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Retinoblastoma Treatment (PDQ®)

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Intraocular Retinoblastoma Treatment

Unilateral Disease
        Standard treatment options
Bilateral Disease
        Standard treatment options
Cavitary Retinoblastoma
Treatment Options Under Clinical Evaluation
        Current Clinical Trials

Treatment of retinoblastoma is individualized and considers the age of the patient, laterality, potential for vision, and intraocular tumor burden. When selecting a treatment option, cure of the disease, preservation of sight, and prevention of late effects should be considered.[1]

Different combinations of the following approaches may be applied to the individual patient depending on whether the patient has unilateral or bilateral disease.

Treatment options for the involved eye include the following:

  1. Enucleation: If the tumor is massive and there is little expectation for useful vision in the affected eye, up-front enucleation may be indicated, depending on laterality. Patients must be monitored closely for orbital recurrence of disease, particularly in the first 2 years after enucleation.[2][Level of evidence: 3iiA] Recurrence in the orbit is often associated with systemic disease (85%) and warrants treatment with aggressive therapy.

  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 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).[3-5] 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 treatments: 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 (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.[9,10]

  4. Systemic chemotherapy: Systemic chemotherapy plays a role both in the adjuvant setting for patients with high-risk pathology, and in the eye-salvage regimens, where it is used in conjunction with aggressive focal treatments. 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.[1,11]; [12][Level of evidence: 3iiDiii] 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 standard regimens incorporate vincristine, carboplatin, and etoposide, although a two-drug regimen without etoposide may also be effective for early intraocular stages.[1,11,14,17-19] The success rate of these trials varies from center to center, but overall, the rate is highest for discrete tumors without vitreous seeding. Local tumor recurrence is not uncommon in the first few years after treatment [20] and can often be successfully treated with focal 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 focal therapy.[21]

    There are data suggesting that the use of systemic chemotherapy may decrease the risk of development of trilateral retinoblastoma.[22]

  5. Ophthalmic artery infusion of 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.[23] Other agents such as topotecan and carboplatin are also being tested, given as single agents or in combination.[24] Ocular salvage rates are higher than 70% when ophthalmic artery infusion of chemotherapy is used as primary treatment, although success rates are inferior when this approach is used after failure of systemic chemotherapy or radiation.[23,25-27] This modality continues to undergo study at very specialized retinoblastoma treatment centers, but preliminary data appear to indicate that this treatment approach results in satisfactory ocular salvage rates as first-line therapy in patients with intraocular unilateral retinoblastoma and as a salvage treatment in patients who have failed other conservative approaches.[23,26-32]; [24,33][Level of evidence: 3iiDiii]; [34,35][Level of evidence: 3iiDiv]

    Small body and ocular size may pose technical limitations to its use in very young patients. Intravenous chemotherapy has been used in neonates and young infants to postpone intra-arterial chemotherapy. One or several cycles of single-agent carboplatin have been used to bridge the time until the child is aged 3 months and weighs 6 kg.[36][Level of evidence: 3iiiDi]

    In a recent report of 81 patients with heritable retinoblastoma, intra-arterial chemotherapy was able to eliminate ophthalmoscopically undetectable tumors present at diagnosis in the majority of patients.[37][Level of evidence: 3iiDi]

    This treatment is not without complications in some cases.[23,30,38,39] Retinal and choroidal vasculopathy may occur in 10% to 20% of patients.[32,40]

  6. Intravitreal chemotherapy: Pilot studies suggest that direct intravitreal injection of melphalan may be effective in controlling active vitreous seeds.[33][Level of evidence: 3iiDi]; [41][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 due to intravitreal injection was 0.007 (95% CI, 0.0008–0.0236).[42]

  7. Subtenon (subconjunctival) chemotherapy: Periocular delivery of carboplatin results in high intraocular concentrations of the agent, and this approach is often used in ocular salvage approaches, particularly when there is a high intravitreous 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 advent of intra-arterial and intravitreal delivery of chemotherapy, periocular administration is now seldomly used.

Unilateral Disease

Standard treatment options

Because unilateral disease is usually massive and there is often no expectation that useful vision can be preserved, up-front surgery (enucleation) is usually recommended. Careful examination of the enucleated specimen by an experienced pathologist is necessary to determine whether high-risk features for metastatic disease are present. These features include anterior chamber seeding, choroidal involvement, tumor beyond the lamina cribrosa, or scleral and extrascleral extension.[19,46-48] Systemic adjuvant therapy with vincristine, doxorubicin, and cyclophosphamide or with 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,[19,49-52]; [53][Level of evidence: 2A] with the suggestion of success compared with historical controls.[54][Level of evidence: 3iiDiii]

Patients with unilateral disease may also be offered chemotherapy and aggressive focal treatments in an attempt to save the eye and preserve vision.[1] Ocular salvage rates correlate with intraocular stage. In selected children with unilateral disease, Reese-Ellsworth (R-E) Group correlated with successful systemic 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.[55] Caution must be exerted with extended systemic chemotherapy and delayed enucleation when tumor control does not appear to be possible. 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.[56]

The delivery of chemotherapy via ophthalmic artery cannulation as initial treatment for advanced unilateral retinoblastoma appears to be more effective than systemic chemoreduction. In the setting of a multidisciplinary, state-of-the-art center, intra-arterial chemotherapy may result in ocular salvage rates in excess of 80% for patients with advanced intraocular unilateral retinoblastoma.[27]; [23,28][Level of evidence: 3iiiDii]; [25][Level of evidence: 3iiiDiv]

Because a proportion of children who present with unilateral retinoblastoma will eventually develop disease in the opposite eye, these children are candidates for genetic counseling and testing and periodic examinations of the unaffected eye, regardless of the treatment they received. Asynchronous bilateral disease occurs most frequently in patients with affected parents and in children diagnosed during the first months of life. Pre-enucleation magnetic resonance imaging has low sensitivity and specificity for the detection of high-risk pathology.[57] As discussed, genetic counseling and testing at the time of diagnosis is the key to defining risk and planning follow-up.

Bilateral Disease

The management of bilateral disease depends on the extent of the disease in each eye. Systemic therapy is generally chosen based on the eye with more extensive disease. Treatment modality options described for unilateral disease may be applied to one or both affected eyes in patients with bilateral disease. Chemoreduction (systemic or intra-arterial) coupled with aggressive focal treatments and very close monitoring is usually the treatment of choice, with the goal of ocular and vision preservation and the delay or avoidance of EBRT and enucleation.

Standard treatment options

Intraocular tumor burden is usually asymmetric. Treatment is dictated by the most advanced eye. While up-front enucleation of an advanced eye and risk-adapted adjuvant chemotherapy may be required, a more conservative approach using primary chemoreduction with close follow-up for response and 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 or intra-arterial chemotherapy and focal consolidation.

A number of large centers in Europe and North America have published trial results that used systemic chemotherapy in conjunction with aggressive focal consolidation for patients with bilateral disease.[1,18,20,21,58-63] Chemotherapy may shrink the tumors (chemoreduction), allowing greater efficacy of subsequent focal therapy.[1] Treatment strategies often differ in terms of chemotherapy regimens and local control measures.

Centers using the R-E Classification for Intraocular Tumors have demonstrated that 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); using this regimen in combination with aggressive focal treatments, enucleation or EBRT may be avoided in R-E Groups I, II, and III eyes.[1,11] Tumors associated with massive vitreous or subretinal seeds have proven problematic.[64] Local control is often transient in patients with vitreous seeding or very large tumors (R-E Group V), and more than one-half of patients may eventually need EBRT and/or enucleation.[1,11] In one study, the addition of high-dose cyclosporine A (a modulator of p-glycoprotein) to the CEV regimen resulted in improved ocular salvage rates.[60]

The International Classification of Retinoblastoma grouping system may be better than the R-E Classification for Intraocular Tumors at predicting success of treatment with systemic chemotherapy in combination with local control. The combinations of carboplatin and etoposide (CE) [65] or CEV [66,67] in conjunction with local control have resulted in ocular salvage rates above 90% for early intraocular disease (Groups A and B eyes), 70% to 90% for Group C eyes, and 40% to 50% for Group D eyes.[65,67,68]; [65][Level of evidence: 3iiDiv] However, for patients with advanced intraocular disease (typically Group D eyes), EBRT is frequently required for ocular salvage.[65]; [66][Level of evidence: 3iiDiii]

For patients with large intraocular tumor burden or with subretinal or vitreous seeds (Groups C and D eyes), the use of periocular chemotherapy, usually in combination with systemic therapy, has been explored.[43,69] In one study, systemic chemoreduction, subtenon carboplatin, and local consolidation resulted in ocular salvage of 47% of Group D eyes. An additional 35% of eyes were salvaged with intensity-modulated radiation therapy.[70][Level of evidence: 2Div] The impact of this approach on ocular salvage is not well defined.

The treatment recommendation for Group E eyes is 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 (P < .001).[56][Level of evidence: 3iiiB]

Delivery of chemotherapy via ophthalmic artery cannulation has also been shown to be feasible and effective in patients with bilateral disease, in both the up-front and salvage settings.[23,28,35][Level of evidence: 3iiDii] However, this treatment should only be performed in an experienced center with a state-of-the-art treatment infrastructure and a dedicated multidisciplinary team.

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 with the risks associated with EBRT in heritable retinoblastoma.

Cavitary Retinoblastoma

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 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.[71]

Treatment Options Under Clinical Evaluation

Studies are planned for a variety of patient groups. The International Classification of Retinoblastoma is being utilized for these trials.

Information about ongoing clinical trials is available from the NCI Web site.

Current Clinical Trials

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

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

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  2. Kim JW, Kathpalia V, Dunkel IJ, et al.: Orbital recurrence of retinoblastoma following enucleation. Br J Ophthalmol 93 (4): 463-7, 2009.  [PUBMED Abstract]

  3. Krasin MJ, Crawford BT, Zhu Y, et al.: Intensity-modulated radiation therapy for children with intraocular retinoblastoma: potential sparing of the bony orbit. Clin Oncol (R Coll Radiol) 16 (3): 215-22, 2004.  [PUBMED Abstract]

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  7. Merchant TE, Gould CJ, Wilson MW, et al.: Episcleral plaque brachytherapy for retinoblastoma. Pediatr Blood Cancer 43 (2): 134-9, 2004.  [PUBMED Abstract]

  8. Shields CL, Mashayekhi A, Sun H, et al.: Iodine 125 plaque radiotherapy as salvage treatment for retinoblastoma recurrence after chemoreduction in 84 tumors. Ophthalmology 113 (11): 2087-92, 2006.  [PUBMED Abstract]

  9. Shields CL, Santos MC, Diniz W, et al.: Thermotherapy for retinoblastoma. Arch Ophthalmol 117 (7): 885-93, 1999.  [PUBMED Abstract]

  10. Francis JH, Abramson DH, Brodie SE, et al.: Indocyanine green enhanced transpupillary thermotherapy in combination with ophthalmic artery chemosurgery for retinoblastoma. Br J Ophthalmol 97 (2): 164-8, 2013.  [PUBMED Abstract]

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  12. Shields CL, Palamar M, Sharma P, et al.: Retinoblastoma regression patterns following chemoreduction and adjuvant therapy in 557 tumors. Arch Ophthalmol 127 (3): 282-90, 2009.  [PUBMED Abstract]

  13. Lumbroso L, Doz F, Urbieta M, et al.: Chemothermotherapy in the management of retinoblastoma. Ophthalmology 109 (6): 1130-6, 2002.  [PUBMED Abstract]

  14. Gombos DS, Kelly A, Coen PG, et al.: Retinoblastoma treated with primary chemotherapy alone: the significance of tumour size, location, and age. Br J Ophthalmol 86 (1): 80-3, 2002.  [PUBMED Abstract]

  15. Abramson DH, Lawrence SD, Beaverson KL, et al.: Systemic carboplatin for retinoblastoma: change in tumour size over time. Br J Ophthalmol 89 (12): 1616-9, 2005.  [PUBMED Abstract]

  16. Dunkel IJ, Lee TC, Shi W, et al.: A phase II trial of carboplatin for intraocular retinoblastoma. Pediatr Blood Cancer 49 (5): 643-8, 2007.  [PUBMED Abstract]

  17. Wilson MW, Rodriguez-Galindo C, Haik BG, et al.: Multiagent chemotherapy as neoadjuvant treatment for multifocal intraocular retinoblastoma. Ophthalmology 108 (11): 2106-14; discussion 2114-5, 2001.  [PUBMED Abstract]

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  19. Aerts I, Sastre-Garau X, Savignoni A, et al.: Results of a multicenter prospective study on the postoperative treatment of unilateral retinoblastoma after primary enucleation. J Clin Oncol 31 (11): 1458-63, 2013.  [PUBMED Abstract]

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  21. Wilson MW, Haik BG, Billups CA, et al.: Incidence of new tumor formation in patients with hereditary retinoblastoma treated with primary systemic chemotherapy: is there a preventive effect? Ophthalmology 114 (11): 2077-82, 2007.  [PUBMED Abstract]

  22. Shields CL, Meadows AT, Shields JA, et al.: Chemoreduction for retinoblastoma may prevent intracranial neuroblastic malignancy (trilateral retinoblastoma). Arch Ophthalmol 119 (9): 1269-72, 2001.  [PUBMED Abstract]

  23. Gobin YP, Dunkel IJ, Marr BP, et al.: Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience. Arch Ophthalmol 129 (6): 732-7, 2011.  [PUBMED Abstract]

  24. Marr BP, Brodie SE, Dunkel IJ, et al.: Three-drug intra-arterial chemotherapy using simultaneous carboplatin, topotecan and melphalan for intraocular retinoblastoma: preliminary results. Br J Ophthalmol 96 (10): 1300-3, 2012.  [PUBMED Abstract]

  25. Peterson EC, Elhammady MS, Quintero-Wolfe S, et al.: Selective ophthalmic artery infusion of chemotherapy for advanced intraocular retinoblastoma: initial experience with 17 tumors. J Neurosurg 114 (6): 1603-8, 2011.  [PUBMED Abstract]

  26. Abramson DH, Marr BP, Dunkel IJ, et al.: Intra-arterial chemotherapy for retinoblastoma in eyes with vitreous and/or subretinal seeding: 2-year results. Br J Ophthalmol 96 (4): 499-502, 2012.  [PUBMED Abstract]

  27. Abramson DH, Marr BP, Brodie SE, et al.: Ophthalmic artery chemosurgery for less advanced intraocular retinoblastoma: five year review. PLoS One 7 (4): e34120, 2012.  [PUBMED Abstract]

  28. Abramson DH, Dunkel IJ, Brodie SE, et al.: Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology 117 (8): 1623-9, 2010.  [PUBMED Abstract]

  29. Shields CL, Bianciotto CG, Jabbour P, et al.: Intra-arterial chemotherapy for retinoblastoma: report No. 1, control of retinal tumors, subretinal seeds, and vitreous seeds. Arch Ophthalmol 129 (11): 1399-406, 2011.  [PUBMED Abstract]

  30. Shields CL, Bianciotto CG, Jabbour P, et al.: Intra-arterial chemotherapy for retinoblastoma: report No. 2, treatment complications. Arch Ophthalmol 129 (11): 1407-15, 2011.  [PUBMED Abstract]

  31. Shields CL, Kaliki S, Shah SU, et al.: Minimal exposure (one or two cycles) of intra-arterial chemotherapy in the management of retinoblastoma. Ophthalmology 119 (1): 188-92, 2012.  [PUBMED Abstract]

  32. Bianciotto C, Shields CL, Iturralde JC, et al.: Fluorescein angiographic findings after intra-arterial chemotherapy for retinoblastoma. Ophthalmology 119 (4): 843-9, 2012.  [PUBMED Abstract]

  33. Ghassemi F, Shields CL: Intravitreal melphalan for refractory or recurrent vitreous seeding from retinoblastoma. Arch Ophthalmol 130 (10): 1268-71, 2012.  [PUBMED Abstract]

  34. Schaiquevich P, Ceciliano A, Millan N, et al.: Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma. Pediatr Blood Cancer 60 (5): 766-70, 2013.  [PUBMED Abstract]

  35. Palioura S, Gobin YP, Brodie SE, et al.: Ophthalmic artery chemosurgery for the management of retinoblastoma in eyes with extensive (>50%) retinal detachment. Pediatr Blood Cancer 59 (5): 859-64, 2012.  [PUBMED Abstract]

  36. Gobin YP, Dunkel IJ, Marr BP, et al.: Combined, sequential intravenous and intra-arterial chemotherapy (bridge chemotherapy) for young infants with retinoblastoma. PLoS One 7 (9): e44322, 2012.  [PUBMED Abstract]

  37. Abramson DH, Francis JH, Dunkel IJ, et al.: Ophthalmic artery chemosurgery for retinoblastoma prevents new intraocular tumors. Ophthalmology 120 (3): 560-5, 2013.  [PUBMED Abstract]

  38. Suzuki S, Yamane T, Mohri M, et al.: Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology 118 (10): 2081-7, 2011.  [PUBMED Abstract]

  39. Munier FL, Beck-Popovic M, Balmer A, et al.: Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma. Retina 31 (3): 566-73, 2011.  [PUBMED Abstract]

  40. Muen WJ, Kingston JE, Robertson F, et al.: Efficacy and complications of super-selective intra-ophthalmic artery melphalan for the treatment of refractory retinoblastoma. Ophthalmology 119 (3): 611-6, 2012.  [PUBMED Abstract]

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  42. Smith SJ, Smith BD: Evaluating the risk of extraocular tumour spread following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol 97 (10): 1231-6, 2013.  [PUBMED Abstract]

  43. Abramson DH, Frank CM, Dunkel IJ: A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 106 (10): 1947-50, 1999.  [PUBMED Abstract]

  44. Marr BP, Dunkel IJ, Linker A, et al.: Periocular carboplatin for retinoblastoma: long-term report (12 years) on efficacy and toxicity. Br J Ophthalmol 96 (6): 881-3, 2012.  [PUBMED Abstract]

  45. Mallipatna AC, Dimaras H, Chan HS, et al.: Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol 129 (6): 738-45, 2011.  [PUBMED Abstract]

  46. Chantada GL, Guitter MR, Fandiño AC, et al.: Treatment results in patients with retinoblastoma and invasion to the cut end of the optic nerve. Pediatr Blood Cancer 52 (2): 218-22, 2009.  [PUBMED Abstract]

  47. Eagle RC Jr: High-risk features and tumor differentiation in retinoblastoma: a retrospective histopathologic study. Arch Pathol Lab Med 133 (8): 1203-9, 2009.  [PUBMED Abstract]

  48. Kaliki S, Shields CL, Rojanaporn D, et al.: High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology 120 (5): 997-1003, 2013.  [PUBMED Abstract]

  49. Uusitalo MS, Van Quill KR, Scott IU, et al.: Evaluation of chemoprophylaxis in patients with unilateral retinoblastoma with high-risk features on histopathologic examination. Arch Ophthalmol 119 (1): 41-8, 2001.  [PUBMED Abstract]

  50. Honavar SG, Singh AD, Shields CL, et al.: Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol 120 (7): 923-31, 2002.  [PUBMED Abstract]

  51. Chantada GL, Dunkel IJ, de Dávila MT, et al.: Retinoblastoma patients with high risk ocular pathological features: who needs adjuvant therapy? Br J Ophthalmol 88 (8): 1069-73, 2004.  [PUBMED Abstract]

  52. Cuenca A, Giron F, Castro D, et al.: Microscopic scleral invasion in retinoblastoma: clinicopathological features and outcome. Arch Ophthalmol 127 (8): 1006-10, 2009.  [PUBMED Abstract]

  53. Chantada GL, Fandiño AC, Guitter MR, et al.: Results of a prospective study for the treatment of unilateral retinoblastoma. Pediatr Blood Cancer 55 (1): 60-6, 2010.  [PUBMED Abstract]

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  55. Shields CL, Honavar SG, Meadows AT, et al.: Chemoreduction for unilateral retinoblastoma. Arch Ophthalmol 120 (12): 1653-8, 2002.  [PUBMED Abstract]

  56. Zhao J, Dimaras H, Massey C, et al.: Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis. J Clin Oncol 29 (7): 845-51, 2011.  [PUBMED Abstract]

  57. Chawla B, Sharma S, Sen S, et al.: Correlation between clinical features, magnetic resonance imaging, and histopathologic findings in retinoblastoma: a prospective study. Ophthalmology 119 (4): 850-6, 2012.  [PUBMED Abstract]

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  59. Murphree AL, Villablanca JG, Deegan WF 3rd, et al.: Chemotherapy plus local treatment in the management of intraocular retinoblastoma. Arch Ophthalmol 114 (11): 1348-56, 1996.  [PUBMED Abstract]

  60. Gallie BL, Budning A, DeBoer G, et al.: Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 114 (11): 1321-8, 1996.  [PUBMED Abstract]

  61. Rodriguez-Galindo C, Chantada GL, Haik BG, et al.: Treatment of retinoblastoma: current status and future perspectives. Curr Treat Options Neurol 9 (4): 294-307, 2007.  [PUBMED Abstract]

  62. Shields CL, Mashayekhi A, Cater J, et al.: Macular retinoblastoma managed with chemoreduction: analysis of tumor control with or without adjuvant thermotherapy in 68 tumors. Arch Ophthalmol 123 (6): 765-73, 2005.  [PUBMED Abstract]

  63. Qaddoumi I, Billups CA, Tagen M, et al.: Topotecan and vincristine combination is effective against advanced bilateral intraocular retinoblastoma and has manageable toxicity. Cancer 118 (22): 5663-70, 2012.  [PUBMED Abstract]

  64. Shields CL, Honavar SG, Shields JA, et al.: Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol 120 (4): 460-4, 2002.  [PUBMED Abstract]

  65. Lumbroso-Le Rouic L, Aerts I, Lévy-Gabriel C, et al.: Conservative treatments of intraocular retinoblastoma. Ophthalmology 115 (8): 1405-10, 1410.e1-2, 2008.  [PUBMED Abstract]

  66. Cohen VM, Kingston J, Hungerford JL: The success of primary chemotherapy for group D heritable retinoblastoma. Br J Ophthalmol 93 (7): 887-90, 2009.  [PUBMED Abstract]

  67. Shields CL, Mashayekhi A, Au AK, et al.: The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113 (12): 2276-80, 2006.  [PUBMED Abstract]

  68. Zage PE, Reitman AJ, Seshadri R, et al.: Outcomes of a two-drug chemotherapy regimen for intraocular retinoblastoma. Pediatr Blood Cancer 50 (3): 567-72, 2008.  [PUBMED Abstract]

  69. Chantada GL, Fandino AC, Carcaboso AM, et al.: A phase I study of periocular topotecan in children with intraocular retinoblastoma. Invest Ophthalmol Vis Sci 50 (4): 1492-6, 2009.  [PUBMED Abstract]

  70. Berry JL, Jubran R, Kim JW, et al.: Long-term outcomes of Group D eyes in bilateral retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage. Pediatr Blood Cancer 60 (4): 688-93, 2013.  [PUBMED Abstract]

  71. Rojanaporn D, Kaliki S, Bianciotto CG, et al.: Intravenous chemoreduction or intra-arterial chemotherapy for cavitary retinoblastoma: long-term results. Arch Ophthalmol 130 (5): 585-90, 2012.  [PUBMED Abstract]