Intraocular Retinoblastoma
Conditions
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.
Interventions
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) | At 2 years | 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. |
| Overall Survival (OS) | At 2 Years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Features Present At Diagnosis - Tumor Involving the Optic Nerve Posterior to the Lamina Cribrosa (LC) as an Independent Finding | At enrollment | Proportion of patients with tumor involving the optic nerve posterior to the lamina cribrosa as an independent. |
| Pathological Features Present at Diagnosis - Scleral Invasion (SI) | At enrollment | Proportion of patients that had scleral invasion at enrollment. |
| Toxicity As Assessed By the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | During planned six cycles of chemotherapy | Number of patients assigned chemotherapy who experienced grade 3 or higher CTC AE toxicity. |
| Pathological Features Present At Diagnosis - Iris Infiltration (II) | At enrollment | Proportion of patients who had iris infiltration at enrollment. |
| Pathological Features Present At Diagnosis - Ciliary Body Infiltration (CBI) | At Enrollment | Proportion of patients who had ciliary body infiltration at enrollment. |
| Pathological Features Present At Diagnosis - Anterior Chamber Seeding (ACS) | At enrollment | Proportion of patients who had anterior chamber seeding at enrollment. |
| Pathological Features Present At Diagnosis - Posterior Uveal Invasion (PVI) | At enrollment | Proportion of patients who had posterior uveal invasion at enrollment. |
Countries
Australia, Canada, India, New Zealand, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 (High Risk) Patients receive liposomal vincristine sulfate IV aged based dosage (Pts \< 36 mos: 0.05 mg/kg, Pts \> 36 mos: 1.5 mg/m2, max dose 2 MG) given IV or infusion on day 1, carboplatin aged based dosage (Pts \< 36 mos: 18.6 mg/kg Pts \> 36 mos: 560 mg/m2) IV on day 1, and Etoposide aged based dosage (Pts \< 36 mos: 5 mg/kg, Pts \> 36 mos: 150 mg/m2) IV on days 1 and 2. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
liposomal vincristine sulfate: Given IV
carboplatin: Given IV
etoposide: Given IV | 108 |
| Group 2 (Not High Risk) Patients undergo observation periodically for at least 5 years. | 223 |
| Total | 331 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible | 3 | 4 |
| Overall Study | Physician Decision | 6 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Group 1 (High Risk) | Total | Group 2 (Not High Risk) |
|---|---|---|---|
| Age, Continuous | 2 years | 2 years | 1 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 56 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 82 Participants | 263 Participants | 181 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 12 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 37 Participants | 100 Participants | 63 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 25 Participants | 17 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 18 Participants | 52 Participants | 34 Participants |
| Race (NIH/OMB) White | 43 Participants | 151 Participants | 108 Participants |
| Region of Enrollment Australia | 6 participants | 14 participants | 8 participants |
| Region of Enrollment Bangladesh | 0 participants | 2 participants | 2 participants |
| Region of Enrollment Canada | 3 participants | 10 participants | 7 participants |
| Region of Enrollment India | 32 participants | 87 participants | 55 participants |
| Region of Enrollment Mexico | 1 participants | 1 participants | 0 participants |
| Region of Enrollment New Zealand | 1 participants | 8 participants | 7 participants |
| Region of Enrollment United States | 65 participants | 209 participants | 144 participants |
| Sex: Female, Male Female | 52 Participants | 159 Participants | 107 Participants |
| Sex: Female, Male Male | 56 Participants | 172 Participants | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 93 | 0 / 0 |
| other Total, other adverse events | 19 / 93 | 0 / 0 |
| serious Total, serious adverse events | 0 / 93 | 0 / 0 |
Outcome results
Primary
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.
Time frame: At 2 years
Population: Only eligible patients are considered in the characterization of EFS at 2 years.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Identified by Central Review as High Risk) | Event-free Survival (EFS) | 0.9394 Estimated Probability |
| Group 2 (Identified by Central Review as Not High Risk) | Event-free Survival (EFS) | 0.9953 Estimated Probability |
Primary
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.
Time frame: At 2 Years
Population: Only eligible patients are considered for this outcome measure. This is calculated as the total number of patients enrolled in each group with the number ineligible in each group subtracted as reported on the participant flow template.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Identified by Central Review as High Risk) | Overall Survival (OS) | 0.9628 Estimated Probability |
| Group 2 (Identified by Central Review as Not High Risk) | Overall Survival (OS) | 1 Estimated Probability |
Secondary
Pathological Features Present At Diagnosis - Anterior Chamber Seeding (ACS)
Proportion of patients who had anterior chamber seeding at enrollment.
Time frame: At enrollment
Population: Central review of the biological materials for this aim was available on only 313 patients. This outcome measure is calculated by combing all groups as characterized in the Patient Flow.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Identified by Central Review as High Risk) | Pathological Features Present At Diagnosis - Anterior Chamber Seeding (ACS) | 0.045 Proportion of patients with ACS |
Secondary
Pathological Features Present At Diagnosis - Ciliary Body Infiltration (CBI)
Proportion of patients who had ciliary body infiltration at enrollment.
Time frame: At Enrollment
Population: Central review of the biological materials for this aim was available on only 313 patients. This outcome measure is calculated by combing all groups as characterized in the Patient Flow.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Identified by Central Review as High Risk) | Pathological Features Present At Diagnosis - Ciliary Body Infiltration (CBI) | 0.019 Proportion of patients with CBI |
Secondary
Pathological Features Present At Diagnosis - Iris Infiltration (II)
Proportion of patients who had iris infiltration at enrollment.
Time frame: At enrollment
Population: Central review of the biological materials for this aim was available on only 313 patients. This outcome measure is calculated by combing all groups as characterized in the Patient Flow.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Identified by Central Review as High Risk) | Pathological Features Present At Diagnosis - Iris Infiltration (II) | 0.029 Proportion of patients with II |
Secondary
Pathological Features Present At Diagnosis - Posterior Uveal Invasion (PVI)
Proportion of patients who had posterior uveal invasion at enrollment.
Time frame: At enrollment
Population: Central review of the biological materials for this aim was available on only 313 patients. This outcome measure is calculated by combing all groups as characterized in the Patient Flow.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Identified by Central Review as High Risk) | Pathological Features Present At Diagnosis - Posterior Uveal Invasion (PVI) | 0.24 Proportion of patients with PVI |
Secondary
Pathological Features Present at Diagnosis - Scleral Invasion (SI)
Proportion of patients that had scleral invasion at enrollment.
Time frame: At enrollment
Population: Central review of the biological materials for this aim was available on only 313 patients. This outcome measure is calculated by combing all groups as characterized in the Patient Flow.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Identified by Central Review as High Risk) | Pathological Features Present at Diagnosis - Scleral Invasion (SI) | 0.016 Proportion of patients with SI |
Secondary
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.
Time frame: At enrollment
Population: Central review of the biological materials for this aim was available on only 313 patients. This outcome measure is calculated by combing all groups as characterized in the Patient Flow.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Identified by Central Review as High Risk) | Pathological Features Present At Diagnosis - Tumor Involving the Optic Nerve Posterior to the Lamina Cribrosa (LC) as an Independent Finding | 0.16 Proportion of patients with LC |
Secondary
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.
Time frame: During planned six cycles of chemotherapy
Population: Adverse experiences as coded using CTC AE version 4 were collected only for patients who received chemotherapy according to protocol guidelines. Of the 105 eligible patients with high risk features, ninety-three (93) were given protocol chemotherapy based on the assessment of the central pathology review, as described in section 4 of the ARET0332.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 (Identified by Central Review as High Risk) | Toxicity As Assessed By the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | 19 participants |