National Cancer Institute

Expert-reviewed information summary about the treatment of retinoblastoma in children.

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.

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).

Retinoblastoma Treatment

General Information About Retinoblastoma

Retinoblastoma is a 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, therefore, needs to be individualized. The management of intraocular retinoblastoma has evolved to a more risk-adapted approach that aims to minimize systemic exposure to drugs, optimize ocular drug delivery, and preserve 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 (CNS) 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. Thus, while the estimated annual incidence in the United States is approximately 4 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 1 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. After invading 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 CNS dissemination (refer to Figure 1).

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


The following screening and monitoring strategies reflect common practices in the management of retinoblastoma.

In children with a positive family history of retinoblastoma, early-in-life screening by fundus exam is performed under general anesthesia at regular intervals according to a schedule based on the absolute estimated risk, as determined by the identification of the mutation in the family and the presence of the mutation in the child. Infants born to affected parents have a dilated eye examination under anesthesia as soon as possible in the first month of life, and a genetic evaluation is performed. Infants with a positive genetic test are examined under anesthesia on a monthly basis. In infants who do not develop disease, monthly exams continue throughout the first year; the frequency of those studies may be decreased progressively during the second and subsequent years. Screening exams 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.

Common practice for the parents and siblings of patients with retinoblastoma is to have screening ophthalmic examinations to exclude an unknown familial disease. Siblings continue to be screened until age 3 to 5 years or until it is confirmed that they do not have an gene mutation.

Clinical Presentation

Age at presentation correlates with laterality; patients with bilateral disease present at a younger age, usually in the first 12 months of life.

Most cases present with leukocoria, which is occasionally first noticed after a flash photograph is taken. Strabismus is the second most common presenting sign and usually correlates with macular involvement. Very advanced intraocular tumors present with pain, orbital cellulitis, glaucoma, or buphthalmos. As the tumor progresses, patients may present with orbital or metastatic disease. Metastases occur in the preauricular and laterocervical lymph nodes, in the CNS, or systemically (commonly in the bones, bone marrow, and liver).

In the United States, children of Hispanic origin and children living in lower socioeconomic conditions have been noted to present with more advanced disease.

Diagnostic Evaluation

The diagnosis of intraocular retinoblastoma is usually made without pathologic confirmation. An examination under anesthesia with a maximally dilated pupil and scleral indentation is required to examine the entire retina. A very detailed documentation of the number, location, and size of tumors; the presence of retinal detachment and subretinal fluid; and the presence of subretinal and vitreous seeds must be performed.

Bidimensional ocular ultrasound and magnetic resonance imaging (MRI) can be useful to differentiate retinoblastoma from other causes of leukocoria and in the evaluation of extrascleral and extraocular extension in children with advanced intraocular retinoblastoma. Optic nerve enhancement by MRI does not necessarily indicate involvement; cautious interpretation of those findings 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.

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 may be performed.

Genetic counseling is recommended for all patients with retinoblastoma. (Refer to the Genetic Counseling section of this summary for more information.)

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 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 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as and polymorphisms. 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.

The genomic landscape of retinoblastoma is driven by alterations in that lead to biallelic inactivation. A rare cause of inactivation is chromothripsis, which may be difficult to detect by conventional methods. Other recurring genomic changes that occur in a small minority of tumors include mutation/deletion, amplification, and amplification. A study of 1,068 unilateral nonfamilial retinoblastoma tumors reported that a small percentage of cases (approximately 3%) lacked evidence of loss. Approximately one-half of these cases with no evidence of loss (representing approximately 1.5% of all unilateral nonfamilial retinoblastoma) showed amplification.

Postdiagnosis Surveillance

Children with a germline 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 gene is determined.

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

Genetic Testing

Blood and tumor samples can be tested to determine whether a patient with retinoblastoma has a mutation in the gene. Once the patient's genetic mutation has been identified, other family members can be screened directly for the mutation with targeted sequencing.

A multistep assay that includes the following may be performed for a complete genetic evaluation of the gene:

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

In cases of somatic mosaicism or cytogenetic abnormalities, the mutations may not be easily detected; more exhaustive techniques such as karyotyping, multiplex ligation-dependent probe amplification, fluorescence hybridization, and methylation analysis of the promoter may be needed. Allele-specific deep (2500x) sequencing of an genomic amplicon from lymphocyte DNA can reveal low-level mosaicism. Because mosaicism is caused by a postzygotic mutation, such a finding obviates the need for serial examination of siblings under anesthesia. Some mutations thought to be heterozygous with Sanger sequencing were also found to be mosaic. Deep sequencing will not discover some mosaic mutations with very low levels of amplification, mutations outside of the amplicon, mutations not found in lymphocytes but in other tissues, or mosaic large rearrangements of . Combining the above techniques, a germline mutation may be detected in more than 90% of patients with heritable retinoblastoma.

The absence of detectable somatic mutations in approximately 3% of unilateral, nonheritable retinoblastoma cases suggests that alternative genetic mechanisms may underlie the development of retinoblastoma. In one-half of these cases, high levels of 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 mutations, chromothripsis is responsible for inactivating the gene.

Genetic Counseling

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. In addition, for one specific mutation, the risk of retinoblastoma in a sibling may depend, in part, on whether the mutation is inherited from the mother or father. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Causes of Retinoblastoma-Related Mortality

While retinoblastoma is a highly curable disease, the challenge for those who treat retinoblastoma is to preserve life and to prevent the loss of an eye, blindness, and other serious effects of treatment that reduce the patient's life span or 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, such as trilateral retinoblastoma and subsequent neoplasms (SNs), have become significant contributors to retinoblastoma-related mortality in the first and subsequent decades of life.

Death from a second neoplasm is the most common cause of death and contributes to about 50% of deaths in patients with bilateral disease and genetically defined heritable retinoblastoma. In the United States, before the advent of chemoreduction as a means of treating heritable or bilateral disease and the implementation of neuroimaging screening, trilateral retinoblastoma contributed to more than 50% of retinoblastoma-related mortality in the first decade after diagnosis.

Trilateral retinoblastoma

Trilateral retinoblastoma is a well-recognized syndrome that occurs in 5% to 15% of patients with heritable retinoblastoma. It is defined by the development of an intracranial midline neuroblastic tumor, which typically develops between the ages of 20 and 36 months.

Trilateral retinoblastoma has been the principal cause of death from retinoblastoma in the United States during the first decade of life. Because of the poor prognosis for patients with trilateral retinoblastoma and the apparent improved survival with early detection and aggressive treatment, screening with routine neuroimaging could potentially detect most cases within 2 years of first diagnosis. Routine baseline brain 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 rate was 67% for those detected at baseline, compared with 11% for the group with a delayed 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 patients 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 risk related to ionizing radiation exposure.

A cystic pineal gland, which is commonly detected by surveillance MRI, needs to be distinguished from a cystic variant of pineoblastoma. In children without retinoblastoma, the incidence of pineal cysts has been reported to be 55.8%. In a case-control study that included 77 children with retinoblastoma and 77 controls, the incidence of pineal cysts was similar (61% and 69%, respectively), and the size and volume of the pineal gland was not significantly different between the groups. However, a cystic component has been described in up to 57% of patients with histologically confirmed trilateral retinoblastoma. An excessive increase in the size of the pineal gland seems to be the strongest parameter indicating a malignant process.

Subsequent neoplasms (SNs)

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

  • Heritable retinoblastoma. Patients with heritable retinoblastoma have a markedly increased incidence of SNs, independent of treatment with radiation therapy. In a German series of 643 patients with heritable retinoblastoma, chemotherapy with or without radiation therapy was the only significant risk factor for the onset of second cancers outside the periorbital region. A possible association between the type of mutation and incidence of SNs may exist, with complete loss of activity associated with a higher incidence of SNs. 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.

    Among retinoblastoma survivors with heritable retinoblastoma, those with an inherited germline mutation are at a slightly higher risk of developing an SN than are those with a de novo mutation; this increase appears to be most significant for melanoma.

  • Past treatment for retinoblastoma with radiation therapy. The cumulative incidence of SNs was reported to be 26% (± 10%) in nonirradiated patients and 58% (± 10%) in irradiated patients by 50 years after diagnosis of retinoblastoma—a rate of about 1% per year. A German series of 633 patients with heritable retinoblastoma demonstrated a 5-year survival of 93%; however, 40 years later, only 80% of patients survived, with most succumbing to radiation-induced SNs (hazard ratio, approximately 3). Other studies analyzing cohorts of patients treated with more advanced radiation planning and delivery technology have reported the SN rates to be about 9.4% in nonirradiated patients and about 30.4% in irradiated patients. In a nonrandomized study that compared two contemporary cohorts of patients with hereditary retinoblastoma who were treated with either photon (n = 31) or proton (n = 55) therapy, the 10-year cumulative incidence of radiation-induced SNs was significantly different between the two groups (0% for proton radiation vs. 14% for photon radiation, = .015). A longer follow-up will be required to further define the risk of SNs associated with proton radiation.

    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; 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.

  • Age at time of radiation therapy. The risk of SNs also appears to depend on the patient's age at the time that external-beam radiation therapy (EBRT) is administered, especially in children younger than 12 months, and the histopathologic types of SNs may be influenced by age.
  • Previous SN. Those who survive SNs are at a sevenfold increased risk for developing another SN. The risk increases an additional threefold for patients treated with radiation therapy.

The issue of balancing long-term tumor control with 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 a predisposition to cancer, but at modest rates when compared with the risks associated with EBRT in heritable retinoblastoma. Despite the known increased risk of acute myeloid leukemia (AML) associated with the use of etoposide, patients with heritable retinoblastoma are not at an increased risk of developing this SN. An initial report conducted by informal survey methods described 15 patients who developed AML after chemotherapy. One-half of the patients also received radiation therapy. This finding has not been substantiated by formal studies. In a single-institution study of 245 patients who received etoposide, only 1 patient had acute promyelocytic leukemia after 79 months. Additionally, the Surveillance, Epidemiology, and End Results (SEER) Program calculated standardized incidence rates for secondary hematopoietic malignancies in 34,867 survivors of childhood cancer. The observed-to-expected ratio of secondary AML in patients treated for retinoblastoma was zero.

Survival from SNs is certainly suboptimal and varies widely across studies. However, with advances in therapy, it is essential that all SNs in survivors of retinoblastoma be treated with curative intent.

Late Effects from Retinoblastoma Therapy

In a report from the Retinoblastoma Survivor Study (N = 470), 87% of survivors of retinoblastoma (mean age, 43 years; median follow-up, 42 years) had at least one medical condition and 71% had a severe or life-threatening condition. The adjusted relative risk of a chronic condition in survivors, compared with nonretinoblastoma controls, was 1.4 ( < .01); the relative risk of a grade 3 or 4 condition was 7.6 ( < .01). After excluding ocular conditions and SNs, this excess risk was found to persist only for those with bilateral disease.

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

  • Diminished orbital growth. Orbital growth is somewhat diminished after enucleation; however, the impact of enucleation on orbital volume may be less after placement of an orbital implant.
  • Visual-field deficits. Patients with retinoblastoma demonstrate a variety of long-term visual-field defects after treatment for their intraocular disease. These defects are related to tumor size, location, and treatment method.

    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.

  • Hearing loss. Because systemic carboplatin is now commonly used in the treatment of retinoblastoma (refer to the Treatment of Intraocular Retinoblastoma and Treatment of Extraocular Retinoblastoma sections of this summary for more information), concern has been raised about hearing loss related to therapy. While two large studies that included children treated with six cycles of carboplatin-containing therapy (18.6 mg/kg per cycle) showed an incidence of treatment-related hearing loss of lower than 1%, a separate series documented some degree of hearing loss in 17% of patients. In the latter study, age younger than 6 months at the time of treatment and higher carboplatin systemic exposures correlated with an increased risk of ototoxicity.

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.

Tumor Pathology of Retinoblastoma

Cone precursor cells are the cell of origin in retinoblastoma. 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, as follows:

  • Flexner-Wintersteiner rosettes are specific to 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 rosettes that are seen in 70% of tumors.
  • Homer Wright rosettes 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 , a useful marker to discriminate retinoblastoma from other malignant, small, round cell tumors.

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.

A pathologist experienced in ocular pathology and retinoblastoma should examine the enucleated specimen. This is particularly relevant to determine risk features of extraocular dissemination (refer to the Treatment of Intraocular Retinoblastoma section of this summary for more information).

Staging and Grouping Systems for Retinoblastoma

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

Intraocular Retinoblastoma

Intraocular retinoblastoma is localized to the eye; it may be confined to the retina or may extend to involve other structures such as the choroid, ciliary body, anterior chamber, and optic nerve head. Intraocular retinoblastoma, however, does not extend beyond the eye into the tissues around the eye or to other parts of the body.

Extraocular Retinoblastoma

Extraocular retinoblastoma extends 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).

Staging Systems

American Joint Committee on Cancer (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. However, the AJCC's TNM (tumor, node, metastasis) staging system is not widely used for pediatric retinoblastoma and patients are not stratified on the basis of prognostic stage groups.

International Retinoblastoma Staging System

The more simplified International Retinoblastoma Staging System (IRSS) 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 (refer to Table 1). A retrospective German study found that the IRSS predicted survival in 633 children with heritable retinoblastoma, of which 582 patients presented with IRSS stage 0 or I disease.

Grouping Systems

Grouping systems are relevant for assessment of intraocular disease extension and are helpful predictors of ocular salvage.

Reese-Ellsworth Classification for Intraocular Tumors

Reese and Ellsworth developed a classification system for intraocular retinoblastoma that has been shown to have prognostic significance for maintenance of sight and control of local disease at a time when surgery and external-beam radiation therapy (EBRT) were the primary treatment options. However, developments in the conservative management of intraocular retinoblastoma have made the Reese-Ellsworth grouping system less predictive for eye salvage and less helpful in guiding treatment. This grouping system is seldom used.

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. This system seems to be a better predictor of treatment success. The International Classification of Retinoblastoma system may also help predict high-risk histopathology. In a study of more than 500 patients with retinoblastoma, histopathologic evidence of high-risk disease was noted in 17% of Group D eyes and 24% of Group E eyes. This can be helpful in counseling parents regarding the potential need for postoperative systemic therapy.

  • Small intraretinal tumors away from foveola and disc.
    • All tumors are 3 mm or smaller in greatest dimension, confined to the retina
    • All tumors are located further than 3 mm from the foveola and 1.5 mm from the optic disc.
  • All remaining discrete tumors confined to the retina.
    • All other tumors confined to the retina not in Group A.
    • Tumor-associated subretinal fluid less than 3 mm from the tumor with no subretinal seeding.
  • Discrete local disease with minimal subretinal or vitreous seeding.
    • Tumor(s) are discrete.
    • Subretinal fluid, present or past, without seeding involving up to one-fourth of the retina.
    • Local fine vitreous seeding may be present close to discrete tumor.
    • Local subretinal seeding less than 3 mm (2 DD) from the tumor.
  • Diffuse disease with significant vitreous or subretinal seeding.
    • Tumor(s) may be massive or diffuse.
    • Subretinal fluid present or past without seeding, involving up to total retinal detachment.
    • Diffuse or massive vitreous disease may include “greasy” seeds or avascular tumor masses.
    • Diffuse subretinal seeding may include subretinal plaques or tumor nodules.
  • Presence of any one or more of the following poor prognosis features.
    • Tumor touching the lens.
    • Tumor anterior to anterior vitreous face involving ciliary body or anterior segment.
    • Diffuse infiltrating retinoblastoma.
    • Neovascular glaucoma.
    • Opaque media from hemorrhage.
    • Tumor necrosis with aseptic orbital cellulites.
    • Phthisis bulbi.

Treatment Option Overview for Retinoblastoma

Treatment planning by a multidisciplinary team of cancer specialists—including a pediatric oncologist, ophthalmologist, and radiation oncologist—with 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 to improve the likelihood of ocular salvage and vision preservation.

The goals of therapy are the following:

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

Treatment of retinoblastoma is tailored to the intraocular and extraocular disease burden, disease laterality, germline 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. Many treatments considered to be standard of care have not been studied in a randomized fashion.

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

  • Enucleation.
  • Local treatment (cryotherapy, laser therapy, and brachytherapy).
  • Systemic chemotherapy.
  • Ophthalmic artery infusion of chemotherapy (intra-arterial chemotherapy).
  • Intravitreal chemotherapy.
  • Subtenon chemotherapy (subconjunctival chemotherapy).
  • Radiation therapy (external-beam radiation therapy [EBRT], brachytherapy).

The treatment options for intraocular, extraocular, and recurrent retinoblastoma are described in Table 2.


Upfront removal of the eye is indicated for large tumors filling the vitreous for which there is little or no likelihood of restoring vision, in cases of extension to the anterior chamber, or in the presence of neovascular glaucoma. Patients must be monitored closely for orbital recurrence of disease, particularly in the first 2 years after enucleation.[] Enucleation is also used as a salvage treatment in cases of disease progression or recurrence in patients receiving eye-salvage management. The pathology specimen must be carefully examined to identify patients who are at high risk of extraocular dissemination and who may require adjuvant chemotherapy.

Local Treatment (Cryotherapy, Laser Therapy, and Brachytherapy)

For patients undergoing eye-salvage treatment, aggressive local therapy is always required. Local treatment is administered by the ophthalmologist directly to the tumor.

  • Cryotherapy: Cryotherapy is based on the application of a cryoprobe to the sclera in the immediate vicinity of the retinal tumor. Cryotherapy is used as primary therapy or with chemotherapy for tumors smaller than 4 disc diameters (DD) in the anterior portion of the retina.
  • Laser therapy: Laser therapy may be used as primary therapy for small tumors or in combination with chemotherapy for larger tumors. Traditional photocoagulation (argon laser), in which the laser was applied around the tumor to target the tumor vasculature, has given way to thermotherapy (diode laser). Thermotherapy is delivered directly to the tumor surface via infrared wavelengths of light.
  • Brachytherapy (plaque radiation therapy): For larger tumors that are not amenable to cryotherapy or laser therapy, brachytherapy can provide an effective means for local control (refer to the Radiation Therapy section of this summary for more information).

Systemic Chemotherapy

Systemic chemotherapy plays a role in the following:

  • Adjuvant setting for patients with high-risk pathology. Different regimens have been used in the management of patients with high-risk pathology in the enucleated specimen. Most regimens include a three-drug combination of vincristine, etoposide, and carboplatin, either alone or alternating with cyclophosphamide and an anthracycline.
  • Treatment of patients with extraocular and metastatic disease. Patients with extraocular disease benefit from more intensive therapy. While a standard treatment has not been determined, responses to cisplatin-based regimens, with consolidation with high-dose chemotherapy and autologous hematopoietic stem cell rescue for patients with extraorbital disease, have been reported.
  • Chemoreductive treatment in conjunction with aggressive local treatment for patients undergoing ocular salvage treatments.

During the past two decades, the standard of care has been systemic chemotherapy to reduce tumor volume (chemoreduction) to facilitate the use of local treatments and to avoid the long-term effects of radiation therapy.; []; []; [] 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. Chemotherapy may also be continued or initiated with concurrent local control. Eye grouping as defined by the International Classification of Retinoblastoma is the best predictor of ocular salvage using this approach. In a single-institution, nonrandomized study of 345 patients diagnosed with Group D or E tumors, primary enucleation and adjuvant chemotherapy for high-risk pathology was compared with systemic chemotherapy with or without subsequent enucleation as needed. The incidence of local recurrence and metastasis was less than 1%, regardless of the approach. As opposed to 100% enucleation, subsequent enucleation was performed in only 41% of children who received systemic chemoreduction, none of whom were found to have high-risk pathology in the chemoreduced eye.[]

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.

Ophthalmic Artery Infusion of Chemotherapy (Intra-arterial Chemotherapy)

Direct delivery of chemotherapy into the eye via cannulation of the ophthalmic artery is a feasible and effective method for ocular salvage.

Melphalan is the most common and most effective agent used. It is often combined with topotecan or carboplatin when responses are suboptimal or there is very advanced intraocular disease.

For patients with treatment-naive eyes, the 2-year radiation-free ocular survival rate is 86% to 90%. Outcome after intra-arterial chemotherapy correlates with the extent of intraocular burden, as follows:

  • Patients with early intraocular disease (Group B and C eyes) have an excellent outcome and may be treated with single-agent therapy.
  • Group D eyes have a worse outcome, with radiation-free ocular survival rates of 80% for eyes with subretinal seeding and 65% for eyes with vitreous seeding. Some centers have reported higher ocular salvage rates for unilateral Group D and E eyes using a three-drug chemotherapy regimen. For patients with very advanced intraocular disease, an alternative treatment is the use of systemic chemotherapy followed by consolidation with intra-arterial melphalan.
  • Ocular salvage rates when intra-arterial chemotherapy administration is used as salvage treatment for patients with recurrent or progressive disease are consistently lower, with globe survival rates of 50% to 60%. However, the use of a more intensive three-drug regimen with melphalan, topotecan, and carboplatin in patients who have progressed after standard systemic and focal therapies has reported radiation-free ocular salvage rates of 75% at 2 years.

Patients with bilateral disease can undergo tandem intra-arterial administration. In those circumstances, patients are at higher risk of systemic toxicity caused by melphalan exposure, and single-agent carboplatin may be used to treat the less-advanced eye during the tandem procedure. For neonates and very young infants where the cannulization of the ophthalmic artery is not feasible, treatment with single-agent systemic carboplatin until the infant is aged 3 months or weighs 6 kg, followed by consolidation with intra-arterial chemotherapy, has been shown to be very effective, with a 1-year radiation-free ocular survival rate of 95%.

Vitreous seeds may be difficult to control with intra-arterial chemotherapy. Anterior chamber seeding after intra-arterial chemotherapy can occur, as detected clinically in one series of 6 of 12 eyes (50%) and histopathologically in 8 of 12 eyes (67%). This finding suggests that intra-arterial chemotherapy may have greater efficacy in posterior segment disease.

Complications related to intra-arterial chemotherapy include the following:

  • Retinal detachment (19.3%).
  • Vitreous hemorrhage (18.1%).
  • Ptosis (13.6%).
  • Dysmotility (6.5%).
  • Vascular and ischemic effects (6.2%).
  • Optic atrophy (3.4%).
  • Phthisis (2.7%).

Major vascular complications related to the procedure are very rare; no strokes or significant acute neurological events have been reported by the most experienced groups. However, stenosis of the ophthalmic artery and occlusion of the retinal artery have been documented; the risk of thrombosis is significantly increased in children with thrombophilia.

The impact of the intraocular vascular changes on vision has not been fully assessed because of the young age of the first cohorts of patients treated. Most patients do not have substantial electroretinographic changes, and preservation of central vision has been reported. However, in patients with heavily pretreated eyes, intensive intra-arterial chemotherapy may result in worsening of retinal function.

Another risk associated with intra-arterial chemotherapy is the exposure to ionizing radiation during fluoroscopy. Radiation doses per procedure can be as high as 191 mGy to the affected eye and 35 mGy to the contralateral eye, although doses as low as 1 mGy per procedure have been reported. After multiple procedures, cumulative doses can reach 0.1 to 0.2 Gy, which can be cataractogenic and potentially carcinogenic in this susceptible population. Long-term outcome data reported by Japanese investigators seem to indicate that there is no increase in the incidence of second malignancies; however, longer follow-up will be required to fully ascertain the risks associated with the procedure.

The risk of metastatic progression with direct ocular delivery of chemotherapy appears to be very low; however, up to 20 cases of patients treated with intra-arterial chemotherapy who subsequently developed metastases have been reported.

Intravitreal Chemotherapy

Studies suggest that direct intravitreal injection of melphalan or topotecan may be effective in controlling active vitreous seeds.; []; [] A retrospective study of 264 eyes (250 children) treated with intravitreal melphalan for vitreous seeds over a two-decade period reported a 68% complete remission rate. There was a low incidence of extraocular spread that occurred in children with high-risk features.[] Because of initial concerns about the potential for tumor dissemination, the use of intravitreal chemotherapy was limited. However, a review calculated that the proportion of patients with extraocular tumor spread, potentially as the result of intravitreal injection, is negligible.

A meta-analysis reported that significant side effects are uncommon.[] The current era of retinoblastoma management using intra-arterial chemotherapy plus intravitreal chemotherapy (as needed for vitreous seeding) has improved globe salvage in eyes with advanced retinoblastoma.[]

Subtenon Chemotherapy (Subconjunctival Chemotherapy)

Periocular delivery of carboplatin results in high intraocular concentrations of the agent, and this treatment is often used in ocular salvage approaches, particularly when there is a high vitreal tumor burden. Carboplatin is administered by the treating ophthalmologist into the subtenon space, and it is generally used in conjunction with systemic chemotherapy and local ophthalmic therapies for patients with vitreous disease. Responses have also been noted with subtenon topotecan.

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.

Radiation Therapy

  • EBRT: Retinoblastoma is a very radiosensitive malignancy. EBRT doses ranging from 35 Gy to 46 Gy usually result in long-term remissions. Because of the need to sedate young children and the intricacies of field planning, special expertise in pediatric radiation therapy is important. Radiation therapy is used in cases of progression after conservative approaches, in patients with extraocular extension, and as part of the management of patients with metastatic disease.

    Newer methods of delivering EBRT are being applied in an attempt to reduce adverse long-term effects. This includes intensity-modulated radiation therapy and proton-beam radiation therapy (charged-particle radiation therapy). 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 SNs was significantly different between the two groups (0% for proton radiation vs. 14% for photon radiation, = .015).

    EBRT in infants causes growth failure of the orbital bones and results in cosmetic deformity. EBRT also increases the risk of SNs in children with heritable retinoblastoma.

  • Brachytherapy (plaque radiation therapy): Indications for plaque radiation therapy include solitary tumors with a diameter ranging between 6 mm and 15 mm, tumor thickness of 10 mm or less, and tumor location of more than 3 mm from the optic disc or fovea. The most commonly used radioisotope is iodine I 125, although others such as iridium Ir 192 and ruthenium Ru 106 are also effective. In combination with appropriate use of chemotherapy and other forms of focal consolidation, brachytherapy can be very effective in the treatment of localized retinal tumors that are not amenable to other means of local therapy.

Special Considerations for the Treatment of Children with Cancer

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; this approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will provide optimal survival and quality of life:

  • An ophthalmologist with extensive experience in the treatment of children with retinoblastoma.
  • Primary care physician.
  • Pediatric surgical subspecialists.
  • Radiation oncologists.
  • Pediatric medical oncologists/hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.

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. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring 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.)

Treatment of Intraocular Retinoblastoma

Treatment Options for Unilateral Intraocular Retinoblastoma

Treatment options for unilateral intraocular 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 high-risk features include the following:

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

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

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.; []

Conservative ocular salvage approaches

Conservative ocular salvage approaches, such as systemic chemotherapy and local-control treatments, may be offered in an attempt to save the eye and preserve vision. Ocular salvage rates correlate with intraocular grouping. While the possibility of saving the eye without the use of external-beam radiation therapy (EBRT) exceeds 80% for children with early intraocular disease, the ocular outcomes for children with advanced intraocular disease are poor, with less than 40% ocular salvage rates, even after the use of EBRT.

Thus, 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, particularly for Group D eyes.; [] In the setting of a multidisciplinary state-of-the-art center, intra-arterial chemotherapy may result in ocular salvage rates of approximately 80% to 90% for patients with advanced intraocular unilateral retinoblastoma.; []; [] (Refer to the Ophthalmic Artery Infusion of Chemotherapy [Intra-arterial Chemotherapy] section of this summary for more information.)

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 receive. Asynchronous bilateral disease occurs most frequently in patients with affected parents and in children diagnosed during the first months of life.

Treatment Options for Bilateral Intraocular Retinoblastoma

Treatment options for bilateral intraocular retinoblastoma include the following:

The goal of therapy for bilateral retinoblastoma is ocular and vision preservation and the delay or avoidance of EBRT and enucleation. Intraocular tumor burden is usually asymmetric, and treatment is dictated by the most advanced eye. Systemic therapy is generally selected on the basis of the eye with more extensive disease. Treatment options described for unilateral disease may be applied to one or both affected eyes in patients with bilateral disease. 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 monitoring for response and aggressive local treatment is usually the treatment of choice. 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. The backbone of the chemoreduction has generally been carboplatin, etoposide, and vincristine. While the less toxic combination of vincristine and carboplatin can provide disease control for a significant proportion of patients, ocular salvage appears to be superior when etoposide is included in the regimen.[] Similar results were achieved in one single-institution study when topotecan was substituted for etoposide in a combination regimen.[] 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.; []

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

    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 have been explored. Using this intensive approach, eye survival may approach a rate of 70% at 60 months.[]

  • Group E: The treatment for Group E eyes is usually 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.[]

Delivery of chemotherapy via ophthalmic artery cannulation has also been shown to be feasible and effective as tandem administration and in the salvage setting in patients with newly diagnosed bilateral disease.[] 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.

Treatment Options for Cavitary Retinoblastoma

Treatment options for cavitary retinoblastoma include the following:

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.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of Extraocular Retinoblastoma

In high-income countries, few patients with retinoblastoma present with extraocular disease. Extraocular disease may be localized to the soft tissues surrounding the eye or to the optic nerve beyond the margin of resection. However, further extension may progress into the brain and meninges, with subsequent seeding of the spinal fluid and as distant metastatic disease involving the lungs, bones, and bone marrow.

Treatment Options for Extraocular Retinoblastoma

Orbital and locoregional retinoblastoma

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.

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 a 10 Gy boost to the chiasm (total of 46 Gy).

CNS disease

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.[]

Trilateral retinoblastoma

Treatment options for trilateral retinoblastoma include the following:

Trilateral retinoblastoma is usually associated with a pineal lesion or, less commonly, a suprasellar lesion. In patients with the heritable form of retinoblastoma, CNS disease is less likely the result of metastatic or regional spread than of a primary intracranial focus, such as a pineal tumor. The prognosis for patients with trilateral retinoblastoma is very poor; most patients die of disseminated neuraxis disease in less than 9 months. 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 radiation 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.

(Refer to the Trilateral retinoblastoma section in the Causes of Retinoblastoma-Related Mortality section of this summary for more information about trilateral retinoblastoma, including screening with neuroimaging.)

Extracranial metastatic retinoblastoma

Treatment options for extracranial metastatic retinoblastoma include the following:

Hematogenous metastases may develop in the bones, bone marrow and, less frequently, the liver. Although long-term survival has been reported with conventional chemotherapy, these reports should be considered anecdotal; metastatic retinoblastoma is not curable with conventional chemotherapy. In the last two decades, 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.; []

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of Progressive or Recurrent Retinoblastoma

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

Treatment Options for Progressive or Recurrent Intraocular Retinoblastoma

Treatment options for progressive or recurrent intraocular 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 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 radiation therapy, can be successful in eradicating tumor.

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.[] 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. intra-arterial chemotherapy has been used after primary intra-arterial chemotherapy. However, patients often require other treatment methods because of disease progression after second-line intra-arterial chemotherapy. Radiation therapy should be considered for patients who have not been previously irradiated. Finally, enucleation may be required in cases of progressive disease after all eye-salvaging treatments have failed.

Treatment Options for Progressive or Recurrent Extraocular Retinoblastoma

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

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 a cure, particularly for patients with extracranial recurrence (refer to the Treatment of Extraocular Retinoblastoma section of this summary for more information). For patients with disease recurrence after those intensive approaches, clinical trials may be considered.

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.[] After enucleation for recurrence, high-resolution magnetic resonance imaging with orbital coils can be helpful in distinguishing orbital recurrence from postsurgical enhancement.

Treatment Options Under Clinical Evaluation for Progressive or Recurrent Retinoblastoma

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

  • (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI–Children's Oncology Group Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

    Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the website for APEC1621 (NCT03155620).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Changes to This Summary (09/19/2017)

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.

Treatment Option Overview for Retinoblastoma

Revised text to state that studies suggest that direct intravitreal injection of melphalan or topotecan may be effective in controlling active vitreous seeds. Also revised text to state that because of initial concerns about the potential for tumor dissemination, the use of intravitreal chemotherapy was limited. However, a review calculated that the proportion of patients with extraocular tumor spread, potentially as the result of intravitreal injection, is negligible.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of retinoblastoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Retinoblastoma Treatment are:

  • Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
  • Karen J. Marcus, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
  • Thomas A. Olson, MD (AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus)
  • Carlos Rodriguez-Galindo, MD (St. Jude Children's Research Hospital)
  • Nita Louise Seibel, MD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to 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 . Available at: Accessed . [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 on the Managing Cancer Care page.

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