Stratification: Patients will be stratified into 3 groups hypothesized to have different prognoses and requiring different treatment.
Stage 2 or 3: Patients with orbital disease (including microscopic trans-scleral invasion seen on enucleation pathology), optic nerve margin (+), and/or regional nodal disease, but no other sites of metastases.
Stage 4a: Patients with overt distant metastatic disease (such as bone, bone marrow, and/or liver) but no detectable CnS involvement.
Stage 4b: Patients with overt CnS involvement (brain parenchyma, leptomeninges and CSF cytology). Patients with trilateral retinoblastoma will be included. Patients with extradural/dural disease, but without parenchymal or leptomeningeal disease should not be included and will be considered to be Stage 4a patients.
overview of Treatment Plan: Protocol therapy will consist of 3 reporting periods; induction, Consolidation with Stem Cell Rescue and external Beam Radiation Therapy.
Stage 2 and 3 patients will receive induction chemotherapy and external Beam Radiation Therapy, but will not receive Consolidation therapy (High-Dose Chemotherapy with Stem Cell Rescue).
Stage 4a and 4b patients will receive induction chemotherapy, Stem Cell Harvesting, Consolidation with Stem
Cell Rescue, and depending on response to induction chemotherapy, possibly external Beam Radiation Therapy.
induction consists of 4 cycles of chemotherapy; each cycle will be 3 weeks in duration. induction therapy may be Standard induction or alternative induction (for patients who have significant ototoxicity or preexisting hearing and/or visual impairment). Consolidation therapy includes high dose chemotherapy with stem cell rescue using peripheral blood stem cells harvested during induction; Consolidation lasts 4 to 6 weeks. external Beam Radiation Therapy for Stage 2 and Stage 3 patients will begin after Cycle 4 of induction chemotherapy. For Stage 4 patients who will receive external Beam Radiation Therapy, this will be after autologous stem cell infusion.
although brachytherapy is described in this protocol, it will not be performed at this particular institution.
1. Age: Patients must be no greater than 10 years of age at study enrollment.
2. Histologic Diagnosis: 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 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.
3. Performance Level: Patients must have a performance status corresponding to ECOG scores of 0, 1, or 2. Use Karnofsky for patients >16 years of age and Lansky for patients <= 16 years of age.
4. Prior Therapy: 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.
5. Adequate Bone Marrow Function defined as: peripheral absolute neutrophil count (ANC) >= 750uL and 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.
6. Adequate Renal Function defined as: creatinine clearance or radioisotope GFR >= 70ml/min/1.73 m2 or a serum creatinine based on age/gender as listed in the protocol.
7. Adequate Liver Function defined as: total bilirubin <= 1.5 x upper limit of normal (ULN) for age, and SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age.
8. All patients and/or their parents or legal guardians must sign a written informed consent.
9. All institutional, FDA, and NCI requirements for human studies must be met.