Español
Questions About Cancer? 1-800-4-CANCER
  • Print
  • Email
  • Facebook
  • Twitter
  • Google+
  • Pinterest

Retinoblastoma Treatment (PDQ®)

Table of Contents

General Information About Retinoblastoma

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 is particularly important in the management of retinoblastoma; it 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:

  • An ophthalmologist with extensive experience in the treatment of children with retinoblastoma.
  • Primary care physician.
  • 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 and their 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 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.)

Retinoblastoma is a rare pediatric cancer that requires a careful integration of multidisciplinary care. Treatment of retinoblastoma aims to save the patient's life and preserve useful vision, and thus, needs to be individualized. The management of intraocular retinoblastoma has evolved to a more risk-adapted approach that aims at minimizing systemic exposure to drugs, optimizing ocular drug delivery, and preserving useful vision.

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.

Retinoblastoma is a cancer of the very young child; two-thirds of all cases of retinoblastoma are diagnosed before age 2 years, and 95% of cases are diagnosed before age 5 years.[5] Thus, while the estimated annual incidence in the United States is approximately four cases per 1 million children younger than 15 years, the age-adjusted annual incidence in children aged 0 to 4 years is 10 to 14 cases per 1 million (approximately one in 14,000–18,000 live births).

Anatomy

Retinoblastoma arises from the retina, and its growth is usually under the retina and toward the vitreous. Involvement of the ocular coats and optic nerve occurs as a sequence of events as the tumor progresses. Invasion of the choroid is common, although occurrence of massive invasion is usually limited to advanced disease. Following invasion of the choroid, the tumor gains access to systemic circulation and creates the potential for metastases. Further progression through the ocular coats leads to invasion of the sclera and the orbit. Progression through the optic nerve and past the lamina cribrosa increases the risk of systemic and central nervous system (CNS) dissemination. Anteriorly, tumor invading the anterior chamber may gain access to systemic circulation through the canal of Schlemm.

Anatomy of the eye; two-panel drawing showing the outside and inside of the eye. The top panel shows the outside of the eye, including the eyelid, pupil, sclera, and iris. The bottom panel shows the inside of the eye, including the ciliary body, canal of Schlemm, cornea, lens, vitreous humor, retina, choroid, optic nerve, and lamina cribrosa.
Figure 1. Anatomy of the eye showing the outside and inside of the eye, including the eyelid, pupil, sclera, iris, ciliary body, canal of Schlemm, cornea, lens, vitreous humor, retina, choroid, optic nerve, and lamina cribrosa. The vitreous humor is a gel that fills the center of the eye.


Clinical Presentation

Age at presentation correlates with laterality; patients with bilateral disease present at a younger age, usually in the first 12 months of life. Most cases present with leukocoria, which is occasionally first noticed after a flash photograph is taken. Strabismus is the second most common presenting sign and usually correlates with macular involvement. Very advanced intraocular tumors present with pain, glaucoma, or buphthalmos. As the tumor progresses, patients may present with orbital or metastatic disease. Metastases occur in the CNS or systemically (commonly in the bones, bone marrow, and liver).

Diagnostic Evaluation

The diagnosis of intraocular retinoblastoma is usually made without pathologic confirmation. An examination under anesthesia with a maximally dilated pupil and scleral indentation is required to examine the entire retina. A very detailed documentation of the number, location, and size of tumors, the presence of retinal detachment and subretinal fluid, and the presence of subretinal and vitreous seeds must be performed. Additional imaging studies include bidimensional ocular ultrasound and magnetic resonance imaging (MRI) (preferred over computed tomography [CT] to avoid radiation exposure). These imaging studies are important to evaluate extraocular extension and to differentiate retinoblastoma from other causes of leukocoria.

Evaluation of the presence of metastatic disease also needs to be considered in the subgroup of patients with suspected extraocular extension by imaging or high-risk pathology in the enucleated eye (i.e., massive choroidal invasion or involvement of the sclera or the optic nerve beyond the lamina cribrosa). In these cases, bone scintigraphy, bone marrow aspirates and biopsies, and lumbar puncture are performed.

Genetic counseling is recommended for all patients with retinoblastoma.

Heritable and Nonheritable Forms of Retinoblastoma

Retinoblastoma is a tumor that occurs in heritable (25%–30%) and nonheritable (70%–75%) forms. Heritable disease is defined by the presence of a germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25% of cases) or may have occurred in utero at the time of conception in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.

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] All children with bilateral disease and approximately 15% of patients with unilateral 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]

Postdiagnosis Surveillance

Children with a germline RB1 mutation may continue to develop new tumors for a few years after diagnosis and treatment; for this reason, they need to be examined frequently. It is common practice for examinations to occur every 2 to 4 months for at least 28 months.[9] The interval between exams is based on the stability of the disease and age of the child (i.e., less frequent visits as the child ages).

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.

Genetic Testing and Counseling

Blood and tumor samples can be tested 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.[10]

Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out.[11] A multistep assay that includes the following may be performed for a complete genetic evaluation of the RB1 gene:[11]

  • DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions.
  • Southern blot analysis to characterize genomic rearrangements.
  • Transcript analysis to characterize potential splicing mutations buried within introns.

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 suggests that alternative genetic mechanisms may underlie the development of retinoblastoma.[12] Approximately 3% of unilateral, nonheritable retinoblastoma cases have no somatic RB1 alterations. In half of these cases, high levels of MYCN amplification have been reported; these patients had distinct, aggressive, histologic features and a median age at diagnosis of 4 months.[13]

Genetic counseling is an integral part of the management of patients with retinoblastoma and their families, regardless of clinical presentation; counseling assists parents in understanding the genetic consequences of each form of retinoblastoma and in estimating the risk of disease in family members.[10] Genetic counseling, however, is not always straightforward. Approximately 10% of children with retinoblastoma have somatic genetic mosaicism, which contributes to the difficulty of genetic counseling.[14] (Refer to the PDQ summaries on Cancer Genetics Risk Assessment and Counseling and Cancer Genetics Overview for more information.)

Because of the poor prognosis of trilateral retinoblastoma, screening with neuroimaging until age 5 years is a common practice in the follow-up of children with the heritable form of the disease. (Refer to the Trilateral retinoblastoma section of this summary for more information.)

Retinoblastoma-Related Mortality

While retinoblastoma is a highly curable disease, the 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 patient's 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 and subsequent decades of life, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality. Death from an SN is the most common cause of death and contributes to more than 50% of deaths for patients with bilateral disease.[15] In the United States, before the advent of chemoreduction as a means of treating heritable or bilateral disease, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis.[16]

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 between the ages of 20 and 36 months.[17]

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 most cases within 2 years of first diagnosis. Although it is not clear whether early diagnosis can impact survival, screening with MRI 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.[17] CT scans are generally avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation. At the time of diagnosis, patients who are asymptomatic of an intracranial tumor have a better outcome than do patients who are symptomatic.[17]

Approximately 5% to 10% of children with heritable retinoblastoma develop pineal gland cysts detected by MRI; these cyst abnormalities must be distinguished from the pineoblastoma that typically defines trilateral retinoblastoma.[18,19]

Subsequent neoplasms (SNs)

Survivors of retinoblastoma have a high risk of developing SNs. Factors that influence this risk include the following:

  • Heritable retinoblastoma. Patients with heritable retinoblastoma have a markedly increased incidence of SNs, independent of treatment with radiation therapy.[15,20,21] A possible association may exist between the type of RB1 mutation and incidence of SNs, with complete loss of RB1 activity associated with a higher incidence of SNs.[22] 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.[23,24] Among retinoblastoma survivors with heritable retinoblastoma, those with an inherited germline mutation are at a slightly higher risk of an SN than are those with a de novo mutation; this increase appears to be most significant for melanoma.[25]
  • Past treatment for retinoblastoma with radiation therapy. The cumulative incidence of SNs 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.[26] However, more recent studies analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients.[27] Preliminary data suggest that proton radiation therapy may further lower the risk of radiation-induced malignancies in survivors of retinoblastoma.[28]

    The most common SN is sarcoma, specifically 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, and a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of SNs occur within irradiated tissue, and one-third of SNs occur outside the radiation field.[21,26,27,29]

  • Age at time of radiation therapy. The risk of SNs also appears to be dependent on the patient's age at the time that external-beam radiation therapy is administered, especially in children younger than 12 months, and the histopathologic types of SNs may be influenced by age.[27,30,31] These data support a genetic predisposition to soft tissue sarcomas in addition to the risk of osteosarcoma.[29]
  • Previous SN. Those who survive SNs are at a sevenfold increased risk for developing another SN.[32] The risk increases an additional threefold for patients treated with radiation therapy.[33]

An increased incidence of acute myeloid leukemia in children with heritable retinoblastoma has been suggested; however, no evidence is available to support this suggestion.[34]; [35][Level of evidence: 3iiiA] Of 245 patients who received etoposide, only one patient had acute promyelocytic leukemia after 79 months.[34]

No clear increase in SNs exists in patients without a germline retinoblastoma mutation beyond that associated with the treatment.[26,36]

Survival from SNs is certainly suboptimal and varies widely across studies.[20,23,36-39] However, with advances in therapy, it is essential that all SNs be treated with curative intent.[40]

Late Effects from Retinoblastoma Therapy

As previously discussed, patients with heritable retinoblastoma have an increased incidence of SNs. (Refer to the Subsequent neoplasms section of this summary for more information.) Other late effects that may occur after treatment for retinoblastoma include the following:

  • Diminished orbital growth. Orbital growth is somewhat diminished after enucleation; however, the impact of enucleation on orbital volume may be less after placement of an orbital implant.[41]
  • Visual-field deficits. 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.[42]

    One study of visual acuity after treatment with systemic chemotherapy and local 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 of at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.[43]

  • Hearing loss. Because systemic carboplatin is now commonly used in the treatment of retinoblastoma (refer to the Treatment Options for Unilateral and Bilateral Retinoblastoma and Treatment Options for 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,[44] another series documented hearing loss in 17% of patients.[45] Age younger than 6 months at the time of treatment and higher carboplatin systemic exposures appear to correlate with an increased risk of otologic toxic effects.[45,46]

References

  1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [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, 2013, Section 28. Also available online. Last accessed December 15, 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, 2013, Section 29. Also available online. Last accessed December 15, 2014.
  5. Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed December 17, 2014.
  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. Abramson DH, Mendelsohn ME, Servodidio CA, et al.: Familial retinoblastoma: where and when? Acta Ophthalmol Scand 76 (3): 334-8, 1998. [PUBMED Abstract]
  10. 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]
  11. Clark R: Retinoblastoma: genetic testing and counseling. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 441-6.
  12. 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]
  13. 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]
  14. Dommering CJ, Mol BM, Moll AC, et al.: RB1 mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients. J Med Genet 51 (6): 366-74, 2014. [PUBMED Abstract]
  15. Shinohara ET, DeWees T, Perkins SM: Subsequent malignancies and their effect on survival in patients with retinoblastoma. Pediatr Blood Cancer 61 (1): 116-9, 2014. [PUBMED Abstract]
  16. Broaddus E, Topham A, Singh AD: Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93 (1): 24-7, 2009. [PUBMED Abstract]
  17. 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]
  18. Beck Popovic M, Balmer A, Maeder P, et al.: Benign pineal cysts in children with bilateral retinoblastoma: a new variant of trilateral retinoblastoma? Pediatr Blood Cancer 46 (7): 755-61, 2006. [PUBMED Abstract]
  19. Ramasubramanian A, Kytasty C, Meadows AT, et al.: Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 156 (4): 825-9, 2013. [PUBMED Abstract]
  20. 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]
  21. MacCarthy A, Bayne AM, Brownbill PA, et al.: Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer 108 (12): 2455-63, 2013. [PUBMED Abstract]
  22. 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]
  23. 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]
  24. 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]
  25. 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]
  26. Wong FL, Boice JD Jr, Abramson DH, et al.: Cancer incidence after retinoblastoma. Radiation dose and sarcoma risk. JAMA 278 (15): 1262-7, 1997. [PUBMED Abstract]
  27. Kleinerman RA, Tucker MA, Tarone RE, et al.: Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 23 (10): 2272-9, 2005. [PUBMED Abstract]
  28. Sethi RV, Shih HA, Yeap BY, et al.: Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy. Cancer 120 (1): 126-33, 2014. [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. 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]
  33. 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]
  34. 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]
  35. 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]
  36. Dunkel IJ, Gerald WL, Rosenfield NS, et al.: Outcome of patients with a history of bilateral retinoblastoma treated for a second malignancy: the Memorial Sloan-Kettering experience. Med Pediatr Oncol 30 (1): 59-62, 1998. [PUBMED Abstract]
  37. 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]
  38. 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]
  39. 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]
  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. 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]
  42. Abramson DH, Melson MR, Servodidio C: Visual fields in retinoblastoma survivors. Arch Ophthalmol 122 (9): 1324-30, 2004. [PUBMED Abstract]
  43. 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]
  44. 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]
  45. 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]
  46. Leahey A: A cautionary tale: dosing chemotherapy in infants with retinoblastoma. J Clin Oncol 30 (10): 1023-4, 2012. [PUBMED Abstract]

Tumor Pathology of Retinoblastoma

Retinoblastoma arises from the photoreceptor elements of the inner layer of the retina. Microscopically, the appearance of retinoblastoma depends on the degree of differentiation. Undifferentiated retinoblastoma is composed of small, round, densely packed cells with hypochromatic nuclei and scant cytoplasm. Several degrees of photoreceptor differentiation have been described and are characterized by distinctive arrangements of tumor cells. The Flexner-Wintersteiner rosettes are specific for retinoblastoma; these structures consist of a cluster of low, columnar cells arranged around a central lumen that is bounded by an eosinophilic membrane analogous to the external membrane of the normal retina. The lumen contains an acid mucopolysaccharide similar to that found around normal rods and cones. These rosettes are seen in 70% of tumors. Homer-Wright rosettes, on the other hand, are composed of irregular circlets of tumor cells arranged around a tangle of fibrils with no lumen or internal-limiting membrane. Horner-Wright rosettes are infrequently seen in retinoblastoma and are most often seen in other neuroblastic tumors, such as neuroblastoma and medulloblastoma.

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 cone-rod homeobox, also known as CRX, a useful marker to discriminate retinoblastoma from other malignant, small, round cell tumors.[1,2]

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]

Staging and Grouping Systems for Retinoblastoma

The staging of patients with retinoblastoma requires close coordination of radiologists, pediatric oncologists, and ophthalmologists. Several staging and grouping systems have been proposed for retinoblastoma.[1] Overall assessment of retinoblastoma extension is documented by staging systems; intraocular extension, which is relevant for ocular salvage, is documented by grouping systems. For treatment purposes, retinoblastoma is categorized into intraocular and extraocular disease.

Intraocular Retinoblastoma

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 Retinoblastoma

Extraocular retinoblastoma has extended beyond the eye. It may be confined to the tissues around the eye (orbital retinoblastoma); it may have spread to the central nervous system (CNS); or, it may have spread systemically to the bone marrow or lymph nodes (metastatic retinoblastoma). Magnetic resonance imaging (MRI) can be useful in the evaluation of extrascleral and extraocular disease in children with advanced intraocular retinoblastoma. Optic nerve enhancement by MRI does not necessarily indicate involvement and cautious interpretation is needed.[2] The detection of the synthetase of ganglioside GD2 mRNA by reverse transcriptase-polymerase chain reaction in the cerebrospinal fluid at the time of diagnosis may be a marker for CNS disease.[3]

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
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.
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.
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
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.
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.

International Retinoblastoma Staging System

The more simplified International Retinoblastoma Staging System has been proposed by an international consortium of ophthalmologists and pediatric oncologists.[4] It is more widely used in the clinical setting than the AJCC staging system.

Table 7. International Retinoblastoma Staging System
StageDescription
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. However, developments in the conservative management of intraocular retinoblastoma have made the Reese-Ellsworth grouping system less predictive for eye salvage and less helpful in guiding treatment.[5] This grouping system is seldom used.

Group I: Very favorable for maintenance of sight

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

Group II: Favorable for maintenance of sight

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

Group III: Possible for maintenance of sight

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

The new International Classification of Retinoblastoma staging system has been developed with the goal of providing a simpler, more user-friendly classification that is more applicable to current therapies. This new system is based on the extent of tumor seeding within the vitreous cavity and subretinal space, rather than on tumor size and location, and this system seems to be a better predictor of treatment success.[5-8] This classification system may also help 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. Such predication can be helpful in counseling parents regarding the potential need for postoperative systemic therapy.[9]

  • 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. Khurana A, Eisenhut CA, Wan W, et al.: Comparison of the diagnostic value of MR imaging and ophthalmoscopy for the staging of retinoblastoma. Eur Radiol 23 (5): 1271-80, 2013. [PUBMED Abstract]
  3. Laurent VE, Sampor C, Solernou V, et al.: Detection of minimally disseminated disease in the cerebrospinal fluid of children with high-risk retinoblastoma by reverse transcriptase-polymerase chain reaction for GD2 synthase mRNA. Eur J Cancer 49 (13): 2892-9, 2013. [PUBMED Abstract]
  4. 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]
  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. Murphree L: Staging and grouping of retinoblastoma. In: Singh A, Damato B: Clinical Ophthalmic Oncology. Philadelphia, Pa: Saunders Elsevier, 2007, pp 422-7.
  7. 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]
  8. 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]
  9. 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 for Retinoblastoma

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 recommended before the initiation of treatment in order to improve the likelihood of ocular salvage and vision preservation.

The goals of therapy are the following:

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

Treatment of retinoblastoma is tailored to the intraocular and extraocular disease burden, disease laterality, germline RB1 gene status, and potential for preserving vision. For patients presenting with intraocular disease, particularly those with bilateral eye involvement, a conservative approach consisting of tumor reduction with intravenous or ophthalmic artery chemotherapy, coupled with aggressive local therapy, may result in high ocular salvage rates. Radiation therapy, one of the most effective treatments in retinoblastoma, is usually reserved for cases of intraocular or extraocular disease progression.

A risk-adapted, judicious combination of the following therapeutic options should be considered:

  1. Enucleation: Upfront removal of the eye is indicated for large tumors filling the vitreous for which there is little or no likelihood of restoring vision, and in cases of extension to the anterior chamber or in the presence of neovascular glaucoma. Patients must be monitored closely for orbital recurrence of disease, particularly in the first 2 years after enucleation.[2][Level of evidence: 3iiA] Enucleation is also used as a salvage treatment in cases of disease progression or recurrence.
  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 applied 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] Radiation therapy is used in cases of progression after conservative approaches, in patients with extraocular extension, and as part of the management of patients with metastatic disease.

      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 treatment: 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: Laser therapy may be used as primary therapy for small tumors or in combination with chemotherapy for larger tumors. Traditional photocoagulation (argon laser), in which the laser was applied around the tumor, has given way to thermotherapy (diode laser). Thermotherapy is delivered directly to the tumor surface via infrared wavelengths of light.[9,10]
  4. Systemic chemotherapy: Systemic chemotherapy plays a role in the following:
    • Adjuvant setting for patients with high-risk pathology.
    • Treatment of patients with extraocular and metastatic disease.
    • As chemoreductive treatment in conjunction with aggressive local treatment for patients undergoing ocular-salvage treatments.

    During the past two decades, systemic chemotherapy to reduce tumor volume (chemoreduction) to facilitate the use of local treatments and to avoid the long-term effects of radiation therapy has been the standard of care.[11,12]; [13][Level of evidence: 3iiDiii] The success rate for eye salvage varies from center to center, but overall good ocular outcomes are consistently obtained for discrete tumors without vitreous seeding.[11,12,14-16] Chemotherapy may also be continued or initiated with concurrent local control treatments.[17] Eye grouping as defined by the International Classification of Retinoblastoma is the best predictor of ocular salvage using this approach.

    Local tumor recurrence is not uncommon in the first few years after treatment [16] and can often be successfully treated with local 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 local therapy.[18]

    There are data suggesting that the use of systemic chemotherapy may decrease the risk of developing trilateral retinoblastoma.[19]

  5. Ophthalmic artery infusion of chemotherapy (intra-arterial 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.[20] Other agents, such as topotecan and carboplatin, are also being tested and administered as single agents or in combination.[21,22]

    This modality continues to undergo study at very specialized retinoblastoma treatment centers, but data indicate that this treatment approach results in ocular salvage rates greater than 80% as first-line therapy in patients with intraocular unilateral retinoblastoma, although salvage rates of patients in whom other conservative approaches failed may be less.[20,23-29]; [21,30][Level of evidence: 3iiDiii]; [31,32][Level of evidence: 3iiDiv]

    Small ocular and body size may pose technical limitations to the use of this modality in very young patients. Intravenous chemotherapy with one or several cycles of single-agent carboplatin has been used to delay the initiation of intra-arterial chemotherapy in neonates and young infants until the child is aged 3 months and weighs 6 kg.[33][Level of evidence: 3iiiDi]

    Data also suggest that the cumulative incidence of new tumors in patients with heritable retinoblastoma is lower after intra-arterial chemotherapy than after other ocular salvage treatments.[34][Level of evidence: 3iiDi]

    This treatment is not without complications.[20,25,35-37] Retinal and choroidal vasculopathy may occur in 10% to 20% of patients.[28,38] Vision loss and vascular injury caused by complications of the catheterization or from the high dose of melphalan have been reported, although good vision was maintained.[39]

  6. Intravitreal chemotherapy: Intravitreal chemotherapy is considered investigational. Pilot studies suggest that direct intravitreal injection of melphalan may be effective in controlling active vitreous seeds.[30][Level of evidence: 3iiDi]; [40][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 the result of intravitreal injection, is negligible.[41] A meta-analysis reported that significant side effects are uncommon.[42][Level of evidence: 3iiiDiv]
  7. Subtenon (subconjunctival) chemotherapy: Periocular delivery of carboplatin results in high intraocular concentrations of the agent, and this treatment is often used in ocular salvage approaches, particularly when there is a high vitreal 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 development of new treatments for retinoblastoma, such as intra-arterial and intravitreal delivery of chemotherapy, subtenon chemotherapy is being used less often in the clinical setting.

The issue of balancing long-term tumor control and the consequences of chemotherapy is unresolved. Most patients who receive chemotherapy 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. An initial report conducted by informal survey methods described 15 patients who developed acute myeloid leukemia after chemotherapy. Half of the patients also received radiation therapy.[46] This finding has not been substantiated by formal studies. A more recent report of 245 consecutive patients treated with vincristine, carboplatin, and etoposide found a single patient with subsequent acute promyelocytic leukemia. This patient had also undergone EBRT.[47] Additionally, the Surveillance, Epidemiology, and End Result Registry (SEER) calculated standardized incidence rates for secondary hematopoietic malignancies in 34,867 survivors of childhood cancer. The observed-to-expected ratio of secondary acute myeloid leukemia in patients treated for retinoblastoma was zero.[48]

The standard treatment options for intraocular, extraocular, and recurrent retinoblastoma are described in Table 8.

Table 8. Standard Treatment Options for Retinoblastoma
Stage/CategoryStandard Treatment Options
CNS = central nervous system; EBRT = external-beam radiation therapy.
Intraocular retinoblastoma: 
 Unilateral retinoblastomaEnucleation followed by chemotherapy
  Conservative ocular salvage approaches:
 Chemoreduction with either systemic chemotherapy with subtenon chemotherapy or ophthalmic artery infusion chemotherapy
 Local treatments including cryotherapy, thermotherapy, and plaque radiation therapy
 EBRT
 Bilateral retinoblastomaEnucleation for large intraocular tumors, followed by risk-adapted chemotherapy when the eye and vision cannot be saved
  Conservative ocular salvage approaches when the eye and vision can be saved:
 Chemoreduction with either systemic chemotherapy with subtenon chemotherapy or ophthalmic artery infusion chemotherapy
 Local treatments including cryotherapy, thermotherapy, and plaque radiation therapy
 EBRT
Extraocular retinoblastoma: 
 Orbital and locoregional retinoblastomaChemotherapy
  Radiation therapy
 CNS diseaseSystemic chemotherapy and CNS-directed therapy
  Systemic chemotherapy followed by myeloablative chemotherapy and stem cell rescue
 Trilateral retinoblastomaSystemic chemotherapy followed by surgery and myeloablative chemotherapy with stem cell rescue
  Systemic chemotherapy followed by surgery and radiation therapy
 Extracranial metastatic retinoblastomaSystemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue and radiation therapy
Progressive or recurrent intraocular retinoblastomaEnucleation
  Radiation therapy (external-beam or plaque radiation therapy)
  Local treatments (cryotherapy or thermotherapy)
  Salvage chemotherapy (systemic or intra-arterial)
Progressive or recurrent extraocular retinoblastomaSystemic chemotherapy and radiation therapy for orbital disease (not a standard treatment)
  Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue, and radiation therapy for extraorbital disease (not a standard treatment)

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. 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, 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. Lumbroso L, Doz F, Urbieta M, et al.: Chemothermotherapy in the management of retinoblastoma. Ophthalmology 109 (6): 1130-6, 2002. [PUBMED Abstract]
  18. 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]
  19. Ramasubramanian A, Kytasty C, Meadows AT, et al.: Incidence of pineal gland cyst and pineoblastoma in children with retinoblastoma during the chemoreduction era. Am J Ophthalmol 156 (4): 825-9, 2013. [PUBMED Abstract]
  20. 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]
  21. 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]
  22. Francis JH, Gobin YP, Dunkel IJ, et al.: Carboplatin +/- topotecan ophthalmic artery chemosurgery for intraocular retinoblastoma. PLoS One 8 (8): e72441, 2013. [PUBMED Abstract]
  23. 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]
  24. 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]
  25. 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]
  26. 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]
  27. 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]
  28. 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]
  29. 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]
  30. Ghassemi F, Shields CL: Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol 130 (10): 1268-71, 2012. [PUBMED Abstract]
  31. 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]
  32. 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]
  33. 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]
  34. 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]
  35. 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]
  36. 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]
  37. Sarici A, Kizilkilic O, Celkan T, et al.: Blue toe syndrome as a complication of intra-arterial chemotherapy for retinoblastoma. JAMA Ophthalmol 131 (6): 801-2, 2013. [PUBMED Abstract]
  38. 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]
  39. Tsimpida M, Thompson DA, Liasis A, et al.: Visual outcomes following intraophthalmic artery melphalan for patients with refractory retinoblastoma and age appropriate vision. Br J Ophthalmol 97 (11): 1464-70, 2013. [PUBMED Abstract]
  40. 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]
  41. 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]
  42. Smith SJ, Smith BD, Mohney BG: Ocular side effects following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol 98 (3): 292-7, 2014. [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. 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]
  47. 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]
  48. Rihani R, Bazzeh F, Faqih N, et al.: Secondary hematopoietic malignancies in survivors of childhood cancer: an analysis of 111 cases from the Surveillance, Epidemiology, and End Result-9 registry. Cancer 116 (18): 4385-94, 2010. [PUBMED Abstract]

Treatment Options for Unilateral and Bilateral Retinoblastoma

Standard Treatment Options for Unilateral Retinoblastoma

Standard treatment options for unilateral retinoblastoma include the following:

  1. Enucleation for large intraocular tumors, followed by risk-adapted chemotherapy when the eye cannot be saved.
  2. Conservative ocular salvage approaches when the eye and vision can be saved.
    • Chemoreduction with either of the following:
      • Systemic chemotherapy with subtenon chemotherapy.
      • Ophthalmic artery infusion chemotherapy.
    • Local treatments including cryotherapy, thermotherapy, and plaque radiation therapy.
    • External-beam radiation therapy (EBRT).

Enucleation followed by chemotherapy

Because unilateral disease is usually massive and often there is no expectation that useful vision can be preserved, up-front surgery (enucleation) is commonly performed. 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 the following:[1-5]

  • Anterior chamber seeding.
  • Massive choroidal involvement.
  • Tumor beyond the lamina cribrosa.
  • Scleral and extrascleral extension.

Pre-enucleation magnetic resonance imaging has low sensitivity and specificity for the detection of high-risk pathology.[6]

Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide or with vincristine, carboplatin, and etoposide has been used to prevent the development of metastatic disease in patients with certain high-risk features assessed by pathologic review after enucleation.[3,7,8]; [9][Level of evidence: 2A]

Conservative ocular salvage approaches

Conservative ocular salvage approaches, such as chemotherapy and local-control treatments, may be offered in an attempt to save the eye and preserve vision.[10] Ocular salvage rates correlate with intraocular stage. In selected children with unilateral disease, the Reese-Ellsworth (R-E) Group was correlated with ocular outcomes. While the possibility of saving the eye without the use of EBRT was greater than 80% for children with R-E Group II or III disease, the ocular outcomes for children with R-E Group V eyes were poor, with less than 40% ocular salvage rates, even after the use of EBRT.[11]

Caution must be exerted with extended systemic chemotherapy administration and delayed enucleation when tumor control does not appear to be possible, particularly for Group E eyes. 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.[12]

The delivery of chemotherapy via ophthalmic artery cannulation as initial treatment for advanced unilateral retinoblastoma appears to be more effective than does systemic chemotherapy for chemoreduction. In the setting of a multidisciplinary state-of-the-art center, intra-arterial chemotherapy may result in ocular salvage rates greater than 80% for patients with advanced intraocular unilateral retinoblastoma.[13]; [14,15][Level of evidence: 3iiiDii]; [16][Level of evidence: 3iiiDiv]

Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, these children undergo 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.

Standard Treatment Options for Bilateral Retinoblastoma

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. Systemic or intra-arterial chemotherapy (chemoreduction) coupled with aggressive local treatments and very close monitoring is usually the treatment of choice; the goal is ocular and vision preservation and the delay or avoidance of EBRT and enucleation.

Standard treatment options for bilateral retinoblastoma include the following:

  1. Enucleation for large intraocular tumors, followed by risk-adapted chemotherapy when the eye and vision cannot be saved.
  2. Conservative ocular salvage approaches when the eye and vision can be saved.
    • Chemoreduction with either of the following:
      • Systemic chemotherapy with subtenon chemotherapy.
      • Ophthalmic artery infusion chemotherapy.
    • Local treatments including cryotherapy, thermotherapy, and plaque radiation therapy.
    • EBRT.

Intraocular tumor burden is usually asymmetric, and 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 aggressive local treatment may be indicated. EBRT is now reserved for patients whose eyes do not respond adequately to primary systemic or intra-arterial chemotherapy and local consolidation.

A number of large centers have published trial results that used systemic chemotherapy in conjunction with aggressive local consolidation for patients with bilateral disease.[10,17-25] The backbone of the chemoreduction has generally been carboplatin, etoposide, and vincristine. Chemotherapy shrinks the tumors (chemoreduction), allowing greater efficacy of subsequent local therapy.[10] Treatment strategies often differ in terms of chemotherapy regimens and local control measures. Using this approach, the International Classification of Retinoblastoma grouping system has been proven to predict ocular salvage.[26,27]; [28][Level of evidence: 3iiDiv]

  • Groups A and B: Systemic chemotherapy in conjunction with local control have resulted in ocular salvage rates greater than 90% for early intraocular disease.[27-29]
  • Groups C and D: Ocular salvage rates using this approach are 70% to 90% for Group C eyes and 40% to 50% for Group D eyes.[27-29] However, for patients with more advanced intraocular disease (typically Group D eyes), EBRT is frequently required for ocular salvage.[28]; [29][Level of evidence: 3iiDiii]

    For patients with large intraocular tumor burden with subretinal or vitreous seeds (Groups D eyes), the administration of higher doses of carboplatin, coupled with subtenon carboplatin, and the addition of lower doses of EBRT (36 Gy) for patients with persistent disease has been explored. Using this intensive approach, eye survival may approach a rate of 70% at 60 months.[30][Level of evidence: 2Div]

  • Group E: The treatment 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.[12][Level of evidence: 3iiiB]

Delivery of chemotherapy via ophthalmic artery cannulation has also been shown to be feasible and effective in patients with newly diagnosed bilateral disease as tandem administration and in the salvage setting.[14,15,31,32][Level of evidence: 3iiDii] Bilateral administrations increase the risk of systemic toxicity caused by melphalan exposure.[33] In these circumstances, intra-arterial chemotherapy with single-agent carboplatin may be used to treat the less-advanced eye during the tandem procedure.[34] These treatments should only be performed in an experienced center with a state-of-the-art treatment infrastructure and a dedicated multidisciplinary team.

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 the 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.[35]

Treatment Options Under Clinical Evaluation for Intraocular Retinoblastoma

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

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

  • ARET12P1 (NCT02097134) (Intra-arterial Melphalan in Treating Younger Patients With Unilateral Retinoblastoma): This pilot clinical trial is studying whether unilateral Group D retinoblastoma, or retinoblastoma affecting one eye that has spread to the vitreous fluid, can be treated with intra-arterial injection. This may provide children with unilateral retinoblastoma a lower chance of needing surgery to remove the eye and reduce the severity of treatment side effects.

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. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. 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]
  11. Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol 120 (12): 1653-8, 2002. [PUBMED Abstract]
  12. 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]
  13. 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]
  14. 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]
  15. 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]
  16. 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]
  17. 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]
  18. 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]
  19. 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]
  20. 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]
  21. 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]
  22. 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]
  23. 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]
  24. 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]
  25. 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]
  26. 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]
  27. Shields CL, Mashayekhi A, Au AK, et al.: The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113 (12): 2276-80, 2006. [PUBMED Abstract]
  28. 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]
  29. 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]
  30. 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]
  31. Abramson DH, Dunkel IJ, Brodie SE, et al.: Bilateral superselective ophthalmic artery chemotherapy for bilateral retinoblastoma: tandem therapy. Arch Ophthalmol 128 (3): 370-2, 2010. [PUBMED Abstract]
  32. 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]
  33. Schaiquevich P, Buitrago E, Taich P, et al.: Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients. Invest Ophthalmol Vis Sci 53 (7): 4205-12, 2012. [PUBMED Abstract]
  34. Francis JH, Gobin YP, Brodie SE, et al.: Experience of intra-arterial chemosurgery with single agent carboplatin for retinoblastoma. Br J Ophthalmol 96 (9): 1270-1, 2012. [PUBMED Abstract]
  35. 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]

Treatment Options for Extraocular Retinoblastoma

In high-income 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 progress 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

Standard treatment options for extraocular retinoblastoma (orbital and locoregional) include the following:

  1. Chemotherapy.
  2. Radiation therapy.

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 used. 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, delay of surgery until response to chemotherapy is achieved (usually two or three courses of treatment) has been effective. 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 are considered to have extraocular disease and are treated using systemic therapy, similar to that used for macroscopic orbital disease, and irradiation of the entire orbit (36 Gy) with 10 Gy boost to the chiasm (total of 46 Gy).[2]

CNS disease

Standard treatment options for extraocular retinoblastoma (CNS disease) include the following:

  1. Systemic chemotherapy and CNS-directed therapy.
  2. Systemic chemotherapy followed by myeloablative chemotherapy and stem cell rescue.

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 used traditionally, there is no preclinical or clinical evidence to support its use. The administration of radiation therapy to these patients is controversial. Responses have been observed with craniospinal radiation 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

Standard treatment options for trilateral retinoblastoma include the following:

  1. Systemic chemotherapy followed by surgery and myeloablative chemotherapy with stem cell rescue.
  2. Systemic chemotherapy followed by surgery and radiation therapy.

Trilateral retinoblastoma is usually associated with a pineal lesion or, less commonly, as a suprasellar lesion.[5-7] In patients with the heritable form of retinoblastoma, CNS disease is less likely the result of metastatic or regional spread than of 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.[8,9] Trilateral retinoblastoma has been the principal cause of death from retinoblastoma in the United States during the first decade of life.[7]

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.[10]

Because of the poor prognosis of trilateral retinoblastoma, screening with neuroimaging is a common practice in the follow-up of children with the heritable form of the disease. 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 not determined. MRI screening may be needed as often as every 6 months until the child is age 5 years. Given the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral retinoblastoma, routine screening might detect most cases within 2 years. However, it is not clear whether screening by neuroimaging improves survival.[8]

Computed tomography scans are avoided for routine screening in these children to minimize exposure to ionizing radiation.

Extracranial metastatic retinoblastoma

Standard treatment options for extracranial metastatic retinoblastoma include the following:

  1. Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue and radiation therapy.

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.[11-17]; [18][Level of evidence: 3iiA]

Treatment Options Under Clinical Evaluation for Extraocular Retinoblastoma

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

  • 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. Paulino AC: Trilateral retinoblastoma: is the location of the intracranial tumor important? Cancer 86 (1): 135-41, 1999. [PUBMED Abstract]
  7. Blach LE, McCormick B, Abramson DH, et al.: Trilateral retinoblastoma--incidence and outcome: a decade of experience. Int J Radiat Oncol Biol Phys 29 (4): 729-33, 1994. [PUBMED Abstract]
  8. 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]
  9. Marcus DM, Brooks SE, Leff G, et al.: Trilateral retinoblastoma: insights into histogenesis and management. Surv Ophthalmol 43 (1): 59-70, 1998 Jul-Aug. [PUBMED Abstract]
  10. 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]
  11. 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]
  12. 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]
  13. Rodriguez-Galindo C, Wilson MW, Haik BG, et al.: Treatment of metastatic retinoblastoma. Ophthalmology 110 (6): 1237-40, 2003. [PUBMED Abstract]
  14. Dunkel IJ, Aledo A, Kernan NA, et al.: Successful treatment of metastatic retinoblastoma. Cancer 89 (10): 2117-21, 2000. [PUBMED Abstract]
  15. 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]
  16. 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]
  17. 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]
  18. 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]

Treatment of Progressive or Recurrent Retinoblastoma

The prognosis for a patient with progressive or recurrent retinoblastoma depends on the site and extent of the progression or recurrence and previous treatment received. Intraocular and extraocular recurrence have very different prognoses and are treated in distinctly different ways.

Treatment options for progressive or recurrent intraocular retinoblastoma include the following:

  1. Enucleation.
  2. Radiation therapy (external-beam or plaque radiation therapy).
  3. Local treatments (cryotherapy or thermotherapy).
  4. Salvage chemotherapy (systemic or intra-arterial).

Treatment options for progressive or recurrent extraocular retinoblastoma include the following:

  1. Systemic chemotherapy and radiation therapy for orbital disease.
  2. Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue and radiation therapy for extraorbital disease.

New intraocular tumors can arise in patients with the heritable form of disease, whose eyes have been treated with local control measures only, because every cell in the retina carries the RB1 mutation; this should not be considered a recurrence. Even with previous treatment consisting of chemoreduction and local control measures in very young patients with heritable retinoblastoma, surveillance may detect new tumors at an early stage and additional local control therapy, including plaque brachytherapy, can be successful in eradicating tumor.[1-5]

When the recurrence or progression of retinoblastoma is confined to the eye and is small, the prognosis for sight and survival may be excellent with local therapy only.[6][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.[7] Radiation therapy should be considered for patients that have not been previously irradiated. Finally, enucleation may be required in cases of progressive disease after all eye-salvaging treatments have failed.

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.[8][Level of evidence: 3iiA]

If the recurrence or progression is extraocular, the chance of survival is poor.[9] However, the use of intensive systemic chemotherapy and consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue may improve the chance of cure, particularly for patients with extracranial recurrence (refer to the Treatment Options for Extraocular Retinoblastoma section of this summary for more information). For patients recurring after those intensive approaches, clinical trials may be considered.

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. Shields CL, Honavar SG, Shields JA, et al.: Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol 120 (4): 460-4, 2002. [PUBMED Abstract]
  2. Gombos DS, Kelly A, Coen PG, et al.: Retinoblastoma treated with primary chemotherapy alone: the significance of tumour size, location, and age. Br J Ophthalmol 86 (1): 80-3, 2002. [PUBMED Abstract]
  3. Shields CL, Shelil A, Cater J, et al.: Development of new retinoblastomas after 6 cycles of chemoreduction for retinoblastoma in 162 eyes of 106 consecutive patients. Arch Ophthalmol 121 (11): 1571-6, 2003. [PUBMED Abstract]
  4. Lee TC, Hayashi NI, Dunkel IJ, et al.: New retinoblastoma tumor formation in children initially treated with systemic carboplatin. Ophthalmology 110 (10): 1989-94; discussion 1994-5, 2003. [PUBMED Abstract]
  5. Wilson MW, Haik BG, Billups CA, et al.: Incidence of new tumor formation in patients with hereditary retinoblastoma treated with primary systemic chemotherapy: is there a preventive effect? Ophthalmology 114 (11): 2077-82, 2007. [PUBMED Abstract]
  6. 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]
  7. 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]
  8. Kim JW, Kathpalia V, Dunkel IJ, et al.: Orbital recurrence of retinoblastoma following enucleation. Br J Ophthalmol 93 (4): 463-7, 2009. [PUBMED Abstract]
  9. Broaddus E, Topham A, Singh AD: Survival with retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93 (1): 24-7, 2009. [PUBMED Abstract]

Changes to This Summary (10/24/2014)

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.

General Information about Retinoblastoma

Revised Figure 1 to include the canal of Schlemm and lamina cribrosa.

Treatment Option Overview for Retinoblastoma

Added Francis et al. as reference 22.

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

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

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>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site’s Contact Form.

Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.

Chat online

The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

Write to us

For more information from the NCI, please write to this address:

  • NCI Public Inquiries Office
  • 9609 Medical Center Dr.
  • Room 2E532 MSC 9760
  • Bethesda, MD 20892-9760

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).

  • Updated: October 24, 2014