Combination Chemotherapy, Autologous Stem Cell Transplant, and/or Radiation Therapy in Treating Young Patients With Extraocular Retinoblastoma
Combination Chemotherapy, Autologous Stem Cell Transplant, and/or Radiation Therapy in Treating Young Patients With Extraocular Retinoblastoma
This phase III trial is studying the side effects and how well giving combination
 chemotherapy together with autologous stem cell transplant and/or radiation therapy works in
 treating young patients with extraocular retinoblastoma. Giving chemotherapy before an
 autologous stem cell transplant stops the growth of tumor cells by stopping them from
 dividing or killing them. After treatment, stem cells are collected from the patient?s blood
 and/or bone marrow and stored. More chemotherapy is given to prepare the bone marrow for the
 stem cell transplant. The stem cells are then returned to the patient to replace the
 blood-forming cells that were destroyed by the chemotherapy. Radiation therapy uses high
 energy x-rays to kill tumor cells. Giving radiation therapy after combination chemotherapy
 and/or autologous stem cell transplant may kill any remaining tumor cells.
OBJECTIVES:

 I. To estimate the proportion of 3 groups of patients with extraocular retinoblastoma (stage
 2 and 3: regional extra-ocular disease;, stage 4a: disseminated metastatic disease not
 involving the central nervous system [CNS]; or stage 4b: patients with CNS disease) who
 achieve long-term event-free survival after treatment with aggressive multimodality therapy
 compared to historical controls.

 II. To estimate the response rate to the induction phase of the regimen. III. To evaluate the
 toxicities associated with this regimen.

 OUTLINE:

 INDUCTION CHEMOTHERAPY: Patients receive vincristine intravenously (IV) on days 0, 7, and 14,
 cisplatin IV over 6 hours on day 0, cyclophosphamide IV over 1 hour and etoposide IV over 1
 hour on days 1 and 2, and filgrastim (G-CSF) subcutaneously (SC) beginning on day 3 and
 continuing until blood counts recover.

 Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or
 unacceptable toxicity.

 After completion of induction chemotherapy, patients with stage 2 or 3 disease who have at
 least a partial response proceed to radiotherapy. Patients with stage 4a or 4b disease who
 have at least a partial response proceed to high-dose consolidation chemotherapy and
 autologous stem cell infusion.

 STEM CELL HARVESTING (stage 4a or 4b disease only): Peripheral blood stem cells (preferred)
 or bone marrow cells are collected after at least 1 course of induction chemotherapy.

 HIGH-DOSE CONSOLIDATION CHEMOTHERAPY (stage 4a or 4b disease only): Patients receive
 carboplatin IV over 4 hours on days -8 to -6 and thiotepa IV over 3 hours and etoposide IV
 over 3 hours on days -5 to -3.

 AUTOLOGOUS STEM CELL INFUSION (stage 4a or 4b disease only): Patients undergo autologous stem
 cell infusion on day 0. Patients then receive filgrastim subcutaneously (SC) beginning on day
 1 and continuing until blood counts recover.

 RADIOTHERAPY: Patients with stage 2 or 3 disease (orbital and/or regional involvement)
 undergo radiotherapy to sites that were initially involved beginning within 42 days after the
 start of course 4 of induction chemotherapy. Patients with stage 4a or 4b disease undergo
 radiotherapy to sites initially involved based on response beginning approximately 42 days
 after autologous stem cell infusion. Patients with stage 4a disease who achieve a complete
 response to induction chemotherapy or with less than 5 mm of residual tumor at the time of
 planned irradiation, or patients with stage 4b disease who achieve a complete response to
 induction chemotherapy do not undergo radiotherapy.

 After completion of study therapy, patients are followed every 3 months for 1 year and then
 annually thereafter for 9 years.
Inclusion Criteria:

 -  Patients must have histologic or cytologic verification of extra-ocular
 retinoblastoma; extra-ocular disease includes orbital disease, optic nerve involvement
 at the surgical margin, regional nodal disease, and/or overt distant metastatic
 disease (at sites such as bone, bone marrow, liver and/or the central nervous system);
 patients with trilateral retinoblastoma will also be included in this protocol

 -  Patients with a CNS lesion consistent with trilateral or stage 4b disease may be
 enrolled without tissue confirmation if (1) unequivocal leptomeningeal disease is
 present on brain or spine magnetic resonance imaging (MRI) scan and/or (2) the
 primary tumor is at least 2 cm in diameter, predominantly solid, and demonstrates
 enhancement on the post-gadolinium images; however, even in such cases surgery
 should be given serious consideration

 -  Patients must have a performance status corresponding to Eastern Cooperative Oncology
 Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and
 Lansky for patients =< 16 years of age

 -  No prior chemotherapy or radiotherapy for the extra-ocular retinoblastoma may have
 been administered prior to entering this study; prior treatment (chemotherapy and/or
 radiation therapy) for intra-ocular retinoblastoma is permissible

 -  Peripheral absolute neutrophil count (ANC) >= 750/uL

 -  If the ANC and/or platelet count are not adequate, but due to bone marrow
 metastatic disease, these criteria will be waived

 -  Platelet count >= 75,000/uL (transfusion independent)

 -  If the ANC and/or platelet count are not adequate, but due to bone marrow
 metastatic disease, these criteria will be waived

 -  Creatinine clearance OR radioisotope glomerular filtration rate >= 70 mL/min/1.73 m^2
 or a serum creatinine based on age/gender as follows:

 -  0.4 mg/dL (1 month to < 6 months of age)

 -  0.5 mg/dL (6 months to < 1 year of age)

 -  0.6 mg/dL (1 years to < 2 years of age)

 -  0.8 mg/dL (2 years to < 6 years of age)

 -  1.0 mg/dL (6 years to < 10 years of age)

 -  1.2 mg/dL (10 years to < 13 years of age)

 -  1.5 mg/dL (male) or 1.4 mg/dL (female) (13 years to < 16 years of age)

 -  1.7 mg/dL (male) or 1.4 mg/dL (female) (>= 16 years of age)

 -  Total bilirubin =< 1.5 times upper limit of normal (ULN)

 -  Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or
 serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x
 upper limit of normal (ULN)

 -  All patients and/or their parents or legal guardians must sign a written informed
 consent

 -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
 (NCI) for human studies must be met