

  4. Dunkel IJ, Chan HS, Jubran R, et al.: High-dose chemotherapy with autologous hematopoietic stem cell rescue for stage 4B retinoblastoma. Pediatr Blood Cancer 55 (1): 149-52, 2010.  [PUBMED Abstract]

  5. Rodjan F, de Graaf P, Brisse HJ, et al.: Trilateral retinoblastoma: neuroimaging characteristics and value of routine brain screening on admission. J Neurooncol 109 (3): 535-44, 2012.  [PUBMED Abstract]

  6. Dunkel IJ, Jubran RF, Gururangan S, et al.: Trilateral retinoblastoma: potentially curable with intensive chemotherapy. Pediatr Blood Cancer 54 (3): 384-7, 2010.  [PUBMED Abstract]

  7. 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]

  8. 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]

  9. 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]

  10. Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of metastatic retinoblastoma. Ophthalmology 110 (6): 1237-40, 2003.  [PUBMED Abstract]

  11. Dunkel IJ, Aledo A, Kernan NA, et al.: Successful treatment of metastatic retinoblastoma. Cancer 89 (10): 2117-21, 2000.  [PUBMED Abstract]

  12. 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]

  13. 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]

  14. Palma J, Sasso DF, Dufort G, et al.: Successful treatment of metastatic retinoblastoma with high-dose chemotherapy and autologous stem cell rescue in South America. Bone Marrow Transplant 47 (4): 522-7, 2012.  [PUBMED Abstract]

  15. Dunkel IJ, Khakoo Y, Kernan NA, et al.: Intensive multimodality therapy for patients with stage 4a metastatic retinoblastoma. Pediatr Blood Cancer 55 (1): 55-9, 2010.  [PUBMED Abstract]

Recurrent Intraocular Retinoblastoma Treatment

The prognosis for a patient with recurrent or progressive retinoblastoma depends on the site and extent of the recurrence or progression and previous treatment. Metastasis in retinoblastoma generally occurs within 1 year of diagnosis.[1] New intraocular tumors can arise in patients with the heritable form of disease whose eyes have been treated with focal measures only, since every cell in the retina carries the RB1 mutation; this is not technically recurrence. Even with prior treatment consisting of chemoreduction and focal measures in very young patients with heritable retinoblastoma, surveillance may detect new tumors at an early stage and additional focal therapy, including plaque brachytherapy, can be successful in eradicating tumor.[2-6] 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.[7][Level of evidence: 3iiDiv] If the recurrence or progression is confined to the eye but is extensive, the prognosis for sight is poor; however, survival remains excellent. Intra-arterial chemotherapy into the ophthalmic artery has been effective in patients who relapse after systemic chemotherapy and radiation therapy.[8] Recurrence in the orbit after enucleation is treated with aggressive chemotherapy in addition to local radiation therapy because of the high risk of metastatic disease.[9][Level of evidence: 3iiA] If the recurrence or progression is extraocular, the chance of survival is poor, with death usually occurring within 6 months.[1] In this circumstance, the treatment depends on many factors, including individual patient considerations. Clinical trials may be appropriate to consider.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent retinoblastoma. 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.

References
  1. Broaddus E, Topham A, Singh AD: Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93 (1): 24-7, 2009.  [PUBMED Abstract]

  2. 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]

  3. 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]

  4. 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]

  5. 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]

  6. 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]

  7. Chan MP, Hungerford JL, Kingston JE, et al.: Salvage external beam radiotherapy after failed primary chemotherapy for bilateral retinoblastoma: rate of eye and vision preservation. Br J Ophthalmol 93 (7): 891-4, 2009.  [PUBMED Abstract]

  8. Schaiquevich P, Ceciliano A, Millan N, et al.: Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma. Pediatr Blood Cancer 60 (5): 766-70, 2013.  [PUBMED Abstract]

  9. Kim JW, Kathpalia V, Dunkel IJ, et al.: Orbital recurrence of retinoblastoma following enucleation. Br J Ophthalmol 93 (4): 463-7, 2009.  [PUBMED Abstract]

Changes to This Summary (12/06/2013)

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.

This summary was comprehensively reviewed.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary



Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of retinoblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Retinoblastoma Treatment are:

  • Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
  • Karen J Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Thomas A. Olson, MD (AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus)
  • Carlos Rodriguez-Galindo, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Nita Louise Seibel, MD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Retinoblastoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/retinoblastoma/HealthProfessional. Accessed <MM/DD/YYYY>.

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