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Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(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. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1,3,4] Between 1975 and 2010, childhood cancer mortality has decreased by more than 50%.[1,3,4] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Retinoblastoma is a relatively uncommon tumor of childhood that arises in the retina and accounts for about 3% of the cancers occurring in children younger than 15 years. The estimated annual incidence in the United States is approximately 4 cases per 1 million children younger than 15 years. Although retinoblastoma may occur at any age, it most often occurs in younger children; the annual incidence is 10 to 14 cases per 1 million in children aged 0 to 4 years. Ninety-five percent of cases are diagnosed before age 5 years, and two-thirds of these cases occur before age 2 years. Older age is usually associated with more advanced disease and a poorer prognosis.
Heritable and Nonheritable Forms of Retinoblastoma
Retinoblastoma is a tumor that occurs in heritable (25% to 30%) and nonheritable (70% to 75%) forms. Heritable disease is defined by the presence of a positive family history, multifocal retinoblastoma, or an identified germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25%) or may have occurred in utero at the time of conception in patients with sporadic disease (75%). Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4.[6,7] Approximately 85% of patients with unilateral retinoblastoma do not have the heritable form of the disease, whereas all children with bilateral disease are presumed to have the heritable form, even though only 25% have an affected parent. In heritable retinoblastoma, tumors tend to be diagnosed at a younger age than in the nonheritable form of the disease. Unilateral retinoblastoma in children younger than 1 year raises concern for heritable disease, whereas older children with a unilateral tumor are more likely to have the nonheritable form of the disease.[8,9]
Children with the heritable form of retinoblastoma may continue to develop new tumors for a few years after diagnosis and treatment; for this reason, they need to be examined frequently for the development of new tumors. It is recommended that they be examined every 2 to 4 months for at least 28 months. The interval between exams is based on the age of the child (less frequent visits as the child ages) and the stability of the disease.
Early-in-life screening by fundus exams under general anesthesia at regular intervals, according to a schedule based on the absolute estimated risk, can improve prognosis in terms of globe sparing and use of less-intensive, ocular-salvage treatments in children with a positive family history of retinoblastoma. Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, periodic examinations of the unaffected eye are performed until the germline status of the RB1 gene is determined.
The parents and siblings of patients with retinoblastoma should have screening ophthalmic examinations to exclude an unknown familial disease. Siblings should continue to be screened until age 3 to 5 years or until it is confirmed that they do not have a genetic mutation.
Blood and/or tumor samples can be screened to determine if a patient with retinoblastoma has a mutation in the RB1 gene. Once the patient's genetic mutation has been identified, other family members can be screened directly for the mutation. The RB1 gene is located within the q14 band of chromosome 13. Exon by exon sequencing of the RB1 gene demonstrates germline mutation in 90% of patients with heritable retinoblastoma.[12,13,14] Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out. A multistep assay including DNA sequencing to identify mutations within coding exons and immediate flanking intronic regions, Southern blot analysis to characterize genomic rearrangements, and transcript analysis to characterize potential splicing mutations buried within introns may need to be performed for a complete genetic evaluation of the RB1 gene. In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected, and more exhaustive techniques such as karyotyping, multiplex ligation-dependent probe amplification, fluorescence in situ hybridization, and methylation analysis of the RB1 promoter may be needed. The absence of detectable RB1 mutations in some patients may suggest that alternative genetic mechanisms may underlie the development of retinoblastoma. In a report of 29 patients with clinical retinoblastoma and no evidence of a RB1 mutation, 15 demonstrated high levels of MYCN amplification. These patients had distinct, aggressive, histologic features and a median age at diagnosis of 4 months.
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.[14,18] Genetic counseling, however, is not always straightforward. Families with retinoblastoma may have a founder mutation with embryonic mutagenesis causing genetic mosaicism of gametes. A significant proportion (10%–18%) of children with retinoblastoma have somatic genetic mosaicism,[20,21] making the genetic story more complex and contributing to the difficulty of genetic counseling.
(Refer to the PDQ summaries on Cancer Genetics Risk Assessment and Counseling and Cancer Genetics Overview for more information.)
Factors Influencing Mortality
The present challenge for those who treat retinoblastoma is to preserve life and to prevent the loss of an eye, blindness, and other serious effects of treatment that reduce the life span or the quality of life. With improvements in the diagnosis and management of retinoblastoma over the past several decades, metastatic retinoblastoma is observed less frequently in the United States and other developed nations. As a result, other causes of retinoblastoma-related mortality in the first decade of life, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality. In the United States, before the advent of chemoreduction as a means of treating bilateral (heritable) disease, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis.
Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with heritable retinoblastoma and is defined by the development of an intracranial midline neuroblastic tumor, which typically develops more than 20 months after the diagnosis of retinoblastoma. Patients who are asymptomatic at the time of diagnosis with an intracranial tumor have a better outcome than patients who are symptomatic.
Given the poor prognosis of trilateral retinoblastoma and the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral disease, routine neuroimaging could potentially detect the majority of cases within 2 years of first diagnosis. Although it is not clear whether early diagnosis can impact survival, screening with magnetic resonance imaging has been recommended as often as every 6 months for 5 years for those suspected of having heritable disease or those with unilateral disease and a positive family history. Computed tomography scans are generally avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.
Subsequent neoplasms (SNs)
Patients with heritable retinoblastoma have a markedly increased frequency of SNs.[24,25] There may be an association between type of RB1 mutation and incidence of SNs, with complete loss of RB1 activity having a higher incidence of SNs. The cumulative incidence was reported to be 26% (± 10%) in nonirradiated patients and 58% (± 10%) in irradiated patients by 50 years after diagnosis of retinoblastoma—a rate of about 1% per year. 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. The most common SN is osteosarcoma, followed by soft tissue sarcoma and melanoma; these malignancies may occur inside or outside of the radiation field, although most are radiation-induced. The carcinogenic effect of radiation therapy is associated with the dose delivered, particularly for subsequent sarcomas, where a step-wise increase is apparent at all dose categories. In irradiated patients, two-thirds of SNs occur within irradiated tissue, and one-third occur outside the radiation field.[27,28,29]
The risk of SNs also appears to be dependent on the patient's age at the time the external-beam radiation therapy is given, especially in children younger than 12 months, and the histopathologic types of SNs may be influenced by age.[28,30,31] These data support a genetic predisposition to soft tissue sarcomas, in addition to the risk of osteosarcoma.
There is no evidence of an increased incidence of acute myeloid leukemia in children with heritable retinoblastoma.; [Level of evidence: 3iiiA] Of 245 patients, all of whom received etoposide, only one patient had acute promyelocytic leukemia after 79 months.
With the increase in survival of patients with heritable retinoblastoma, it has become apparent that they are also at risk of developing epithelial cancers late in adulthood. A marked increase in mortality from lung, bladder, and other epithelial cancers has been described.[34,35]
Survival from SNs is certainly suboptimal and varies widely across studies.[25,34,36,37,38,39] However, with advances in therapy, it is essential that all SNs be treated with curative intent. Those who survive SNs are at a sevenfold increased risk for developing another SN. The risk further increases threefold when patients are treated with radiation therapy for their retinoblastoma. Retinoblastoma survivors with bilateral disease and an inherited germline mutation are at a slightly higher risk of a SN than those without an inherited mutation; this increase appears to be most significant for melanoma.
There is no clear increase in SNs in patients without a germline retinoblastoma mutation beyond that associated with the treatment.[27,39]
Late Effects from Retinoblastoma Therapy
Orbital growth is somewhat diminished after enucleation; however, the impact of enucleation on orbital volume may be less after placement of an orbital implant.
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. One study of visual acuity after treatment with systemic chemotherapy and focal ophthalmic therapy was conducted in 54 eyes in 40 children. After a mean follow-up of 68 months, 27 eyes (50%) had a final visual acuity of 20/40 or better, and 36 eyes (67%) had final visual acuity of 20/200 or better. The clinical factors that predicted visual acuity of 20/40 or better were a tumor margin at least 3 mm from the foveola and optic disc and an absence of subretinal fluid.
Because systemic carboplatin is now commonly used in the treatment of retinoblastoma (refer to the Intraocular Retinoblastoma and Extraocular Retinoblastoma sections of this summary for more information), concern has been raised about hearing loss related to therapy. While an analysis of 164 children treated with six cycles of carboplatin-containing therapy (18.6 mg/kg per cycle) showed no loss of hearing among children who had a normal initial audiogram, another series documented hearing loss in 17% of patients. Age younger than 6 months at the time of treatment and higher carboplatin systemic exposures appear to correlate with an increased risk of ototoxicity.[48,49]
Retinoblastoma is composed mainly of undifferentiated anaplastic cells that arise from the retina. Histology shows similarity to neuroblastoma and medulloblastoma, including aggregation around blood vessels, necrosis, calcification, and Flexner-Wintersteiner rosettes. Retinoblastomas are characterized by marked cell proliferation, as evidenced by high mitosis counts, extremely high MIB-1 labeling indices, and strong diffuse nuclear immunoreactivity for CRX, a useful marker to discriminate retinoblastoma from other malignant small round cell tumors.[1,2]
Cavitary retinoblastoma, 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. These tumors have been associated with minimal visible tumor response to chemotherapy, which is thought to be a sign of tumor differentiation.
Although there are several staging systems available for retinoblastoma, for the purpose of treatment, retinoblastoma is categorized into intraocular and extraocular disease. Overall assessment of retinoblastoma extension is documented by staging systems; the intraocular extension, which is relevant for ocular salvage, is documented by grouping systems.
Intraocular 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).
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
Pathologic classification system
International Retinoblastoma Staging System
A simplified staging system, the International Retinoblastoma Staging System, has been proposed by an international consortium of ophthalmologists and pediatric oncologists.
Grouping systems are relevant for assessment of intraocular disease extension and are helpful predictors of ocular salvage.
Reese-Ellsworth Classification for Intraocular Tumors
Reese and Ellsworth developed a classification system for intraocular retinoblastoma that has been shown to have prognostic significance for maintenance of sight and control of local disease at a time when surgery and external-beam radiation therapy (EBRT) were the primary treatment options.
Group I: very favorable for maintenance of sight
Group II: favorable for maintenance of sight
Group III: possible for maintenance of sight
Group IV: unfavorable for maintenance of sight
Group V: very unfavorable for maintenance of sight
International Classification of Retinoblastoma
There is a new grouping system for retinoblastoma, which may offer greater precision in stratifying risk for newer therapies. The International Classification of Retinoblastoma that is used in the current Children's Oncology Group treatment studies and in some institutional studies has been shown to assist in predicting those who are likely to be cured without the need for enucleation or EBRT.[3,4,5,6] The International Classification of Retinoblastoma was able to predict high-risk histopathology in a study of over 500 patients with retinoblastoma. Histopathologic evidence of high-risk disease was noted in 17% of Group D and 24% of Group E eyes in this study. Such predication can be helpful in counseling parents regarding the need for postoperative systemic therapy.
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. Evaluation at specialized treatment centers is highly suggested before the initiation of treatment in order to improve the likelihood of ocular salvage.
The goals of therapy are threefold:
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. Eyes with glaucoma and those in which glaucoma resulted in buphthalmia are significantly associated with high-risk pathology and the occurrence of microscopically residual tumor. 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]
Routine bone marrow biopsy and lumbar puncture are not indicated, except when there is a high level of suspicion that the tumor has spread beyond the globe.[8,9,10]
It is not uncommon for patients with retinoblastoma to have extensive disease within one eye at diagnosis, with either massive tumors involving more than one-half of the retina, multiple tumors diffusely involving the retina, or obvious seeding of the vitreous. For those with bilateral disease, systemic therapy may be used to treat the more severe eye.[11,12]
Metastasis from retinoblastoma generally develops within 1 year of diagnosis. If there is no metastatic disease by 5 years after treatment, the patient is generally considered cured.
Treatment of retinoblastoma is individualized and considers the age of the patient, laterality, potential for vision, and intraocular tumor burden. When selecting a treatment option, cure of the disease, preservation of sight, and prevention of late effects should be considered.
Different combinations of the following approaches may be applied to the individual patient depending on whether the patient has unilateral or bilateral disease.
Treatment options for the involved eye include the following:
Multiagent chemotherapy is generally used, although carboplatin as a single agent causes shrinkage of retinoblastoma tumors.; [Level of evidence: 3iiiDiii] Most standard regimens incorporate vincristine, carboplatin, and etoposide, although a two-drug regimen without etoposide may also be effective for early intraocular stages.[1,11,14,17,18,19] The success rate of these trials varies from center to center, but overall, the rate is highest for discrete tumors without vitreous seeding. Local tumor recurrence is not uncommon in the first few years after treatment  and can often be successfully treated with focal therapy. Among patients with heritable disease, younger patients and those with a positive family history are more likely to form new tumors. Chemotherapy may treat small, previously undetected lesions by slowing their growth, and this may improve overall salvage with focal therapy.
There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma.
Small body and ocular size may pose technical limitations to its use in very young patients. Intravenous chemotherapy has been used in neonates and young infants to postpone intra-arterial chemotherapy. One or several cycles of single-agent carboplatin have been used to bridge the time until the child is aged 3 months and weighs 6 kg.[Level of evidence: 3iiiDi]
In a recent report of 81 patients with heritable retinoblastoma, intra-arterial chemotherapy was able to eliminate ophthalmoscopically undetectable tumors present at diagnosis in the majority of patients.[Level of evidence: 3iiDi]
This treatment is not without complications in some cases.[23,30,38,39] Retinal and choroidal vasculopathy may occur in 10% to 20% of patients.[32,40]
Standard treatment options
Because unilateral disease is usually massive and there is often no expectation that useful vision can be preserved, up-front surgery (enucleation) is usually recommended. Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These features include anterior chamber seeding, choroidal involvement, tumor beyond the lamina cribrosa, or scleral and extrascleral extension.[19,46,47,48] Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide or with vincristine, carboplatin, and etoposide has been used in patients with certain high-risk features assessed by pathologic review after enucleation to prevent the development of metastatic disease,[19,49,50,51,52]; [Level of evidence: 2A] with the suggestion of success compared with historical controls.[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. Ocular salvage rates correlate with intraocular stage. In selected children with unilateral disease, Reese-Ellsworth (R-E) Group correlated with successful systemic chemoreduction; 11% of children classified as having R-E Group II or III disease, 60% of children having R-E Group IV disease, and 100% of children having R-E Group V disease required enucleation or EBRT within 5 years of treatment. Caution must be exerted with extended systemic chemotherapy and delayed enucleation when tumor control does not appear to be possible. Pre-enucleation chemotherapy for eyes with advanced intraocular disease may result in downstaging and underestimate the pathological evidence of extraretinal and extraocular disease, thus increasing the risk of dissemination.
The delivery of chemotherapy via ophthalmic artery cannulation as initial treatment for advanced unilateral retinoblastoma appears to be more effective than systemic chemoreduction. In the setting of a multidisciplinary, state-of-the-art center, intra-arterial chemotherapy may result in ocular salvage rates in excess of 80% for patients with advanced intraocular unilateral retinoblastoma.; [23,28][Level of evidence: 3iiiDii]; [Level of evidence: 3iiiDiv]
Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, these children are candidates for genetic counseling and testing and periodic examinations of the unaffected eye, regardless of the treatment they received. Asynchronous bilateral disease occurs most frequently in patients with affected parents and in children diagnosed during the first months of life. Pre-enucleation magnetic resonance imaging has low sensitivity and specificity for the detection of high-risk pathology. 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 is generally chosen based on the eye with more extensive disease. Treatment modality options described for unilateral disease may be applied to one or both affected eyes in patients with bilateral disease. Chemoreduction (systemic or intra-arterial) coupled with aggressive focal treatments and very close monitoring is usually the treatment of choice, with the goal of ocular and vision preservation and the delay or avoidance of EBRT and enucleation.
Intraocular tumor burden is usually asymmetric. Treatment is dictated by the most advanced eye. While up-front enucleation of an advanced eye and risk-adapted adjuvant chemotherapy may be required, a more conservative approach using primary chemoreduction with close follow-up for response and focal treatment (e.g., cryotherapy or laser therapy) may be indicated. EBRT is now reserved for patients whose eyes do not respond adequately to primary systemic or intra-arterial chemotherapy and focal consolidation.
A number of large centers in Europe and North America have published trial results that used systemic chemotherapy in conjunction with aggressive focal consolidation for patients with bilateral disease.[1,18,20,21,58,59,60,61,62,63] Chemotherapy may shrink the tumors (chemoreduction), allowing greater efficacy of subsequent focal therapy. Treatment strategies often differ in terms of chemotherapy regimens and local control measures.
Centers using the R-E Classification for Intraocular Tumors have demonstrated that the goal to save eyes may be achievable for tumors that are R-E Group IV or lower. The backbone of the chemoreduction protocols has generally been carboplatin, etoposide, and vincristine (CEV); using this regimen in combination with aggressive focal treatments, enucleation or EBRT may be avoided in R-E Groups I, II, and III eyes.[1,11] Tumors associated with massive vitreous or subretinal seeds have proven problematic. Local control is often transient in patients with vitreous seeding or very large tumors (R-E Group V), and more than one-half of patients may eventually need EBRT and/or enucleation.[1,11] In one study, the addition of high-dose cyclosporine A (a modulator of p-glycoprotein) to the CEV regimen resulted in improved ocular salvage rates.
The International Classification of Retinoblastoma grouping system may be better than the R-E Classification for Intraocular Tumors at predicting success of treatment with systemic chemotherapy in combination with local control. The combinations of carboplatin and etoposide (CE)  or CEV [66,67] in conjunction with local control have resulted in ocular salvage rates above 90% for early intraocular disease (Groups A and B eyes), 70% to 90% for Group C eyes, and 40% to 50% for Group D eyes.[65,67,68]; [Level of evidence: 3iiDiv] However, for patients with advanced intraocular disease (typically Group D eyes), EBRT is frequently required for ocular salvage.; [Level of evidence: 3iiDiii]
For patients with large intraocular tumor burden or with subretinal or vitreous seeds (Groups C and D eyes), the use of periocular chemotherapy, usually in combination with systemic therapy, has been explored.[43,69] In one study, systemic chemoreduction, subtenon carboplatin, and local consolidation resulted in ocular salvage of 47% of Group D eyes. An additional 35% of eyes were salvaged with intensity-modulated radiation therapy.[Level of evidence: 2Div] The impact of this approach on ocular salvage is not well defined.
The treatment recommendation for Group E eyes is up-front enucleation. The use of prolonged systemic chemotherapy for Group E eyes to avoid or delay enucleation has been associated with lower disease-specific survival (P < .001).[Level of evidence: 3iiiB]
Delivery of chemotherapy via ophthalmic artery cannulation has also been shown to be feasible and effective in patients with bilateral disease, in both the up-front and salvage settings.[23,28,35][Level of evidence: 3iiDii] However, this treatment should only be performed in an experienced center with a state-of-the-art treatment infrastructure and a dedicated multidisciplinary team.
The unresolved issues are long-term tumor control and the consequences of chemotherapy. Most of these patients are exposed to etoposide, which has been associated with secondary leukemia in patients without predisposition to cancer, but at modest rates when compared with the risks associated with EBRT in heritable retinoblastoma.
In patients with cavitary retinoblastoma, minimal visual response is seen after intravenous chemotherapy and/or intra-arterial chemotherapy. Despite the blunted clinical response, cavitary retinoblastoma has a favorable long-term outcome with stable tumor regression and globe salvage. Aggressive or prolonged chemotherapy or adjunctive therapies are generally not necessary. In a retrospective series of 26 cavitary retinoblastomas that were treated with intravenous chemoreduction and/or intra-arterial chemotherapy, the mean reduction in tumor base was 22% and mean reduction in tumor thickness was 29%. Despite minimal reduction, tumor recurrence was noted in only one eye, globe salvage was achieved in 22 eyes, and there were no cases of metastasis or death during 49 months (range, 6–189 months) of follow-up.
Treatment Options Under Clinical Evaluation
Studies are planned for a variety of patient groups. The International Classification of Retinoblastoma is being utilized for these trials.
Information about ongoing clinical trials is available from the NCI Web site.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with intraocular retinoblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
In developed countries, few patients with retinoblastoma present with extraocular disease. Extraocular disease may be localized to the soft tissues surrounding the eye or to the optic nerve beyond the margin of resection. However, further extension may occur into the brain and meninges with subsequent seeding of the spinal fluid, and as distant metastatic disease involving the lungs, bones, and bone marrow.
Standard Treatment Options
Orbital and locoregional retinoblastoma
Orbital retinoblastoma occurs as a result of progression of the tumor through the emissary vessels and sclera. For this reason, transscleral disease is considered to be extraocular and should be treated as such. Orbital retinoblastoma is isolated in 60% to 70% of cases. Treatment includes systemic chemotherapy and radiation therapy; with this approach, 60% to 85% of patients can be cured. Because most recurrences occur in the central nervous system (CNS), regimens using drugs with well-documented CNS penetration are recommended. Different chemotherapy regimens have proven to be effective, including vincristine, cyclophosphamide, and doxorubicin and platinum- and epipodophyllotoxin-based regimens, or a combination of both.[1,2,3] For patients with macroscopic orbital disease, it is recommended that surgery be delayed until response to chemotherapy is achieved (usually two or three courses of treatment). Patients then undergo enucleation and receive an additional four to six courses of chemotherapy. Next, local control is consolidated with orbital irradiation (40 Gy to 45 Gy). Using this approach, orbital exenteration is not indicated. Patients with isolated involvement of the optic nerve at the transsection level receive similar systemic treatment, and irradiation includes the entire orbit (36 Gy) with 10 Gy boost to the chiasm (total 46 Gy).
Central nervous system disease
Intracranial dissemination occurs by direct extension through the optic nerve and its prognosis is dismal. Treatment for these patients includes platinum-based intensive systemic chemotherapy and CNS-directed therapy. Although intrathecal chemotherapy has been traditionally used, there is no preclinical or clinical evidence to support its use. Although the use of irradiation in these patients is controversial, responses have been observed with craniospinal irradiation using 25 Gy to 35 Gy to the entire craniospinal axis and a boost (10 Gy) to sites of measurable disease. Therapeutic intensification with high-dose, marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue has been explored, but its role is not yet clear.[Level of evidence: 3iiA]
Trilateral retinoblastoma is usually associated with a pineal lesion with a cystic appearance that can be misleading or, less commonly, as a suprasellar lesion. In patients with the heritable form of retinoblastoma, CNS disease is less likely the result of metastatic or regional spread than a primary intracranial focus, such as a pineal tumor. The prognosis for patients with trilateral retinoblastoma is very poor; most patients die of disseminated neuraxis disease in less than 9 months. While pineoblastomas occurring in older patients are sensitive to radiation therapy, current strategies are directed towards avoiding irradiation by using intensive chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue, an approach similar to those being used in the treatment of brain tumors in infants.
Because of the poor prognosis of trilateral retinoblastoma, screening neuroimaging is a common practice. Routine baseline brain magnetic resonance imaging (MRI) is recommended at diagnosis because it may detect trilateral retinoblastoma at a subclinical stage. In a small series of patients, the 5-year overall survival was 67% for those detected at baseline, compared with 11% for the group with a delayed diagnosis. The value of screening with MRI for those suspected of having heritable disease or those with unilateral disease and a positive family history is under discussion. It has been recommended as often as every 6 months for up to 5 years. Given the short interval between the diagnosis of retinoblastoma and the occurrence of trilateral retinoblastoma, routine screening might detect the majority of cases within 2 years. However, it is not clear whether screening by neuroimaging improves survival. Computed tomography scans should be avoided for routine screening in these children because of the perceived risk of exposure to ionizing radiation.
Extracranial metastatic retinoblastoma
Hematogenous metastases may develop in the bones, bone marrow, and less frequently, in the liver. Although long-term survivors have been reported with conventional chemotherapy, these reports should be considered anecdotal; metastatic retinoblastoma is not curable with conventional chemotherapy. In recent years, however, studies of small series of patients have shown that metastatic retinoblastoma can be cured using high-dose, marrow-ablative chemotherapy and autologous hematopoietic stem cell rescue.[8,9,10,11,12,13,14]; [Level of evidence: 3iiA]
Two reports suggest that there may be a role for intensive multimodality therapy with autologous stem cell rescue for patients with metastatic retinoblastoma.[4,15][Level of evidence: 3iiA] A few responses were noted in CNS (including trilateral) and systemic metastases.
The following is an example of national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
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.
The prognosis for a patient with recurrent or progressive retinoblastoma depends on the site and extent of the recurrence or progression and previous treatment. Metastasis in retinoblastoma generally occurs within 1 year of diagnosis. New intraocular tumors can arise in patients with the heritable form of disease whose eyes have been treated with focal measures only, since every cell in the retina carries the RB1 mutation; this is not technically recurrence. Even with prior treatment consisting of chemoreduction and focal measures in very young patients with heritable retinoblastoma, surveillance may detect new tumors at an early stage and additional focal therapy, including plaque brachytherapy, can be successful in eradicating tumor.[2,3,4,5,6] When the recurrence or progression of retinoblastoma is confined to the eye and is small, the prognosis for sight and survival may be excellent with local therapy only.[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. 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.[Level of evidence: 3iiA] If the recurrence or progression is extraocular, the chance of survival is poor, with death usually occurring within 6 months. In this circumstance, the treatment depends on many factors, including individual patient considerations. Clinical trials may be appropriate to consider.
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.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was comprehensively reviewed.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
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:
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:
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.
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.
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.
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.
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.
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For more information from the NCI, please write to this address:
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.
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).
Last Revised: 2013-12-06
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