Unilateral Disease
        Standard treatment options
        Treatment options under clinical evaluation
Bilateral Disease
        Standard treatment options
Future Directions
        Treatment options under clinical evaluation
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ¹ for more information.)

Treatment of retinoblastoma should be planned after the extent of the tumor within and outside the eye is known. Treatment options consider both cure and preservation of sight.[1-4]

Treatment options for the involved eye include the following:

1. Enucleation, if the tumor is massive or if there is little expectation for useful vision.



2. External-beam radiation therapy (EBRT) with doses ranging from 35 Gy to 46 Gy. 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 used at many centers in an attempt to reduce adverse long-term effects. This includes intensity-modulated radiation therapy (IMRT), stereotactic radiation therapy, and proton-beam radiation therapy.[5-7] The Children's Oncology Group (COG) is conducting a clinical trial in which reduced-dose (26 Gy) IMRT is being used in combination with chemoreduction.



3. Cryotherapy, used in addition to radiation or in place of photocoagulation for lesions smaller than 4 disc diameters (DD) in the anterior portion of the retina.



4. Light coagulation (photocoagulation), occasionally used alone with small tumors. In patients with early-stage disease, light coagulation is usually used in addition to radiation therapy or when there is limited recurrence following radiation therapy. Photocoagulation is used for posteriorly located tumors that are smaller than 4 DD, distinct from the optic nerve head and macula, and without involvement of large nutrient vessels or choroid involvement. Thermotherapy delivered via infrared radiation is an alternative to laser photocoagulation.[8]



5. Brachytherapy with radioactive plaques for either focal unilateral presentations or recurrent disease following previous EBRT.[9-11]



6. Systemic chemotherapy: During the past 10 years, systemic chemotherapy to reduce tumor volume (chemoreduction) and to avoid the long-term effects of radiation therapy for patients with intraocular tumors has succeeded in rendering many eyes amenable to treatment with cryotherapy or photocoagulation.[1,2,12] Chemotherapy may also be continued or initiated with concurrent local control interventions.[13] Factors such as tumor location (macula), patient age (patient older than 2 months), and tumor size correlate with responsiveness to chemotherapy.[13,14] Multiagent chemotherapy is generally used although carboplatin as a single agent causes shrinkage of retinoblastoma tumors.[15,16][Level of evidence: 3iiiDiii] Most tumors treated with vincristine and carboplatin require additional local therapy;[1,2,12,17,18] the addition of etoposide to the chemotherapy regimen may improve outcome.[14,19] One study utilized carboplatin and etoposide with focal therapy, without vincristine and found acceptable vision salvage rates for Reese-Ellsworth (R-E) Groups I through IV and International Classification Groups A and B retinoblastoma.[20] The success rate of these trials varies from center to center, but overall, the rate is highest for tumors that are unilateral or unifocal and without vitreous seeding (see below). There are emerging data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma.[21] Local tumor recurrence is not uncommon in the first few years after treatment,[22] and can often be successfully treated with focal therapy.[11] Among patients with heritable disease, younger patients and those with a positive family history are more likely to form new tumors. Chemotherapy may treat small previously undetected lesions by slowing their growth and this may improve overall salvage with focal therapy.[23]



7. Subtenon (subconjunctival) chemotherapy: Carboplatin is administered by the treating ophthalmologist into the subconjunctival space. This modality is undergoing testing in phase I and II trials and is generally used in conjunction with systemic chemotherapy and local ophthalmic therapies for retinoblastoma with vitreous seeding. This approach offers some promise in this group of patients.[24,25]

Because unilateral disease is usually massive and there is often no expectation that useful vision can be preserved, surgery (enucleation) is usually undertaken and radiation therapy is not given to the tumor bed. Even this is being tested, however, as patients with unilateral disease have been treated with chemotherapy in an attempt to preserve vision in the affected eye.[2,26,27] One study revealed that children with retinoblastoma who present with obvious external findings of leukocoria, strabismus, or red eye detectable by their family or pediatrician most often require enucleation. Children who manifest no obvious external findings can often avoid enucleation.[28]

When there is potential for preservation of sight because the tumors are smaller, treatment with other modalities (radiation therapy, photocoagulation, cryotherapy, thermotherapy, chemoreduction, and brachytherapy) instead of surgery should be considered. In selected children with unilateral disease, chemoreduction reduced the need for enucleation or EBRT to 68% within 5 years of treatment. R-E Group correlated with successful chemoreduction: 11% of children classified as having R-E Group II or III disease, 60% of children having R-E Group IV disease, and 100% of children having R-E Group V disease required enucleation or EBRT within 5 years of treatment.[29]

Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, it is very important that children with unilateral retinoblastoma receive periodic examinations of the unaffected eye. Asynchronous bilateral disease occurs most frequently in families with affected parents.

Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These include anterior chamber seeding, choroidal involvement, tumor beyond the lamina cribrosa, intraocular hemorrhage, or scleral and extrascleral extension.[30] Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide, or vincristine, carboplatin, and etoposide, has been used in patients with certain high-risk features assessed by pathologic review after enucleation to prevent the development of metastatic disease.[31-33]

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 Web site ².

• The COG is currently conducting a study of unilateral retinoblastoma with high-risk features using a standard regimen of six cycles of carboplatin, etoposide and vincristine.

The management of bilateral disease depends on the extent of the disease in each eye. Systemic therapy should be chosen based on the eye with more extensive disease.

Usually the disease is more advanced in one eye, with less involvement in the other eye. The standard of care in the past has been to enucleate the more involved eye; however, if there is potential for vision in both eyes, bilateral irradiation or chemoreduction with close follow-up for response and focal treatment (e.g., cryotherapy or laser therapy) is indicated.

A number of large centers in Europe and North America have published trial results using systemic chemotherapy for patients whose intraocular tumors are not initially amenable to local management.[2,18,20,22,23,27,28,34-42] Examples of such tumors are those that are too large to be treated with either cryotherapy, laser photocoagulation, or plaque radiation therapy (brachytherapy). Another example is the newborn with a tumor over the optic nerve head. All these situations share the likelihood that local therapy would limit vision as to offer little improvement over enucleation. Most centers have limited this approach to patients with bilateral disease, reasoning that for patients with unilateral disease, the morbidity of enucleation is modest. When disease is massive and there is no expectation that useful vision can be preserved, surgery is usually undertaken and radiation therapy is not given.

In all cases, the goal of chemotherapy is the reduction (hence the term chemoreduction) of tumor volume, making possible the use of local therapy (cryotherapy, photocoagulation, thermotherapy, plaque radiation therapy).[2,30] All centers reporting to date have demonstrated the short-term goal is achievable, especially for tumors that are R-E group IV or lower, reporting responses in nearly 75% of eyes. Group V tumors, particularly those with vitreous seeding, have proven problematic. Subretinal seeds have a recurrence rate of 5% following chemotherapy.[20,23,43]

The backbone of the chemoreduction protocols has generally been carboplatin, etoposide, and vincristine (CEV). Studies from The Children’s Hospital of Philadelphia and Wills Eye Hospital reported complete success in the avoidance of enucleation or EBRT in R-E Group I, II, and III eyes when patients were treated for six cycles.[1,2,19] Other available data have been published in abstract form, and larger studies with more mature data are still required to make definitive conclusions. A similar study at Children’s Hospital of Los Angeles reported 13 Group B (R-E Groups I–IV) eyes treated with only three courses of this chemotherapy with 6 of 11 patients successfully treated. Three patients were salvaged with further chemotherapy only, for a total of 9 of 11 (82%) patients who did not require enucleation and/or EBRT.[36] However, local control was often transient in patients with vitreous seeding or very large tumors (R-E Group V), and fewer than half of patients were treated successfully without requiring EBRT and/or enucleation.[1,2] Several strategies have been used in an attempt to overcome this problem. Researchers reported the use of nine courses of CEV with the addition of high-dose cyclosporine A as a modulator of the p-glycoprotein for eight R-E Group V eyes with an 88% (7/8 eyes) success rate without the use of EBRT or enucleation.[37,38] However, researchers using the Gallie regimen in ten R-E Group V eyes, reported only a 20% (2/10 eyes) success rate.[39]

Using the International Classification system for intraocular retinoblastoma applied to these data retrospectively, approximately 30% of Group Cs' and 70% of Group Ds' eyes failed systemic chemotherapy alone and achieved responses in pilot studies. (Refer to the Future Directions ³ section of this summary for a more complete description of the International Classification system.)

This has led to newer adjuvant therapies, including subtenon (subconjunctival) carboplatin in pilot studies that also use higher doses of carboplatin or etoposide.[24,25]

Two studies using the International Classification have found somewhat discrepant results, perhaps in part due to differences in approaches to systemic chemotherapy and focal therapy. One study using carboplatin and etoposide, found that vision salvage rate without EBRT for eyes with Group A and B tumors was 77.3% but was only 26.9% for eyes with Group C and D tumors.[20][Level of evidence: 3iiDiv] In contrast, the other study using protocols containing carboplatin, etoposide, and vincristine, with some Group C and D patients treated with higher doses of carboplatin, found treatment success in 100% of Group A, 93% of Group B, 90% of Group C, and 47% of Group D eyes.[44]

The unresolved issues are long-term tumor control and the consequences of chemotherapy. Most of these patients are exposed to etoposide, which has been associated with secondary leukemia in patients without predisposition to cancer, but at modest rates when compared to the risk of EBRT in heritable retinoblastoma. In a retrospective database and literature review, ocular and pediatric oncologists at referral centers in Europe and the Americas and the Retinoblastoma databases at the National Institutes of Health and the Ophthalmic Oncology Service at Memorial Sloan-Kettering Cancer Center conducted a study of secondary acute myeloid leukemia among patients treated for retinoblastoma. Fifteen patients were identified, 12 patients (79%) had received chemotherapy with a topoisomerase II inhibitor, and eight (43%) had received chemotherapy with an epipodophyllotoxin. Ten children died of their leukemia. [45]

Whether patients with heritable retinoblastoma will have greater susceptibility to chemotherapy-induced second tumors is not known. Some patients will progress, and the risk of exposure both to chemotherapy and irradiation in this population has not been determined.

Studies are planned for a variety of patient groups. The International Classification system is being utilized for these trials. This classification schema is based on the extent and location of intraocular retinoblastoma and is being used in the upcoming series of protocols from the COG. The preliminary version of this system was verified to be reproducible with preliminary data from five centers that staged their patients on an Internet site in August 2000. Experience with a closely related grouping system has been published.[3] Data have been published using this system in a study of chemotherapy for intraocular retinoblastoma, where stage appeared to assist in prognosis for successful treatment without enucleation or EBRT.[44]

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site ².

• For patients Group B disease, COG is investigating the use of vincristine and carboplatin chemoreduction combined with local ophthalmic therapies, without the use of etoposide.



• For patients with Group C or D disease, COG is investigating use of higher doses of systemic carboplatin, combined with subconjunctival carboplatin and lower doses of EBRT, using intensity-modulated approaches.



• Also under investigation is the use of adenovirus-mediated gene therapy for treatment of vitreous tumor seeding.[46]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with intraocular retinoblastoma ⁴. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ².

References

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Glossary Terms

Consecutive case series (not population-based) with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with progression-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.