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Retinoblastoma Treatment (PDQ®)

Treatment Option Overview for Retinoblastoma

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.[1] 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:

  • 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.

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:

  1. Enucleation: Upfront removal of the eye is indicated for large tumors filling the vitreous for which there is little or no likelihood of restoring vision, and 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.[2][Level of evidence: 3iiA] Enucleation is also used as a salvage treatment in cases of disease progression or recurrence.
  2. Radiation therapy:
    • External-beam 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. 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).[3-5] 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.

      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.

    • Brachytherapy: Brachytherapy with radioactive plaques is very effective in the treatment of localized retinal tumors that are not amenable to other means of local therapy.[6-8]
  3. Local treatment: For patients undergoing eye-salvage treatment, aggressive local therapy is required.
    • Cryotherapy: Cryotherapy is based on the application of a cryoprobe to the sclera in the immediate vicinity of the retinal tumor. It 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, has given way to thermotherapy (diode laser). Thermotherapy is delivered directly to the tumor surface via infrared wavelengths of light.[9,10]
  4. Systemic chemotherapy: Systemic chemotherapy plays a role in the following:
    • Adjuvant setting for patients with high-risk pathology.
    • Treatment of patients with extraocular and metastatic disease.
    • As chemoreductive treatment in conjunction with aggressive local treatment for patients undergoing ocular-salvage treatments.

    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.[11,12]; [13][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.[11,12,14-16] Chemotherapy may also be continued or initiated with concurrent local control treatments.[17] 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 [16] and can often be successfully treated with local therapy.[8] 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.[18]

    There are data suggesting that the use of systemic chemotherapy may decrease the risk of developing trilateral retinoblastoma.[19]

  5. 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 commonly used chemotherapeutic agent.[20] Other agents, such as topotecan and carboplatin, are also being tested and administered as single agents or in combination.[21,22]

    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.[20,23-29]; [21,30][Level of evidence: 3iiDiii]; [31,32][Level of evidence: 3iiDiv]

    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.[33][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.[34][Level of evidence: 3iiDi]

    This treatment is not without complications.[20,25,35-37] Retinal and choroidal vasculopathy may occur in 10% to 20% of patients.[28,38] 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.[39]

  6. Intravitreal chemotherapy: Intravitreal chemotherapy is considered investigational. Pilot studies suggest that direct intravitreal injection of melphalan may be effective in controlling active vitreous seeds.[30][Level of evidence: 3iiDi]; [40][Level of evidence: 3iiiDiii] While concerns of the potential for tumor dissemination have limited its use, a recent review calculated that the proportion of patients with extraocular tumor spread, potentially the result of intravitreal injection, is negligible.[41] A meta-analysis reported that significant side effects are uncommon.[42][Level of evidence: 3iiiDiv]
  7. Subtenon (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.[43,44] Responses have also been noted with subtenon topotecan.[45]

    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.[46] 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.[47] 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.[48]

The standard treatment options for intraocular, extraocular, and recurrent retinoblastoma are described in Table 8.

Table 8. Standard Treatment Options for Retinoblastoma
Stage/Category Standard Treatment Options
CNS = central nervous system; EBRT = external-beam radiation therapy.
Intraocular retinoblastoma:  
  Unilateral retinoblastoma Enucleation followed by chemotherapy
Conservative ocular salvage approaches:
—Chemoreduction with either systemic chemotherapy with subtenon chemotherapy or ophthalmic artery infusion chemotherapy
—Local treatments including cryotherapy, thermotherapy, and plaque radiation therapy
  Bilateral retinoblastoma Enucleation for large intraocular tumors, followed by risk-adapted chemotherapy when the eye and vision cannot be saved
Conservative ocular salvage approaches when the eye and vision can be saved:
—Chemoreduction with either systemic chemotherapy with subtenon chemotherapy or ophthalmic artery infusion chemotherapy
—Local treatments including cryotherapy, thermotherapy, and plaque radiation therapy
Extraocular retinoblastoma:  
  Orbital and locoregional retinoblastoma Chemotherapy
Radiation therapy
  CNS disease Systemic chemotherapy and CNS-directed therapy
Systemic chemotherapy followed by myeloablative chemotherapy and stem cell rescue
  Trilateral retinoblastoma Systemic chemotherapy followed by surgery and myeloablative chemotherapy with stem cell rescue
Systemic chemotherapy followed by surgery and radiation therapy
  Extracranial metastatic retinoblastoma Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue and radiation therapy
Progressive or recurrent intraocular retinoblastoma Enucleation
Radiation therapy (external-beam or plaque radiation therapy)
Local treatments (cryotherapy or thermotherapy)
Salvage chemotherapy (systemic or intra-arterial)
Progressive or recurrent extraocular retinoblastoma Systemic chemotherapy and radiation therapy for orbital disease (not a standard treatment)
Systemic chemotherapy followed by myeloablative chemotherapy with stem cell rescue, and radiation therapy for extraorbital disease (not a standard treatment)


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  • Updated: February 2, 2015