National Cancer Institute
Last Modified: October 5, 2012
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 1 Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, an ophthalmologist with extensive experience in the treatment of children with retinoblastoma, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ® Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. 2 At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. 1 Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ® Late Effects of Treatment for Childhood Cancer summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Retinoblastoma is a relatively uncommon tumor of childhood that arises in the retina and accounts for about 3% of the cancers occurring in children younger than 15 years. The estimated annual incidence in the United States is approximately 4 per 1 million children younger than 15 years. Although retinoblastoma may occur at any age, it most often occurs in younger children; the annual incidence is 10 to 14 per 1 million in children aged 0 to 4 years. Ninety-five percent of cases are diagnosed before age 5 years, and two-thirds of these cases occur before age 2 years. Older age is usually associated with more advanced disease and a poorer prognosis. 3
Retinoblastoma is a tumor that occurs in heritable (25% to 30%) and nonheritable (70% to 75%) forms. Hereditary disease is defined by the presence of a positive family history, multifocal retinoblastoma, or an identified germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25%) or may have occurred in utero at the time of conception, in patients with sporadic disease (75%). Hereditary retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4. 4 5 Approximately 85% of patients with unilateral retinoblastoma do not have the hereditary form of the disease, whereas all children with bilateral disease are presumed to have the hereditary form, even though only 20% have an affected parent. In hereditary retinoblastoma, tumors tend to occur at a younger age than in the nonhereditary form of the disease. Unilateral retinoblastoma in children younger than 1 year should raise concern for the hereditary disease, whereas older children with a unilateral tumor are more likely to have the nonhereditary form of the disease. 6 7
Children with the hereditary form of retinoblastoma may continue to develop new tumors for a few years after diagnosis. For this reason, children with hereditary retinoblastoma need to be examined frequently for the development of new tumors. It is recommended that they be examined every 2 to 4 months for at least 28 months. 8 Following treatment, patients require careful surveillance until age 5 years. 9 The interval between exams is based on both the age of the child (more frequent visits as the child ages) and the stability of the disease.
Early-in-life screening by fundus exams under general anesthesia at regular intervals, according to a schedule based on the absolute estimated risk, can improve prognosis in terms of globe sparing in children with positive family histories of retinoblastoma. Intensive screening decreased the need for enucleation and external-beam radiation therapy in a retrospective review of groups of nonscreened versus differently screened children with positive family histories of retinoblastoma. 10
The parents and siblings of patients with retinoblastoma should have screening ophthalmic examinations to exclude an unknown familial disease. Siblings should continue to be screened until age 3 to 5 years or until it is confirmed that they do not have a genetic mutation.
Blood and/or tumor samples can be screened to determine if a retinoblastoma patient has a mutation in the RB1 gene. Once the patient's genetic mutation has been identified, other family members can be screened directly for the mutation. The RB1 gene is located within the q14 band of chromosome 13. Exon by exon sequencing of the RB1 gene demonstrates germline mutation in 90% of patients with hereditary retinoblastoma. 11 12 13 Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out. 14 The multistep assay includes DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions, Southern blot analysis to characterize genomic rearrangements, and transcript analysis to characterize potential splicing mutations buried within introns. This expanded analysis is showing promise in better defining the functional significance of apparently novel mutations in pilot investigations performed at the University of Pennsylvania. Such testing should be performed only at institutions with expertise in RB1 gene mutation analysis. 14 In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected and more exhaustive techniques such as karyotyping, multiplex ligation-dependent probe amplification, and fluorescence in situ hybridization may be needed. The absence of detectable RB1 mutations in some patients may suggest that alternative genetic mechanisms may underlie the development of retinoblastoma. 15
Genetic counseling should be an integral part of the management of patients with retinoblastoma and their families, whether unilateral or bilateral. 16 It is of utmost importance to assist parents in understanding the genetic consequences of each form of retinoblastoma and to estimate risk of disease in family members. 13 16 Genetic counseling, however, is not always straightforward. Families with retinoblastoma may have a founder mutation with embryonic mutagenesis causing genetic mosaicism of gametes. 17 A significant proportion (10%18%) of children with retinoblastoma have somatic genetic mosaicism, 18 19 making the genetic story more complex and contributing to the difficulty of genetic counseling. 14
The present challenge for those who treat retinoblastoma is to prevent loss of an eye, blindness, and other serious effects of treatment that reduce the life span or the quality of life. With improvements in the diagnosis and management of retinoblastoma over the past several decades, metastatic retinoblastoma is observed less frequently in the United States and other developed nations. As a result, other causes of retinoblastoma-related mortality in the first decade of life, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality. In the United States, before the advent of chemoreduction as a means of treating bilateral (hereditary) disease, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis. 20 21
Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with hereditary retinoblastoma and is defined by the development of an intracranial midline neuroblastic tumor, which typically develops more than 20 months after the diagnosis of retinoblastoma. 22 23 Patients who are asymptomatic at the time of diagnosis with an intracranial tumor have a better outcome than patients who are symptomatic. 22
Given the poor prognosis of trilateral retinoblastoma and the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral disease, routine neuroimaging could potentially detect the majority of cases within 2 years of first diagnosis. 22 While it is not clear whether early diagnosis can impact survival, the frequency of screening with magnetic resonance imaging for those suspected of having hereditary disease or those with unilateral disease and a positive family history has been recommended as often as every 6 months for 5 years. It is unclear if this will have an impact on outcome or survival. 23 Computed tomography scans should be avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.
Patients with hereditary retinoblastoma have a markedly increased frequency of subsequent neoplasms (SNs). 24 25 The cumulative incidence was reported to be 26% ( 10%) in nonirradiated patients and 58% ( 10%) in irradiated patients by 50 years after diagnosis of retinoblastomaa rate of about 1% per year. 26 However, more recent studies analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients. 27 The most common SNs are osteosarcomas, soft tissue sarcomas, or melanomas. There is no evidence of an increased incidence of acute myeloid leukemia in children with hereditary retinoblastoma. 28[Level of evidence: 3iiiA]
A cohort study of 963 patients, who were at least 1-year survivors of hereditary retinoblastoma diagnosed at two U.S. institutions from 1914 through 1984, evaluated risk for soft tissue sarcoma overall and by histologic subtype. Leiomyosarcoma was the most frequent subtype, with 78% being diagnosed 30 or more years after the retinoblastoma diagnosis. Risks were elevated in patients treated with or without radiation therapy, and, in those treated with radiation therapy, sarcomas were seen both within and outside the field of radiation. The carcinogenic effect of radiation increased with dose, particularly for secondary sarcomas where a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of the SNs occur within irradiated tissue and one-third occur outside the radiation field. 26 The risk for SNs is heavily dependent on the patient's age at the time the external-beam radiation therapy is given, especially in children younger than 12 months, and the histopathologic types of SNs may be influenced by age. 27 9 29 These data support a genetic predisposition to soft tissue sarcoma, in addition to the risk of osteosarcoma. 30
It has become apparent that patients with hereditary retinoblastoma are also at risk of developing epithelial cancers late in adulthood. A marked increase in mortality from lung, bladder, and other epithelial cancers has been described. 31 32
Survival from SNs is certainly suboptimal and varies widely across studies. 25 31 33 34 35 36 However, with advances in therapy, it is essential that all SNs be treated with curative intent. 37 Those who survive SNs are at a sevenfold increased risk for developing an SN. 38 The risk further increases threefold when patients are treated with radiation therapy for their retinoblastoma. 39 There is no clear increase in SNs in patients with sporadic retinoblastoma beyond that associated with the treatment. 26 36
Patients with retinoblastoma demonstrate a variety of long-term visual field defects after treatment for their intraocular disease. These defects are related to tumor size, location, and treatment method. 40 One study of visual acuity following treatment with systemic chemotherapy and focal ophthalmic therapy was conducted in 54 eyes in 40 children. After a mean follow-up of 68 months, 27 eyes (50%) had a final visual acuity of 20/40 or better, and 36 eyes (67%) had final visual acuity of 20/200 or better. The clinical factors that predicted visual acuity of 20/40 or better were a tumor margin at least 3 mm from the foveola and optic disc and an absence of subretinal fluid. 41
Since systemic carboplatin is now commonly used in the treatment of retinoblastoma (Refer to Intraocular Retinoblastoma and Extraocular Retinoblastoma sections of this summary for more information), concern has been raised about hearing loss related to therapy. However, an analysis of 164 children treated with six cycles of carboplatin-containing therapy (18.6 mg/kg per cycle) showed no loss of hearing among children who had a normal initial audiogram. 42
Retinoblastoma is composed mainly of undifferentiated anaplastic cells that arise from the retina. Histology shows similarity to neuroblastoma and medulloblastoma, including aggregation around blood vessels, necrosis, calcification, and Flexner-Wintersteiner rosettes. Retinoblastomas are characterized by marked cell proliferation as evidenced by high mitosis counts and extremely high MIB-1 labeling indices. 1
Although there are several staging systems available for retinoblastoma, for the purpose of treatment, retinoblastoma is categorized into intraocular and extraocular disease.
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 (metastatic) retinoblastoma has extended beyond the eye. It may be confined to the tissues around the eye (orbital retinoblastoma), or it may have spread to the central nervous system, bone marrow, or lymph nodes (metastatic retinoblastoma).
Reese 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.
There is a new classification system for retinoblastoma, which may offer greater precision in stratifying risk for newer therapies. The International Classification for Intraocular Retinoblastoma that is used in the current Children's Oncology Group treatment studies, as well in some institutional studies, has been shown to assist in predicting those who are likely to be cured without the need for enucleation or EBRT. 1 2 3 4
Treatment planning by a multidisciplinary team of cancer specialists, including a pediatric oncologist, ophthalmologist, and radiation oncologist, who have experience treating ocular tumors of childhood is required to optimize treatment planning. 1
The type of treatment required depends on both the extent of the disease within the eye and whether the disease has spread beyond the eye, either to the brain or to the rest of the body. 2 Eyes with glaucoma and those in which glaucoma resulted in buphthalmia are significantly associated with high-risk pathology risk factors and the occurrence of microscopically residual tumor. 3 Enucleation is reserved for patients with advanced unilateral intraocular disease with no hope for useful vision in the affected eye. Subsequent risk of extraocular recurrence may be increased in the presence of high-risk histopathologic features such as massive choroid invasion, scleral invasion, and optic nerve invasion. 4 5; 6[Level of evidence: 3iiDi] Clinical features predictive of these histological findings include eyes with glaucoma, especially those that have become buphthalmic. Routine bone marrow biopsy and lumbar puncture are not indicated, except when there is a high level of suspicion that the tumor has spread beyond the globe. 7 8 Examples include patients with an abnormal complete blood count or those whose tumors show massive choroidal involvement and which extend beyond the lamina cribrosa on pathologic examination of the enucleated specimen.
It is not uncommon for patients with retinoblastoma to have extensive disease within one eye at diagnosis, with either massive tumors involving more than one-half of the retina, multiple tumors diffusely involving the retina, or obvious seeding of the vitreous. For those with bilateral disease, systemic therapy may be used to treat the more severe eye. 9 10 There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma. 11
Treatment of retinoblastoma is individualized and considers the age of the patient, laterality, potential for vision, and intraocular tumor burden. Treatment options consider both cure of the disease and preservation of sight. 1 2 3 Different combinations of the following approaches may be applied to the individual patient, considering the two main scenarios, unilateral and bilateral disease.
Multiagent chemotherapy is generally used, although carboplatin as a single agent causes shrinkage of retinoblastoma tumors. 17; ; 18[[Level of evidence: 3iiiDiiiLevel of evidence: 3iiiDiii] Most standard regimens incorporate vincristine, carboplatin, and etoposide, although a two-drug regimen without etoposide may also be effective for early intraocular stages.] Most standard regimens incorporate vincristine, carboplatin, and etoposide, although a two-drug regimen without etoposide may also be effective for early intraocular stages. 1 12 13 16 19 20 21 22 The success rate of these trials varies from center to center, but overall, the rate is highest for discrete tumors without vitreous seeding. Local tumor recurrence is not uncommon in the first few years after treatment The success rate of these trials varies from center to center, but overall, the rate is highest for discrete tumors without vitreous seeding. Local tumor recurrence is not uncommon in the first few years after treatment 23 and can often be successfully treated with focal therapy. and can often be successfully treated with focal therapy. 10 Among patients with hereditary disease, younger patients and those with positive family histories are more likely to form new tumors. Chemotherapy may treat small, previously undetected lesions by slowing their growth, and this may improve overall salvage with focal therapy. Among patients with hereditary disease, younger patients and those with positive family histories are more likely to form new tumors. Chemotherapy may treat small, previously undetected lesions by slowing their growth, and this may improve overall salvage with focal therapy. 24
There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma. 25
Because unilateral disease is usually massive and there is often no expectation that useful vision can be preserved, up-front surgery (enucleation) is usually recommended. Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These features include anterior chamber seeding, choroidal involvement, tumor beyond the lamina cribrosa, or scleral and extrascleral extension. 40 41 42 Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide or with vincristine, carboplatin, and etoposide has been used in patients with certain high-risk features assessed by pathologic review after enucleation to prevent the development of metastatic disease, 43 44 45 46; 47[Level of evidence: 2A] with the suggestion of success compared with historical controls. 48[Level of evidence: 3iiDiii]
Patients with unilateral disease may also be offered chemotherapy and aggressive focal treatments in an attempt to save the eye and preserve vision. 1 49 50 Ocular salvage rates correlate with intraocular stage. 51 In selected children with unilateral disease, R-E Group correlated with successful chemoreduction: 11% of children classified as having R-E Group II or III disease; 60% of children having R-E Group IV disease; and 100% of children having R-E Group V disease required enucleation or EBRT within 5 years of treatment. 52 Caution must be exerted with extended chemotherapy and delayed enucleation when tumor control does not appear to be possible. Pre-enucleation chemotherapy for eyes with advanced intraocular disease may result in downstaging and underestimate the pathological evidence of extraretinal and extraocular disease, thus, increasing the risk of dissemination. 53
Pilot studies have evaluated the delivery of chemotherapy via ophthalmic artery cannulation as initial treatment for advanced unilateral and bilateral intraocular retinoblastoma. In the setting of a multidisciplinary, state-of-the-art center, intra-arterial chemotherapy may result in ocular salvage rates in excess of 80% for patients with advanced intraocular unilateral retinoblastoma. 31 35[Level of evidence: 3iiiDii]; 32[Level of evidence: 3iiiDiv]
Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, it is very important that children with unilateral retinoblastoma receive periodic examinations of the unaffected eye, regardless of the treatment they received. Asynchronous bilateral disease occurs most frequently in patients with affected parents and in children diagnosed during the first months of life. Pre-enucleation magnetic resonance imaging has low sensitivity and specificity for the detection of high-risk pathology. 54 As discussed, genetic counseling and testing at the time of diagnosis is the key to defining risk and planning follow-up.
The management of bilateral disease depends on the extent of the disease in each eye. Systemic therapy should be chosen based on the eye with more extensive disease. Treatment modality options described for unilateral disease may be applied to one or both affected eyes in patients with bilateral disease.
Usually the disease is more advanced in one eye, with less involvement in the other eye. Overall treatment management is dictated by the most advanced eye. While up-front enucleation of an advanced eye and risk-adapted adjuvant chemotherapy may be required, a more conservative approach using primary chemoreduction with close follow-up for response and focal treatment (e.g., cryotherapy or laser therapy) may be indicated. EBRT is now reserved for patients whose eyes do not respond adequately to primary systemic chemotherapy and focal consolidation.
A number of large centers in Europe and North America have published trial results using systemic chemotherapy in conjunction with aggressive focal consolidation for patients with bilateral disease. 1 20 23 24 50 51 55 56 57 58 59 60 61 62 63; 22[Level of evidence: 3iiDiv] Chemotherapy may shrink the tumors (chemoreduction), allowing greater efficacy of subsequent focal therapy. 1 40 Treatment strategies often differ in terms of chemotherapy regimens and local control measures.
Centers using the R-E classification have demonstrated that the goal to save eyes may be achievable for tumors that are R-E Group IV or lower. The backbone of the chemoreduction protocols has generally been carboplatin, etoposide, and vincristine (CEV). Studies from The Children's Hospital of Philadelphia and Wills Eye Hospital reported that enucleation or EBRT may be avoided in R-E Group I, II, and III eyes when patients were treated with six cycles. 1 12 21 Tumors associated with massive vitreous or subretinal seeds have proven problematic. 64 Local control was often transient in patients with vitreous seeding or very large tumors (R-E Group V), and fewer than half of patients were treated successfully without requiring EBRT and/or enucleation. 1 12
Other researchers reported the use of nine courses of CEV with the addition of high-dose cyclosporine A (a modulator of the p-glycoprotein) for eight R-E Group V eyes with an 88% (7 out of 8 eyes) success rate without the use of EBRT or enucleation. 58 59 However, conflicting results were seen in another study using the cyclosporine regimen in ten R-E Group V eyes, which reported only a 20% (2 out of 10 eyes) success rate. 60
The International Classification