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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 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:
(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 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 website.
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. For patients presenting with extraocular retinoblastoma, treatment with intensive chemotherapy is required, including consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue. While most patients with orbital disease and a large proportion of patients with systemic extra–central nervous system metastases can be cured, the prognosis for patients with intracranial disease is dismal.
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. 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).
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. Anteriorly, tumor invading the anterior chamber may gain access to systemic circulation through the canal of Schlemm. Progression through the optic nerve and past the lamina cribrosa increases the risk of systemic and central nervous system (CNS) dissemination.
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.
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).
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 for 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). Patients presenting with these pathological features in the enucleated eye are at high risk of developing metastases. 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 a germ cell before conception or in utero during early embryogenesis 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.
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. 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.
Although a positive finding with current technology confirms susceptibility, a negative finding cannot absolutely rule it out. A multistep assay that includes the following may 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 suggests that alternative genetic mechanisms may underlie the development of retinoblastoma. 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. In another small subset of tumors without detectable somatic RB1 mutations, chromothripsis is responsible for inactivating the RB1 gene.
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. 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. (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.)
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. 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.
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.
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. 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.
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.[19,20]
Subsequent neoplasms (SNs)
Survivors of retinoblastoma have a high risk of developing SNs. Factors that influence this risk include the following:
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.[22,27,28,30]
An increased incidence of acute myeloid leukemia in children with heritable retinoblastoma has been suggested; however, no evidence is available to support this suggestion.; [Level of evidence: 3iiiA] Of 245 patients who received etoposide, only one patient had acute promyelocytic leukemia after 79 months.
No clear increase in SNs exists in patients without a germline retinoblastoma mutation beyond that associated with the treatment.[27,37]
Survival from SNs is certainly suboptimal and varies widely across studies.[21,24,37,38,39,40] However, with advances in therapy, it is essential that all SNs be treated with curative intent.
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:
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.
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. These tumors have been associated with minimal visible tumor response to chemotherapy, which is thought to be a sign of tumor differentiation.
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. 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 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 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. 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.
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
The more simplified International Retinoblastoma Staging System has been proposed by an international consortium of ophthalmologists and pediatric oncologists. It is more widely used in the clinical setting than the AJCC staging system.
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. This grouping system is seldom used.
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
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.[5,6,7,8] 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.
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 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:
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:
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).[3,4,5,6] Preliminary data suggest that proton radiation therapy is associated with a lower risk of radiation-induced malignancy in survivors of heritable retinoblastoma. In a nonrandomized study that compared two contemporary cohorts of patients with heritable retinoblastoma who were treated with either photon or proton radiation therapy, the 10-year cumulative incidence of radiation-induced SN was significantly different between the two groups (0% for proton radiation vs. 14% for photon radiation, P = .015).
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.
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.[13,14]; [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.[13,14,16,17,18] Chemotherapy may also be continued or initiated with concurrent local control treatments. 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  and can often be successfully treated with local 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 local therapy.
There are data suggesting that the use of systemic chemotherapy may decrease the risk of developing trilateral retinoblastoma.
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.[22,25,26,27,28,29,30,31]; [23,32][Level of evidence: 3iiDiii]; [33,34][Level of evidence: 3iiDiv]
In a report of 70 eyes in 67 children, globe salvage was achieved in 72% of primary-treated cases and in 62% of secondary-treated cases at 5 years of follow-up. Secondary-treated cases had received intravenous chemotherapy. Primary intra-arterial therapy achieved globe salvage for group B (100%), group C (100%), group D (94%), and group E (36%) eyes. Of all 70 eyes, complete regression was achieved for solid tumor in 48 of 51 eyes (94%), subretinal seeds in 40 of 42 eyes (95%), and vitreous seeds in 34 of 39 eyes (87%). With 3 years of experience, the combined incidence of ophthalmic, retinal, and choroidal vascular ischemia was reduced to 1%.[Level of evidence: 3iiD]
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.[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.[Level of evidence: 3iiDi]
This treatment is not without complications.[22,27,38,39,40] Retinal and choroidal vasculopathy may occur in 10% to 20% of patients.[30,41] 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.
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. 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. 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.
The standard treatment options for intraocular, extraocular, and recurrent retinoblastoma are described in Table 8.
Standard Treatment Options for Unilateral Retinoblastoma
Standard treatment options for unilateral retinoblastoma include the following:
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:[1,2,3,4,5]
Pre-enucleation magnetic resonance imaging has low sensitivity and specificity for the detection of high-risk pathology.
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]; [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. 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.
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.
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.; [14,15][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 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:
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.[10,18,19,20,21,22,23,24,25,26] The backbone of the chemoreduction has generally been carboplatin, etoposide, and vincristine. Chemotherapy shrinks the tumors (chemoreduction), allowing greater efficacy of subsequent local therapy. 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.[27,28]; [Level of evidence: 3iiDiv]
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.[Level of evidence: 2Div]
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.[14,15,32,33][Level of evidence: 3iiDii] Bilateral administrations increase the risk of systemic toxicity caused by melphalan exposure. In these circumstances, intra-arterial chemotherapy with single-agent carboplatin may be used to treat the less-advanced eye during the tandem procedure. These treatments should only be performed in an experienced center with a state-of-the-art treatment infrastructure and a dedicated multidisciplinary team.
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.
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 website.
Current Clinical Trials
Check the list of NCI-supported 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 website.
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:
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.[1,2,3]
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.
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).
Standard treatment options for extraocular retinoblastoma (CNS disease) include the following:
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.[Level of evidence: 3iiA]
Standard treatment options for trilateral retinoblastoma include the following:
Trilateral retinoblastoma is usually associated with a pineal lesion or, less commonly, as a suprasellar lesion.[5,6,7] 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. Trilateral retinoblastoma has been the principal cause of death from retinoblastoma in the United States during the first decade of life. The prognosis for patients with trilateral retinoblastoma is very poor; most patients die of disseminated neuraxis disease in less than 9 months.[8,9] However, with increased surveillance and aggressive therapy, there has been improvement in survival, from 6% (patients treated before 1995) to 44% (patients treated after 1996).
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 and the apparent improved survival with early detection and aggressive treatment, screening with neuroimaging is a common practice in the monitoring 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. 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.
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:
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.[12,13,14,15,16,17,18]; [Level of evidence: 3iiA]
Check the list of NCI-supported 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 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:
Treatment options for progressive or recurrent extraocular retinoblastoma include the following:
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.[3,4,5,6,7]
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. 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.[Level of evidence: 3iiA]
If the recurrence or progression is extraocular, the chance of survival is poor. 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.
Check the list of NCI-supported 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.
Editorial changes were made to this summary.
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 NCI website's Email Us. 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:
PDQ® Pediatric Treatment Editorial Board. PDQ Retinoblastoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/retinoblastoma/hp/retinoblastoma-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389442]
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 Managing Cancer Care page.
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Last Revised: 2016-03-17
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