Inclusion Criteria:

- Newly diagnosed unilateral retinoblastoma

- Underwent enucleation as primary therapy within the past 5 weeks

- Must enroll and submit pathology slides within 21 days of enucleation

- Adjuvant chemotherapy must begin within 35 days after enucleation

- Disease with or without high-risk histopathologic features

- High-risk features are defined as any of the following:

- Posterior uveal invasion (includes choroidal invasion)

- Any degree of concomitant choroid and/or optic nerve involvement

- Tumor involving the optic nerve posterior to the lamina cribrosa as an
independent finding

- Scleral invasion

- Anterior chamber seeding

- Ciliary body infiltration

- Iris infiltration

- No evidence of extraocular retinoblastoma clinically, by CT scan, or by MRI of the
brain and orbits with and without gadolinium

- No tumor at the cut end of the optic nerve on any eye enucleated as evidenced by
histologic examination prior to study entry

- No systemic metastases as evidenced by bone marrow scan, bone scan, or any other
additional test at study entry

- Lansky performance status 50-100%

- Hemoglobin > 8 g/dL

- Absolute neutrophil count ≥ 1,000/mm³

- Platelet count ≥ 100,000/mm³

- Creatinine adjusted according to age as follows:

- No greater than 0.4 mg/dL (≤ 5 months)

- No greater than 0.5 mg/dL (6 months -11 months)

- No greater than 0.6 mg/dL (1 year-23 months)

- No greater than 0.8 mg/dL (2 years-5 years)

- No greater than 1.0 mg/dL (6 years-9 years)

- No greater than 1.2 mg/dL (10 years-12 years)

- No greater than 1.4 mg/dL (13 years and over [female])

- No greater than 1.5 mg/dL (13 years to 15 years [male])

- No greater than 1.7 mg/dL (16 years and over [male])

- Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

- Bilirubin ≤ 1.5 times upper limit of normal (ULN) for age

- AST or ALT < 2.5 times ULN for age

- No prior therapy other than enucleation

- No prior chemotherapy