Intraocular Retinoblastoma Treatment

Unilateral Disease
        Standard treatment options
        Treatment options under clinical evaluation
Bilateral Disease
        Standard treatment options
Treatment Options Under Clinical Evaluation
Current Clinical Trials

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

Treatment options for the involved eye include the following:

1. Enucleation: Enucleation, if the tumor is massive or if there is little expectation for useful vision in the affected eye. Patients must be followed closely to monitor the remaining eye and assure there is no orbital recurrence of disease, particularly in the first 2 years after enucleation.[5][Level of evidence: 3iiA] Recurrence in the orbit is often associated with systemic disease (85%) and should be treated with aggressive therapy.

2. Radiation therapy:
   • 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, stereotactic radiation therapy, and proton-beam radiation therapy (charged-particle radiation therapy).[6-8] EBRT in infants causes growth failure of the orbital bones and results in cosmetic deformity. It also increases the risk of second cancers in children with hereditary retinoblastoma.

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

3. Cryotherapy: Cryotherapy, used as primary therapy or with chemotherapy for tumors smaller than 4 disc diameters (DD) in the anterior portion of the retina.

4. Laser therapy (Thermotherapy): Laser therapy may be used as primary therapy for small tumors or in combination with chemotherapy for larger tumors. Traditional photocoagulation, in which the laser was applied around the tumor, has given way to thermotherapy. Thermotherapy is delivered directly to the tumor surface via infrared wavelengths of light.[12]

5. Systemic chemotherapy: During the past 15 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 laser therapy.[1,2,13]; [14][Level of evidence: 3iiDiii] Chemotherapy may also be continued or initiated with concurrent local control interventions.[15] Factors such as tumor location (macula), patient age (patient older than 2 months), and tumor size correlate with responsiveness to chemotherapy.[15,16]

   Multiagent chemotherapy is generally used, although carboplatin as a single agent causes shrinkage of retinoblastoma tumors.[17]; [18][Level of evidence: 3iiiDiii] Most tumors treated with vincristine and carboplatin require additional local therapy;[1,2,13,19,20] the addition of etoposide to the chemotherapy regimen may improve outcome.[16,21] 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.[22] The success rate of these trials varies from center to center, but overall, the rate is highest for discrete tumors without vitreous seeding (see below). Local tumor recurrence is not uncommon in the first few years after treatment,[23] and can often be successfully treated with focal therapy.[11] Among patients with hereditary 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.[24]

   There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma.[25]

6. 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.[26,27] Periocular topotecan administered in fibrin sealant has shown activity in patients with recurrent intraocular retinoblastoma.[28] This approach offers some promise in this group of patients.

7. Ophthalmic artery infusion of chemotherapy: Direct delivery of chemotherapy into the eye globe via cannulation of the ophthalmic artery is a feasible and effective method for ocular salvage. Melphalan was the chemotherapeutic agent used in the first studies, although other agents such as topotecan and carboplatin are also being tested. Ocular salvage rates are greater than 70% when used as primary treatment, although success rates are inferior when used after failure of systemic chemotherapy or radiation.[29,30] This modality continues to undergo study at very specialized retinoblastoma treatment centers.[29,31]

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. However, patients with unilateral disease have been treated with chemotherapy in an attempt to preserve vision in the affected eye.[2,32,33] 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.[34]

When there is potential for preservation of sight because the tumors are smaller, treatment with other modalities (radiation therapy, laser therapy [thermotherapy], cryotherapy, 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.[35] Pilot studies have evaluated the delivery of chemotherapy via ophthalmic artery cannulation as initial treatment of advanced unilateral and bilateral intraocular retinoblastoma.[29,31][Level of evidence: 3iiiDii]; [30][Level of evidence: 3iiiDiv]

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 patients 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, or scleral and extrascleral extension.[36-38] 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.[39-42]; [43][Level of evidence: 2A]

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 ¹.

• The Children's Oncology Group (COG) is 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. Treatment modality options described above for unilateral disease may be applied to one or both affected eyes in patients with bilateral disease.

Usually the disease is more advanced in one eye, with less involvement in the other eye. In the past, the standard of care has been to enucleate the more involved eye. 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. However, if there is potential for vision in both eyes, primary chemoreduction with close follow-up for response and focal treatment (e.g., cryotherapy or laser therapy) may be indicated. EBRT is now reserved for patients whose eyes do not respond adequately to primary systemic chemotherapy and focal consolidation.

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.[2,20,23,24,33,34,44-52]; [22][Level of evidence: 3iiDiv] Examples of such tumors are those that are too large to be treated with either cryotherapy, laser therapy, or plaque brachytherapy, or those located adjacent to visually sensitive areas such as the optic nerve and macula. Chemotherapy may shrink the tumors (chemoreduction) allowing greater efficacy of subsequent focal therapy.[2,36] Most centers have limited this approach to patients with bilateral disease, reasoning that for patients with unilateral disease, the morbidity of enucleation is modest. Also, most centers use one of two staging systems. Treatment strategies often differ in terms of chemotherapy regimens and local control measures.

Centers using the R-E classification have demonstrated the goal to save eyes may be achievable for tumors that are R-E Group IV or lower. The backbone of the chemoreduction protocols has generally been carboplatin, etoposide, and vincristine (CEV). Studies from The Children's Hospital of Philadelphia and Wills Eye Hospital reported that enucleation or EBRT may be avoided in R-E Group I, II, and III eyes when patients were treated for six cycles.[1,2,21] Other available data have been published in abstract form, and larger studies with more mature data are still required to make definitive conclusions. Group V tumors, particularly those with vitreous seeding, have proven problematic. Subretinal microscopic tumor has a recurrence rate of 5% following chemotherapy.[24,53]; [22][Level of evidence: 3iiDiv] 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]

Other researchers reported the use of nine courses of CEV with the addition of high-dose cyclosporine A (a modulator of the p-glycoprotein) for eight R-E Group V eyes with an 88% (7 out of 8 eyes) success rate without the use of EBRT or enucleation.[47,48] However, conflicting results were seen in another study using the cyclosporine regimen in ten R-E Group V eyes, which reported only a 20% (2 out of 10 eyes) success rate.[49]

Delivery of chemotherapy via ophthalmic artery cannulation also has been shown to be feasible and effective in patients with bilateral disease.[29,31][Level of evidence: 3iiDii]

The International Classification system for staging intraocular retinoblastoma has also been used in combination with local control. (Refer to the Treatment Options Under Clinical Evaluation ² section of this summary for a more complete description of the International Classification system.) The addition of carboplatin and etoposide (CE) [22,54] or CEV [55,56] have been used in combination with local control. All of these studies are single institution studies that report some salvage of Group C and Group D eyes.[22,56]; [54][Level of evidence: 3iiDiv] However, in another study with carboplatin, etoposide, and local ophthalmic treatment, Group D eyes were at high risk for enucleation.[54]; [55][Level of evidence: 3iiDiii] This has led to newer adjuvant therapies, including subtenon (subconjunctival) carboplatin in pilot studies that also use higher doses of carboplatin or etoposide.[26,27] This therapy has also been studied via the periocular route in a phase I study.[57]

The question of whether eyes classified as Group E can be salvaged is under study. A pilot study evaluated the delivery of chemotherapy via ophthalmic artery cannulation as initial treatment of advanced unilateral and bilateral intraocular retinoblastoma.[31] Patients with Group V disease (usually enucleated) without high-risk features such as metastatic disease or anterior chamber disease were enrolled on the study. The ophthalmic artery was safely cannulated and 27 of 28 eyes avoided enucleation.

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 hereditary retinoblastoma. In a retrospective database and literature review, cases of secondary acute myeloid leukemia were identified among children who received epipodophyllotoxins. The actuarial risk for leukemia is not known and it is unclear whether the risk for children with retinoblastoma receiving topoisomerase II inhibitors exceeds the risk that exists for other children.[58]

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 ongoing 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.[56]

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 ¹.

• The use of adenovirus-mediated gene therapy for treatment of vitreous tumor seeding is under investigation.[59]

• Delivery of chemotherapy via ophthalmic artery cannulation is being evaluated as an initial treatment for advanced unilateral and bilateral disease.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with intraocular retinoblastoma ³. 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 ¹.

References

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