Combination Chemotherapy in Treating Patients with Newly Diagnosed, Previously Untreated Intraocular Retinoblastoma

PRIMARY OBJECTIVE:

I. To evaluate the response (complete response [CR] + partial response [PR]) rate of bilateral disease participants who have at least one eye with advanced intraocular retinoblastoma and subretinal seeding (Stratum B) to two upfront courses of therapy consisting of subconjunctival carboplatin and systemic topotecan (topotecan hydrochloride).

SECONDARY OBJECTIVES:

I. To evaluate the ocular survival of eyes and event-free survival of participants by strata.

II. To prospectively analyze intraocular disease tissue for participants with at least one eye undergoing enucleation in order to identify the mechanism of retinoblastoma (RB)1 bi-allelic inactivation. Participants may undergo upfront enucleation (due to advanced disease at diagnosis) or may receive enucleation due to progressive disease during protocol therapy.

EXPLORATORY BIOLOGIC OBJECTIVES:

I. To identify genetic lesions in intraocular disease tissue by using single nucleotide polymorphism (SNP) arrays for disease tissue and blood samples.

II. Evaluate the relationship between retinoblastoma genetic and epigenetic alterations, histopathological classification and clinical disease behavior.

III. Construct tissue microarrays that will serve as a high-throughput tool for future analysis of molecular genetic alterations in retinoblastoma.

IV. Analysis of the expression of miR-191 in intraocular disease tissue and genotyping of MDM4 SNP 34091 in germline and intraocular disease tissue to identify and correlate micro ribonucleic acid (miR) expression, SNP and clinical features.

V. Analysis and characterization of the vitreous proteome from retinoblastoma patients undergoing enucleation.

EXPLORATORY THERAPEUTIC OBJECTIVES:

I. To describe the outcome of intraocular retinoblastoma with respect to the International Classification for Intraocular Retinoblastoma and the American Joint Committee on Cancer (AJCC).

II. To evaluate the ocular survival of eyes, event-free survival of participants and incidence of ototoxicity in participants less than 6 months old who have early stage intraocular retinoblastoma (Stratum A) and are treated with topotecan in place of platinum therapy for 3 of 6 cycles.

III. To evaluate tumor response (tumor regression and/or calcification by retinopathy [RET]-Cam imaging) to topotecan-containing therapy (stratum B) and focal treatments (stratum A, B or D).

IV. To assess the local control and pattern of failure in patients treated with external beam radiotherapy.

V. To assess the local control and pattern of failure in patient treated with brachytherapy.

VI. To observe and describe the toxicity, both acute and long term, associated with subconjunctival carboplatin therapy.

EXPLORATORY SUPPORTIVE CARE OBJECTIVES:

I. To describe the types of early intervention and low vision (LV) services received by children with RB.

II. To describe the visual, developmental, participation, sensory processing, language and quality of life characteristics of children referred for early intervention (EI) and/or LV services.

III. To describe parent perceived efficacy of low vision assistive devices among those who received assistive devices.

IV. To describe the results of wideband reflectance and tympanometry testing in participants receiving carboplatin therapy.

V. To describe the impact of carboplatin on changes in cochlear function that is detectable with measurement of otoacoustic emissions.

VI. To describe effective methods of monitoring patients treated with carboplatin for sub-clinical changes in cochlear function

EXPLORATORY PHARMOCOLOGY OBJECTIVE:

I. To assess the relationship of selected candidate genetic variants with ototoxicity in participants receiving carboplatin.

OUTLINE: Patients are assigned to 1 of 4 treatment arms.

STRATUM A (EARLY UNILATERAL OR BILATERAL RETINOBLASTOMA): Patients >= 6 months receive vincristine sulfate intravenously (IV) and carboplatin IV over 60 minutes on day 1. Treatment repeats every 3-4 weeks for 8 cycles. Patients < 6 months receive vincristine sulfate IV on day 1 and topotecan hydrochloride IV over 30 minutes on days 1-5 of cycles 1, 3, and 5 and vincristine sulfate IV and carboplatin IV over 60 minutes on day 1 of cycles 2, 4, and 6. Treatment repeats every 3-4 weeks for 6 cycles. Patients may also receive focal treatments comprising cryotherapy, laser photocoagulation, thermotherapy, and plaque radiotherapy any time after diagnosis at the discretion of the treating physician.

STRATUM B (ADVANCED BILATERAL OR ADVANCED UNILATERAL WITH FOVEAL SPARING RETINOBLASTOMA): Patients without extensive subretinal (SR) seeding receive vincristine sulfate IV on day 1 and topotecan hydrochloride IV over 30 minutes on days 1-5 of cycles 1-2. Patients with extensive SR seeding receive topotecan hydrochloride IV over 30 minutes on days 1-5 and carboplatin periocularly on days 1, 2, 3, 4, or 5 of cycles 1-2. Patients achieving at least partial response after 2 cycles then receive vincristine sulfate IV and carboplatin IV over 60 minutes on day 1 of cycles 3, 4, 6, 7, 9, and 10 and vincristine sulfate IV on day 1, topotecan hydrochloride IV over 30 minutes on days 1-5, and carboplatin periocularly over 30 minutes on day 1, 2, 3, 4, or 5 of cycles 5, 8, and/or 11. Treatment repeats every 3-4 weeks for 11 cycles . Patients achieving < partial response after 2 cycles receive vincristine sulfate IV, carboplatin IV over 60 minutes on day 1, etoposide IV on days 1-3, and carboplatin periocularly on day 1, 2, or 3. Treatment repeats every 3-4 weeks for 6 cycles.

STRATUM C (ADVANCED UNILATERAL RETINOBLASTOMA): Patients with low-risk disease do not receive any additional treatment, but will remain on study. Patients with intermediate-risk disease receive vincristine sulfate IV, cyclophosphamide IV, and doxorubicin hydrochloride IV on day 1. Treatment repeats every 3-4 weeks for 4 cycles. Patients with high-risk disease receive vincristine sulfate IV and carboplatin IV over 60 minutes on day 1, and etoposide IV on days 1-3 of cycles 1, 3, and 5, and vincristine sulfate IV, cyclophosphamide IV, and doxorubicin hydrochloride IV on day 1 of cycles 2, 4, and 6. Treatment repeats every 3-4 weeks for 6 cycles.

STRATUM D (BILATERAL RETINOBLASTOMA WITH UPFRONT ENUCLEATION): Patients with low-risk disease and stage I-III disease of the remaining eye receive treatment as in Stratum A. Patients with low-risk disease and stage IV-V disease of the remaining eye receive treatment as in Stratum B. Patients with intermediate- and high-risk disease receive vincristine sulfate IV and carboplatin IV over 60 minutes on day 1, etoposide IV on days 1-3, and carboplatin periocularly on day 1, 2, or 3. Treatment repeats every 3-4 weeks for 6 cycles. Patients may also receive focal treatments comprising cryotherapy, laser photocoagulation, thermotherapy (and thermo-chemotherapy), and episcleral plaque radiotherapy any time after diagnosis at the discretion of the treating physician. Patients may also undergo external beam radiation therapy (EBRT) to any eye in which the disease is considered to be not controllable with focal treatments alone and in patients with enucleated eyes at high-risk of orbital and/or central nervous system (CNS) disease.

After completion of study treatment, patients are followed up every 6 months for 2 years and then every 6-12 months for 3 years.