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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References

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