Vincristine, Carboplatin, and Etoposide or Observation Only in Treating Patients Who Have Undergone Surgery for Newly Diagnosed Retinoblastoma

Study Overview
=================
Brief Summary
-----------------
This phase III trial is studying vincristine, carboplatin, and etoposide to see how well they work compared to observation only in treating patients who have undergone surgery for newly diagnosed retinoblastoma. Drugs used in chemotherapy, such as vincristine, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) after surgery may kill any tumor cells that remain after surgery. Sometimes, after surgery, no additional treatment is needed for the tumor until it progresses. In this case, observation may be sufficient.

Detailed Description
-----------------
OBJECTIVES: I. Prospectively determine the prevalence of high-risk histopathologic features, such as choroidal involvement, optic nerve invasion, and scleral and anterior segment involvement, in patients with newly diagnosed unilateral retinoblastoma who have undergone enucleation. II. Demonstrate that patients without certain high-risk features can be successfully treated with enucleation alone by estimating the event-free survival (EFS) (where an event is defined as the occurrence of extraocular or metastatic disease) and overall survival (OS). III. Estimate the EFS and OS of patients with specific high-risk features who are uniformly treated with adjuvant chemotherapy comprising vincristine, carboplatin, and etoposide. IV. Estimate the incidence of toxicities associated with the proposed adjuvant chemotherapy regimen. OUTLINE: This is a prospective, nonrandomized, multicenter study. Patients are assigned to 1 of 2 groups according to presence of high-risk histopathologic features. GROUP 1 (high-risk features): Patients receive vincristine IV and carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. GROUP 2 (no high-risk features): Patients undergo observation periodically for at least 5 years. GROUP 3 (no consensus regarding high risk features can be reached): Patients undergo Group 1 chemotherapy or observation according to institutional high-risk feature assessment. After completion of study treatment, patients in group 1 are followed periodically for at least 5 years.

Official Title
-----------------
A Study of Unilateral Retinoblastoma With and Without Histopathologic High-Risk Features and the Role of Adjuvant Chemotherapy

Conditions
-----------------
Intraocular Retinoblastoma

Intervention / Treatment
-----------------
* Drug: liposomal vincristine sulfate
* Drug: carboplatin
* Drug: etoposide


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Maximum Age: 6 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (identified by central review as high risk)<br>Includes patients who may or may not require chemotherapy. Patients who require chemotherapy receive vincristine IV and carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1 and 2. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity and patients who complete chemotherapy are followed after completion of therapy periodically for at least 5 years. Patients who do not require chemotherapy undergo observation periodically for at least 5 years. | Drug: liposomal vincristine sulfate<br>* Given IV<br>* Other names: vincristine sulfate liposome injection;Drug: carboplatin<br>* Given IV<br>* Other names: Paraplatin;Drug: etoposide<br>* Given IV<br>* Other names: VP-16-213;|
| No Intervention: Group 2 (identified by central review as not high risk)<br>Patients undergo observation periodically for at least 5 years. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | EFS distributions will be estimated by the Kaplan-Meier method for patients with high risk features according to central review and treated with adjuvant chemotherapy and separately for subjects with central review recommendation of enucleation alone. | At 2 years | 
| Overall Survival (OS) | OS distributions will be estimated by the Kaplan-Meier method for patients with high risk features according to central review and treated with adjuvant chemotherapy and separately for subjects with central review recommendation of enucleation alone. | At 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity As Assessed By the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Number of patients assigned chemotherapy who experienced grade 3 or higher CTC AE toxicity. | During planned six cycles of chemotherapy | 
| Pathological Features Present At Diagnosis - Posterior Uveal Invasion (PVI) | Proportion of patients who had posterior uveal invasion at enrollment. | At enrollment | 
| Pathological Features Present At Diagnosis - Tumor Involving the Optic Nerve Posterior to the Lamina Cribrosa (LC) as an Independent Finding | Proportion of patients with tumor involving the optic nerve posterior to the lamina cribrosa as an independent. | At enrollment | 
| Pathological Features Present at Diagnosis - Scleral Invasion (SI) | Proportion of patients that had scleral invasion at enrollment. | At enrollment | 
| Pathological Features Present At Diagnosis - Anterior Chamber Seeding (ACS) | Proportion of patients who had anterior chamber seeding at enrollment. | At enrollment | 
| Pathological Features Present At Diagnosis - Iris Infiltration (II) | Proportion of patients who had iris infiltration at enrollment. | At enrollment | 
| Pathological Features Present At Diagnosis - Ciliary Body Infiltration (CBI) | Proportion of patients who had ciliary body infiltration at enrollment. | At Enrollment |