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Study of Treatment for Patients With Cancer of the Eye -Retinoblastoma

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ClinicalTrials.gov Identifier: NCT00186888
Recruitment Status : Active, not recruiting
First Posted : September 16, 2005
Results First Posted : August 30, 2011
Last Update Posted : February 15, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Retinoblastoma
Retinal Neoplasm
Interventions Procedure: Enucleation
Drug: Vincristine, Carboplatin
Procedure: Focal Therapies
Radiation: External Beam Radiation
Drug: Vincristine and Topotecan
Drug: Vincristine + Carboplatin + Etoposide
Drug: vincristine, cyclophosphamide, and doxorubicin
Drug: Vincristine, Carboplatin and Etoposide
Procedure: Periocular carboplatin
Other: G-CSF
Enrollment 107
Recruitment Details 107 patients were recruited between February, 2005 and June, 2010 (stratum B) and between February, 2005 and November, 2010 (strata A & C).The primary objective was designed only for stratum B patients who had advanced bilateral retinoblastoma and received the investigational window therapy.
Pre-assignment Details 107 patients were enrolled on the study. Two patients were excluded as they were deemed to be ineligible after study enrollment. One patient was found to have retinal dysplasia rather than retinoblastoma and the other patient had retinoblastoma but did not fit into any of the defined treatment strata for this study.
Arm/Group Title Stratum A Stratum B Stratum C
Hide Arm/Group Description Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. Advanced Unilateral Retinoblastoma. Research participants with unilateral (unifocal or multifocal) advanced (Reese-Ellsworth group IV or V) intraocular disease will undergo upfront enucleation. Adjuvant therapy was also indicated in certain cases.
Period Title: Overall Study
Started 23 27 55
Window Therapy 0 27 0
Completed 19 24 55
Not Completed 4 3 0
Reason Not Completed
Toxicity             0             1             0
Relapse or progression of disease             4             2             0
Arm/Group Title Stratum A Stratum B Stratum C Total
Hide Arm/Group Description Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. Advanced Unilateral Retinoblastoma. Research participants with unilateral (unifocal or multifocal) advanced (Reese-Ellsworth group IV or V) intraocular disease will undergo upfront enucleation. Adjuvant therapy was also indicated in certain cases. Total of all reporting groups
Overall Number of Baseline Participants 23 27 55 105
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 23 participants 27 participants 55 participants 105 participants
5.7  (3.6) 8.5  (4.6) 29.6  (22.1) 18.9  (19.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants 27 participants 55 participants 105 participants
Female
11
  47.8%
13
  48.1%
28
  50.9%
52
  49.5%
Male
12
  52.2%
14
  51.9%
27
  49.1%
53
  50.5%
Tumor Laterality   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants 24 participants 41 participants 77 participants
Bilateral Tumor 3 24 0 27
Unilateral Tumor 9 0 41 50
[1]
Measure Analysis Population Description: Evaluable visual cortex (V1) activation for longitudinal analysis was detected in 77 patients.
1.Primary Outcome
Title Stratum B Response to Window Therapy
Hide Description The primary outcome is to estimate the proportion of stratum B patients responding to 2 courses of window therapy consisting of vincristine and topotecan. Complete Response is the complete regression of all apparent tumor masses in the funduscopic examination and by MRI and ultrasound (US). Partial Response is defined as greater than 50% (but less than 100%) reduction of the tumor masses in the funduscopic examination and by US and MRI, without the appearance of any new lesions. The response must persist for at least 4 weeks. Stratum A and C did not receive window therapy.
Time Frame Six weeks post window therapy
Hide Outcome Measure Data
Hide Analysis Population Description
The primary objective related to stratum B patients only, as these were the patients who were given window therapy consisting of 2 courses of vincristine and topotecan. Of the 27 stratum B patients enrolled, all were included in the analysis of the primary objective.
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 27
Measure Type: Number
Unit of Measure: Participants
Partial response 24
Progressive Disease or New Lesion 2
Failure due to Toxicity 1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Stratum B
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Binomial Proportion
Estimated Value 88.9
Confidence Interval (2-Sided) 95%
71.3 to 96.9
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Stratum B Response Rate of Early Stage Eyes to Window Therapy
Hide Description To estimate the proportion of early stage eyes defined as Reese-Ellsworth Group I, II, or III eyes, that responded to 2 courses of window therapy which consisted of vincristine and topotecan
Time Frame Six weeks post window therapy.
Hide Outcome Measure Data
Hide Analysis Population Description
Among the 27 stratum B patients with 54 eyes with retinoblastoma, 12 eyes were early stage (Reese-Ellsworth group I, II, or III). The remaining 42 eyes were advanced stage and were not included in this analysis.
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 12
Measure Type: Number
Unit of Measure: Participants
Partial response 11
Progressive Disease / New lesion 0
Failure due to Toxicity 1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Stratum B
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Binomial Proportion
Estimated Value 91.7
Confidence Interval (2-Sided) 95%
65.1 to 99.6
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Relationship Between Topotecan Clearance (CL) and CYP3A4/5 Genotype in Stratum B Participants.
Hide Description Blood samples for pharmacokinetic studies were collected at 0 hour (pre-dose), 5 minutes, 1.5 and 2.5 hours after the end of topotecan dose on Course 1 Day 1, Course 2 Day 1, and if further studies were needed, Course 5 Day 1 and Course 8 Day 1. A blood sample for pharmacogenetic studies was collected during the course of therapy on protocol.
Time Frame Courses 1, 2, 5, and 8
Hide Outcome Measure Data
Hide Analysis Population Description

Of the 107 participants enrolled in the overall study, analysis was performed for 19 participants who were enrolled on Stratum B AND who had results for both topotecan clearance and pharmacogenetic studies.

Only wild-type was present in CYP3A5*6, therefore, statistical analysis was not done for these alleles.

Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 19
Median (95% Confidence Interval)
Unit of Measure: Liters/hour/m^2
18.8
(9.8 to 36.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Stratum B
Comments CYP3A4*1B: The null hypothesis is there is not a statistically significant difference between the genotype groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.452
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Stratum B
Comments CYP3A5*3: The null hypothesis is there is not a statistically significant difference between the genotype groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.106
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
4.Secondary Outcome
Title Relationship Between Topotecan Clearance (CL) and ABCG2/B1 Genotype in Stratum B Participants.
Hide Description Blood samples for pharmacokinetic studies were collected at 0 hour (pre-dose), 5 minutes, 1.5 and 2.5 hours after the end of topotecan dose on Course 1 Day 1, Course 2 Day 1, and if further studies were needed, Course 5 Day 1 and Course 8 Day 1. A blood sample for pharmacogenetic studies was collected during the course of therapy on protocol.
Time Frame Courses 1, 2, 5, and 8
Hide Outcome Measure Data
Hide Analysis Population Description

Of the 107 participants enrolled in the overall study, analysis was performed for 19 participants who were enrolled on Stratum B AND who had results for both topotecan clearance and pharmacogenetic studies.

Only wild-type was present in BCRP 15994, therefore, statistical analysis was not done for these alleles.

Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 19
Median (95% Confidence Interval)
Unit of Measure: Liters/hour/m^2
18.8
(9.8 to 36.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Stratum B
Comments BCRP 1143: The null hypothesis is there is not a statistically significant difference between the genotype groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.245
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Stratum B
Comments BCRP 15622: The null hypothesis is there is not a statistically significant difference between the genotype groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.297
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Stratum B
Comments BCRP Exon 2: The null hypothesis is there is not a statistically significant difference between the genotype groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.372
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Stratum B
Comments BCRP Exon 5: The null hypothesis is there is not a statistically significant difference between the genotype groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.844
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Stratum B
Comments Pgp Exon 21: The null hypothesis is there is not a statistically significant difference between the genotype groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.616
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Stratum B
Comments Pgp Exon 26: The null hypothesis is there is not a statistically significant difference between the genotype groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.424
Comments [Not Specified]
Method ANOVA
Comments [Not Specified]
5.Secondary Outcome
Title Event-free Survival of Stratum B Patients Responding to Window Treatment
Hide Description

To estimate the 5-year event-free (EFS) survival of bilateral disease patients with advanced intraocular retinoblastoma in either eye (R-E IV-V) responding to the vincristine/topotecan window, with alternating cycles of vincristine and carboplatin with vincristine, topotecan, and periocular carboplatin, with intensive focal treatments.

Event-free survival will be defined per patient as follows: for patients with one advanced stage eye, the time interval from date on study to date of first event (an event includes external beam radiation or enucleation) of advanced stage eyes, time to first event will be used for the analysis. Event-free survival will be estimated using the method of Kaplan and Meier.

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
Of the total 27 eligible patients in stratum B, 3 patients were not responding to the window therapy; 1 withdrew the consent and was taken off the study, and 2 developed disease progression. Kaplan and Meier estimate of ocular survival was calculated for the remaining 24 patients.
Arm/Group Title Stratum B
Hide Arm/Group Description:

Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.

Two patients (3 eyes) in stratum B received external beam radiation therapy (EBRT), and the same 2 patients later required enucleation of the treated eye, thus the failure (event number) and censoring status were not changed for the 2 patients.

Overall Number of Participants Analyzed 24
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
0.667
(0.478 to 0.855)
6.Secondary Outcome
Title Ocular Survival of Stratum B Patients Responding to Window Treatment
Hide Description

To estimate the 5-year ocular survival of bilateral disease patients with advanced intraocular retinoblastoma in either eye (R-E IV-V) responding to the vincristine/topotecan window, with alternating cycles of vincristine and carboplatin with vincristine, topotecan, and periocular carboplatin, with intensive focal treatments.

Ocular survival will be defined per patient as follows: for patients with one advanced stage eye, the time interval from date on study to date of enucleation of advanced stage eye or date of last follow-up, for patients with two advanced stage eyes, the time to the first enucleation will be used for analysis. Ocular survival will be estimated using the method of Kaplan and Meier. Standard error is 5-year ocular survival

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
From the total of 27 eligible patients in stratum B, 3 patients were not responding to the window therapy; 1 withdrew the consent and was taken off the study, and 2 developed disease progression. Thus, the Kaplan and Meier estimate of ocular survival was calculated for the remaining 24 patients.
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 24
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
0.667
(0.478 to 0.855)
7.Secondary Outcome
Title Event-free Survival of Eyes in Stratum B Patients Responding to Window Treatment
Hide Description

To estimate the 5-year event-free survival (EFS) of eyes of bilateral disease patients with advanced intraocular retinoblastoma in either eye (R-E IV-V) responding to the vincristine/topotecan window, with alternating cycles of vincristine and carboplatin with vincristine, topotecan, and periocular carboplatin, with intensive focal treatments.

Event-free survival of eye will be defined per eye as the time interval from date on study to date of first event (an event includes external beam radiation or enucleation) or to last follow-up date for eyes without events. Event-free survival of eye will be estimated using the method of Kaplan and Meier. Standard error is 5-year EFS.

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
Of the 52 eyes (26 evaluable patients), 2 eyes (2 patients) were removed from analysis as they were not responsive to window therapy. In both cases, the contralateral eye was included in the analysis. One patient with upfront enucleation had only one eye for analysis. Eleven eyes were R-E Group I-III and were excluded. Total: 38 eyes for analysis.
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 25
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
38
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
0.763
(0.628 to 0.898)
8.Secondary Outcome
Title Ocular Survival of Eyes in Stratum B Patients Responding to Window Treatment
Hide Description

To estimate the 5-year ocular survival of eye of bilateral disease patients with advanced intraocular retinoblastoma in either eye (R-E IV-V) responding to the vincristine/topotecan window, with alternating cycles of vincristine and carboplatin with vincristine, topotecan, and periocular carboplatin, with intensive focal treatments.

Ocular survival of eye will be defined per eye as the time interval from date on study to date of enucleation or date of last follow-up. Ocular survival of eye will be estimated using the method of Kaplan and Meier. Standard error is 5-year ocular survival.

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
Of the 52 eyes (26 evaluable patients), 2 eyes (2 patients) were removed from analysis as they were not responsive to window therapy. In both cases, the contralateral eye was included in the analysis. One patient with upfront enucleation had only one eye for analysis. Eleven eyes were R-E Group I-III and were excluded. Total: 38 eyes for analysis.
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 25
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
38
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
0.763
(0.628 to 0.898)
9.Secondary Outcome
Title Event-free Survival of Stratum B Patients Not Responding to Window Treatment
Hide Description To estimate the 5-year event free survival of patients with advanced intraocular retinoblastoma (R-E IV-V) not responding to the vincristine/topotecan window, with a combination of vincristine, carboplatin, etoposide, and periocular carboplatin, with intensive focal treatments.
Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
The study closed to enrollment early due to poor accrual, but it remains open to follow-up. Both patients who developed new lesions in one eye during window therapy had a good response in the contralateral eye, and they continued on protocol therapy with vincristine/topotecan. Therefore, no patients were treated with this combination therapy.
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
10.Secondary Outcome
Title Ocular Survival of Stratum B Patients Not Responding to Window Treatment
Hide Description To estimate the 5-year ocular survival of patients with advanced intraocular retinoblastoma (R-E IV-V) not responding to the vincristine/topotecan window, with a combination of vincristine, carboplatin, etoposide, and periocular carboplatin, with intensive focal treatments.
Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
The study closed to enrollment early due to poor accrual, but it remains open to follow-up. Both patients who developed new lesions in one eye during window therapy had a good response in the contralateral eye, and they continued on protocol therapy with vincristine/topotecan. Therefore, no patients were treated with this combination therapy.
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
11.Secondary Outcome
Title Event-free Survival of Eyes in Stratum B Patients Not Responding to Window Treatment
Hide Description To estimate the 5-year event free survival of the eye of patients with advanced intraocular retinoblastoma (R-E IV-V) not responding to the vincristine/topotecan window, with a combination of vincristine, carboplatin, etoposide, and periocular carboplatin, with intensive focal treatments
Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
The study closed to enrollment early due to poor accrual, but it remains open to follow-up. Both patients who developed new lesions in one eye during window therapy had a good response in the contralateral eye, and they continued on protocol therapy with vincristine/topotecan. Therefore, no patients were treated with this combination therapy.
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
12.Secondary Outcome
Title Ocular Survival of Eyes in Stratum B Patients Not Responding to Window Treatment
Hide Description To estimate the 5-year ocular survival of the eye of patients with advanced intraocular retinoblastoma (R-E IV-V) not responding to the vincristine/topotecan window, with a combination of vincristine, carboplatin, etoposide, and periocular carboplatin, with intensive focal treatments
Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
The study closed to enrollment early due to poor accrual, but it remains open to follow-up. Both patients who developed new lesions in one eye during window therapy had a good response in the contralateral eye, and they continued on protocol therapy with vincristine/topotecan. Therefore, no patients were treated with this combination therapy.
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
13.Secondary Outcome
Title Event-free Survival of Stratum A Patients
Hide Description

To estimate the 5-year event-free survival of patients with early stage intraocular retinoblastoma (R-E I-III) with vincristine and carboplatin with intensive focal treatments.

Event-free survival will be defined per patient as follows: for patients with one advanced stage eye, the time interval from date on study to date of first event (an event includes external beam radiation or enucleation) of advanced stage eyes, time to first event will be used for the analysis. Event-free survival will be estimated using the method of Kaplan and Meier.

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
All 23 stratum A patients received VC treatment and focal therapy.
Arm/Group Title Stratum A
Hide Arm/Group Description:
Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.
Overall Number of Participants Analyzed 23
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
0.688
(0.496 to 0.880)
14.Secondary Outcome
Title Ocular Survival of Stratum A Patients
Hide Description

To estimate the 5-year ocular survival of patients with early stage intraocular retinoblastoma (R-E I-III) with vincristine and carboplatin with intensive focal treatments.

Ocular survival will be defined per patient as follows: for patients with one advanced stage eye, the time interval from date on study to date of enucleation of advanced stage eye or date of last follow-up, for patients with two advanced stage eyes, the time to the first enucleation will be used for analysis. Ocular survival will be estimated using the method of Kaplan and Meier.

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
All 23 stratum A patients received VC treatment and focal therapy.
Arm/Group Title Stratum A
Hide Arm/Group Description:
Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.
Overall Number of Participants Analyzed 23
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
0.688
(0.496 to 0.880)
15.Secondary Outcome
Title Event-free Survival of Eyes of Stratum B Patients
Hide Description

To estimate the 5-year event-free survival of early stage eyes (R-E I-III) of patients with contralateral advanced disease treated with vincristine and topotecan.

Event-free survival of eye will be defined per eye as the time interval from date on study to date of first event (an event includes external beam radiation or enucleation) or to last follow-up date for eyes without events. Event-free survival of eye will be estimated using the method of Kaplan and Meier.

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
The criteria considered eyes of all stratum B patients with R-E I-III (11 eyes in 11 patients).
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 11
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
11
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
1.0 [1] 
(NA to NA)
[1]
There is no event in the data, thus SE=0 and 95% CI is not available.
16.Secondary Outcome
Title Ocular Survival of Eyes of Stratum B Patients
Hide Description

To estimate the 5-year ocular survival of early stage eyes (R-E I-III) of patients with contralateral advanced disease treated with vincristine and topotecan.

Ocular survival will be defined per patient as follows: for patients with one advanced stage eye, the time interval from date on study to date of enucleation of advanced stage eye or date of last follow-up, for patients with two advanced stage eyes, the time to the first enucleation will be used for analysis. Ocular survival will be estimated using the method of Kaplan and Meier.

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
The criteria considered eyes of all stratum B patients with R-E I-III (11 eyes in 11 patients).
Arm/Group Title Stratum B
Hide Arm/Group Description:
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 11
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
11
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
1.0 [1] 
(NA to NA)
[1]
There is no event in the data, thus SE=0 and 95% CI is not available.
17.Secondary Outcome
Title Event-free Survival of Eyes in Stratum A and Stratum B Patients Based on IC Classification
Hide Description

To describe the 5-year event-free survival of the eyes outcome of intraocular retinoblastoma with respect to the new International Classification (IC) for Intraocular Retinoblastoma and the AJCC.

Patients were re-classified into 2 groups of early (IC groups A and B) and advanced (IC groups C, D, and E) retinoblastoma. Analysis was done at eye level since each eye in the same patient could be a different group. Patients from stratum A and B were analyzed separately.

Three eyes (2 patients) in stratum B received external beam radiation therapy (EBRT) and were also coincident with enucleation surgery, so their event status was not changed. Although the 3 eyes had shorter EFS interval because EBRT occurred (less than 2 years) before the surgery, it did not change the 5-year survival probability.

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
For the 23 stratum A patients, 35 eyes (12 bilateral patients, 11 unilateral patients) with IC grouping were analyzed. For 26 Stratum B patients, 1 eye with up-front surgery was excluded from analysis. 51 eyes with IC grouping were analyzed. Participants with bilateral disease may have one eye in each category.
Arm/Group Title Stratum A-Early Disease Stratum A-Advanced Disease Stratum B-Early Disease Stratum B-Advanced Disease
Hide Arm/Group Description:

Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.

The patients were re-classified into 2 groups of early (IC Group=A and B) and advanced (IC Group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.

The patients were re-classified into 2 groups of early (IC Group=A and B) and advanced (IC Group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.

The patients were re-classified into 2 groups of early (IC Group=A and B) and advanced (IC Group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.

The patients were re-classified into 2 groups of early (IC Group=A and B) and advanced (IC Group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Overall Number of Participants Analyzed 18 9 15 25
Overall Number of Units Analyzed
Type of Units Analyzed: Number of Eyes
26 9 16 35
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
0.839
(0.694 to 0.984)
0.667
(0.359 to 0.975)
1.0 [1] 
(NA to NA)
0.743
(0.598 to 0.888)
[1]
There is no event in the data, thus SE=0 and 95% CI is not available.
18.Secondary Outcome
Title Ocular Survival of Eyes in Stratum A and Stratum B Patients Based on IC Classification
Hide Description

To describe the 5-year ocular survival of eyes outcome of intraocular retinoblastoma with respect to the new International Classification (IC) for Intraocular Retinoblastoma and the AJCC.

Patients were re-classified into 2 groups of early (IC groups A and B) and advanced (IC groups C, D, and E) retinoblastoma. Analysis was done at eye level since each eye in the same patient could be a different group. Patients from stratum A and B were analyzed separately.

Three eyes (2 patients) in stratum B received external beam radiation therapy (EBRT) and were also coincident with enucleation surgery, so their event status was not changed. Although the 3 eyes had shorter EFS interval because EBRT occurred (less than 2 years) before the surgery, it did not change the 5-year survival probability.

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
For the 23 stratum A patients, 35 eyes (12 bilateral patients, 11 unilateral patients) with IC grouping were analyzed.For 26 Stratum B patients, 1 eye with up-front surgery was excluded from analysis. 51 eyes with IC grouping were analyzed. Participants with bilateral disease may have one eye in each category.
Arm/Group Title Stratum A-Early Disease Stratum A-Advanced Disease Stratum B-Early Disease Stratum B-Advanced Disease
Hide Arm/Group Description:

Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.

The patients were re-classified into 2 groups of early (IC group=A and B) and advanced (IC group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.

The patients were re-classified into 2 groups of early (IC=A and B) and advanced (IC=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.

The patients were re-classified into 2 groups of early (IC group=A and B) and advanced (IC group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.

The patients were re-classified into 2 groups of early (IC group=A and B) and advanced (IC group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Overall Number of Participants Analyzed 18 9 15 25
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
26 9 16 35
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
0.839
(0.694 to 0.984)
0.667
(0.359 to 0.975)
1.0 [1] 
(NA to NA)
0.743
(0.598 to 0.888)
[1]
There is no event in the data, thus SE=0 and 95% CI is not available.
19.Secondary Outcome
Title Event-free Survival Per Eye in Stratum A and Stratum B Patients Based on AJCC Classification
Hide Description

To describe the 5-year event-free survival of eyes outcome of intraocular retinoblastoma with respect to the new classification of the American Joint Committee on Cancer (AJCC).

For AJCC staging, the patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group. Patients from stratum A and B were analyzed separately

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
For the 23 stratum A patients, 35 eyes (12 bilateral patients, 11 unilateral patients) with IC grouping were analyzed. For 26 Stratum B patients, 1 eye with up-front surgery was excluded from analysis. Participants with bilateral disease may have one eye in each category.
Arm/Group Title Stratum A-Early Disease Stratum A-Advanced Disease Stratum B-Early Disease Stratum B-Advanced Disease
Hide Arm/Group Description:

Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.

The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.

The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.

The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.

The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Overall Number of Participants Analyzed 19 6 18 25
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
29 6 19 32
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
0.857
(0.726 to 0.987)
0.500
(0.100 to 0.900)
1.0 [1] 
(NA to NA)
0.719
(0.563 to 0.875)
[1]
There is no event in the data, thus SE=0 and 95% CI is not available.
20.Secondary Outcome
Title Ocular Survival Per Eye in Stratum A and Stratum B Patients Based on AJCC Classification
Hide Description

To describe the 5-year ocular survival of eyes outcome of intraocular retinoblastoma with respect to the new classification of the American Joint Committee on Cancer (AJCC).

For AJCC staging, the patients were classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma . The analysis was done at eye level since each eye in the same patient could be a different group. Patients from stratum A and B were analyzed separately

Time Frame From date on-study to an event or last follow-up
Hide Outcome Measure Data
Hide Analysis Population Description
For the 23 stratum A patients, 35 eyes (12 bilateral patients, 11 unilateral patients) with IC grouping were analyzed. For 26 Stratum B patients, 1 eye with up-front surgery was excluded from analysis. Participants with bilateral disease may have one eye in each category.
Arm/Group Title Stratum A-Early Disease Stratum A-Advanced Disease Stratum B-Early Disease Stratum B-Advanced Disease
Hide Arm/Group Description:

Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.

The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.

The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.

The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.

The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.

Overall Number of Participants Analyzed 19 6 18 25
Overall Number of Units Analyzed
Type of Units Analyzed: Number of Eyes
29 6 19 32
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: probability
0.857
(0.726 to 0.987)
0.500
(0.100 to 0.900)
1.0 [1] 
(NA to NA)
0.719
(0.563 to 0.875)
[1]
There is no event in the data, thus SE=0 and 95% CI is not available.
21.Secondary Outcome
Title Change in Cognitive Functioning
Hide Description The Early Learning Composite was assessed with Mullen Scales of Early Learning, a measure of developmental functioning appropriate for use with children from birth through age 5. It is an examiner-administered instrument that uses toys, games, pictures, and other objects to elicit information about a child's language, fine and gross motor skills, and overall early learning capabilities. Raw scores are converted to an age-normed standard score (normative mean = 100, SD = 15) for the overall Early Learning Composite. This measure was given at all time points. Higher scores are indicative of better functioning, with scores from 85-115 in the average range.
Time Frame Baseline (at study entry) and at ages 6 months, 1 year, 2 years, 3 years and 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Data was collected from 94 unique patients. All patients were included, regardless of treatment strata. If the patient age at study entry (baseline) was within the window of an identified time point, their information was included with that time point.
Arm/Group Title Baseline 6 Months 1 Year 2 Years 3 Years 5 Years
Hide Arm/Group Description:
At study entry.
Participants at 6 months of age ±3 months.
Participant age was 1 year ±3 months.
Participant age was 2 years ±3 months.
Participant age was 3 years ±3 months.
Participant age was 5 years ±3 months.
Overall Number of Participants Analyzed 25 30 50 64 67 60
Mean (Standard Deviation)
Unit of Measure: units on a scale
91.61  (16.93) 90.96  (17.66) 95.91  (17.98) 88.40  (18.72) 82.12  (19.75) 86.00  (15.31)
22.Secondary Outcome
Title Change in Relevant Daily Living Skills
Hide Description The Adaptive Behavior composite was measured using the Vineland Scales of Adaptive Behavior (VABS) which is an examiner-administered semi-structured interview that assesses adaptive functioning from birth through adulthood. Subscales including motor skills, communication, socialization, and daily living skills combine into an overall adaptive behavior composite which is an age-normed standard score (normative mean = 100, SD = 15). This measure was given at all time points. Higher scores are indicative of better functioning, with scores from 85-115 in the average range.
Time Frame Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Data was collected from 94 unique patients. All patients were included, regardless of treatment strata. If the patient age at study entry (baseline) was within the window of an identified time point, their information was included with that time point.
Arm/Group Title Baseline 6 Months 1 Year 2 Years 3 Years 5 Years
Hide Arm/Group Description:
At study entry.
Participants at 6 months of age ±3 months.
Participant age was 1 year ±3 months.
Participant age was 2 years ±3 months.
Participant age was 3 years ±3 months.
Participant age was 5 years ±3 months.
Overall Number of Participants Analyzed 25 30 50 64 67 60
Mean (Standard Deviation)
Unit of Measure: units on a scale
97.48  (13.35) 104.73  (11.04) 106.06  (10.38) 94.22  (15.44) 96.45  (19.12) 93.03  (17.45)
23.Secondary Outcome
Title Change in Parent Report of Social-Emotional Factors
Hide Description This outcome was measured using the Ages and Stages Questionnaire which is a parent-completed measure of a child's social-emotional functioning. Raw scores are calculated and compared to cut-off points by age (6 months = 45; 1 year = 48; 2 years = 50; 3 years = 59; 5 years =70). Higher scores are indicative of more problems with scores above the cut-off indicating significant concerns warranting additional follow-up. Possible scores range from 0 to 200+, depending on the number of items administered, which varies by the age of the child (19 to 33 items). However, the primary use of this tool is as a screener. Thus, typically, scores are interpreted as they compare to the identified cut-offs, with children who score above the cut-off referred for further evaluation. This measure was given at all time points.
Time Frame Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Data was collected from 94 unique patients. All patients were included, regardless of treatment strata. If the patient age at study entry (baseline) was within the window of an identified time point, their information was included with that time point.
Arm/Group Title Baseline 6 Months 1 Year 2 Years 3 Years 5 Years
Hide Arm/Group Description:
At study entry.
Participants at 6 months of age ±3 months.
Participant age was 1 year ±3 months.
Participant age was 2 years ±3 months.
Participant age was 3 years ±3 months.
Participant age was 5 years ±3 months.
Overall Number of Participants Analyzed 25 30 50 64 67 60
Mean (Standard Deviation)
Unit of Measure: units on a scale
40  (31.12) 19.42  (14.02) 26.28  (13.93) 29.67  (20.83) 40.61  (37.76) 39.93  (34.03)
24.Secondary Outcome
Title Change in Parenting Stress Index (PSI)
Hide Description The PSI is a commonly used measure of parenting stress. In 101 questions, the PSI delineates between stress as a function of child characteristics (e.g., adaptability, demandingness, mood; Child Domain) and stress as a function of parent characteristics (e.g., depression, sense of competence, social isolation; Parent Domain), as well as an overall stress score (Total Stress). Raw scores are calculated (normative means: Child Doman = 98.4; Parent Domain = 122.7; Total Stress Score = 221.1). This measure was given at all time points. Scores range from 131-320 for Total Stress, 69-188 for Parent Domain, and 50-145 for Child Domain, with higher scores indicative of greater stress (Total: >260; Parent: >153, Child: >122).
Time Frame Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years
Hide Outcome Measure Data
Hide Analysis Population Description
Data was collected from 94 unique patients. All patients were included, regardless of treatment strata. If the patient age at study entry (baseline) was within the window of an identified time point, their information was included with that time point.
Arm/Group Title Baseline 6 Months 1 Year 2 Years 3 Years 5 Years
Hide Arm/Group Description:
At study entry.
Participants at 6 months of age ±3 months.
Participant age was 1 year ±3 months.
Participant age was 2 years ±3 months.
Participant age was 3 years ±3 months.
Participant age was 5 years ±3 months.
Overall Number of Participants Analyzed 25 30 50 64 67 60
Mean (Standard Deviation)
Unit of Measure: units on a scale
Child Domain 96.76  (20.91) 93.08  (15.98) 93.27  (14.86) 92.77  (16.23) 94.60  (18.69) 92.49  (19.02)
Parent Domain 109.38  (30.33) 101.56  (22.90) 105.84  (22.90) 105.84  (27.56) 105.92  (24.96) 102.74  (24.97)
Overall Total Stress 207.25  (47.07) 194.84  (23.36) 200.51  (35.98) 198.61  (38.52) 200.23  (40.21) 194.68  (39.84)
25.Secondary Outcome
Title Assessment of School Readiness
Hide Description The Bracken Basic Concepts Scale was used to assess school readiness. It is an examiner-administered measure that assesses per-academic skills including letter and number recognition, shapes, colors, and understanding of sizes and comparisons. Raw scores are converted into age-normed scaled scores (normative mean = 10, SD = 3) for the School Readiness Composite. Higher scores are indicative of stronger pre-academic skills, with scores from 7 to 13 within the Average range.
Time Frame Patients were assessed at 5 years of age
Hide Outcome Measure Data
Hide Analysis Population Description
All patients were included, regardless of treatment strata.
Arm/Group Title 5 Years
Hide Arm/Group Description:
Participant age was 5 years ±3 months.
Overall Number of Participants Analyzed 60
Mean (Standard Deviation)
Unit of Measure: units on a scale
8.96  (3.10)
26.Secondary Outcome
Title Number of Participants With Development of Pineal Cysts
Hide Description The MRI reports from bilateral patients were reviewed and data abstracted regarding pineal gland measurement and information about pineal cysts. The number of participants with change in primary visual cortex function from diagnosis through 6 years after last patient enrollment is reported here.
Time Frame At diagnosis through 6 years after last patient enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
A patient may be included in more than one category due to having more than one cyst.
Arm/Group Title Participants With Bilateral Retinoblastoma
Hide Arm/Group Description:
Results were analyzed for all participants regardless of stratum. All participants received chemotherapy (5 Stratum C, high risk; 11 Stratum A; 27 Stratum B).
Overall Number of Participants Analyzed 43
Measure Type: Count of Participants
Unit of Measure: Participants
Developed new solitary cyst(s) 12
Developed multiple new cysts 15
Growth of pineal cyst 5
Decrease in size (resolution) of pineal cyst 1
No change 11
27.Secondary Outcome
Title Number of Participants With Change in Size of Pineal Gland
Hide Description The MRI reports from bilateral patients were reviewed and data abstracted regarding pineal gland measurement and information about pineal cysts. The number of participants with change in pineal gland size is reported here.
Time Frame From diagnosis through 6 years after last patient enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
Pineal gland size was measured during routine MRI screening. Measurements were compared over time to quantify any change in size. Measurements were compared with standard pediatric norms to determine “prominence” or “mild enlargement” (subjective comparison).
Arm/Group Title Participants With Bilateral Retinoblastoma
Hide Arm/Group Description:
Results were analyzed for all participants regardless of stratum. All participants received chemotherapy (5 Stratum C, high risk; 11 Stratum A; 27 Stratum B).
Overall Number of Participants Analyzed 43
Measure Type: Count of Participants
Unit of Measure: Participants
Prominent or mildly enlarged pineal glands 12
Pineal growth over time 8
No change in pineal gland size 23
28.Secondary Outcome
Title Change in Distortion Product Otoacoustic Emissions (DPOAEs)
Hide Description For DP_amplitude to be considered valid, a baseline DP_SNR (Distortion Product for Signal-to-noise ratio) for each frequency (1000-8000 Hz) and for each ear (left and right) must be = 6 dB. Any ear with invalid amplitude at baseline for each frequency should be excluded. The DPOAEs amplitude levels were averaged across the right and left ears at each frequency in the patients exhibiting valid DPOAE amplitudes in both ears, resulting in mean DPOAE levels. Subsequently, comparisons between baseline and most recent evaluation (collapsed across ears) for each frequency were made to evaluate if a significant decrease in DPOAE amplitude exists between the two time points.
Time Frame From Diagnosis through 5 years after completion of therapy
Hide Outcome Measure Data
Hide Analysis Population Description
A total of 14 patients had “Incomplete data” and were not included in the analysis.
Arm/Group Title Baseline Interim Evaluation Additional Evaluation
Hide Arm/Group Description:
All Stratum B participants with non-missing observation values were included. Stratum B (Advanced Bilateral retinoblastoma) includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
All Stratum B participants with non-missing observation values were included. Stratum B (Advanced Bilateral retinoblastoma) includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
All Stratum B participants with non-missing observation values were included. Stratum B (Advanced Bilateral retinoblastoma) includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Overall Number of Participants Analyzed 13 12 4
Mean (Standard Deviation)
Unit of Measure: dB
1000 Hz Number Analyzed 3 participants 12 participants 4 participants
17.7  (16.6) 5.5  (2.5) 4.5  (1.7)
1400 Hz Number Analyzed 6 participants 12 participants 4 participants
16.6  (3.6) 9.4  (2.5) 8.2  (2.8)
2000 Hz Number Analyzed 11 participants 12 participants 4 participants
15.1  (1.7) 13.0  (1.8) 11.0  (1.4)
2800 Hz Number Analyzed 13 participants 12 participants 4 participants
11.6  (2.0) 12.2  (1.9) 8.4  (3.2)
4000 Hz Number Analyzed 13 participants 12 participants 4 participants
15.3  (4.8) 11.3  (1.9) 3.4  (6.6)
6000 Hz Number Analyzed 13 participants 12 participants 4 participants
13.3  (2.0) 12.9  (2.2) 5.7  (8.6)
8000 Hz Number Analyzed 12 participants 12 participants 4 participants
5.0  (1.9) -2.0  (3.2) -9.9  (6.0)
29.Secondary Outcome
Title Mean Primary Visual Cortex Function: Cluster Size
Hide Description

Functional magnetic resonance imagining (fMRI) was used to investigate primary visual cortex (V1) response to visual stimulation in 105 children being treated for intraocular retinoblastoma. Primary visual cortex activity was assessed in each subject using blood oxygenation level-dependent (BOLD) signal. The BOLD signal was analyzed via a general linear model using Statistical Parametric Mapping software (SPM, Wellcome Institute of Neuology, London).

Voxel volume/peak BOLD response is a measurement of the volume of activation of the cortex. There is no known association with visual outcome at this time.

Time Frame At diagnosis through 6 years after last patient enrollment
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Stratum A Stratum B Stratum C
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Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Advanced Unilateral Retinoblastoma. Research participants with unilateral (unifocal or multifocal) advanced (Reese-Ellsworth group IV or V) intraocular disease will undergo upfront enucleation. Adjuvant therapy was also indicated in certain cases.
Overall Number of Participants Analyzed 12 24 41
Overall Number of Units Analyzed
Type of Units Analyzed: Number of exams
33 152 122
Mean (Standard Deviation)
Unit of Measure: number activated voxels (negative BOLD)
2372  (2640) 1080  (2916) 2105  (2476)
30.Secondary Outcome
Title Mean Primary Visual Cortex Function: Maximum T-value
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Functional magnetic resonance imagining (fMRI) was used to investigate primary visual cortex (V1) response to visual stimulation in 105 children being treated for intraocular retinoblastoma. Primary visual cortex activity was assessed in each subject using blood oxygenation level-dependent (BOLD) signal. The BOLD signal was analyzed via a general linear model using Statistical Parametric Mapping software (SPM, Wellcome Institute of Neurology, London). The maximum t-statistic in activated cluster (negative BOLD) is provided.

Voxel volume/peak BOLD response is a measurement of the volume of activation of the cortex. There is no known association with visual outcome at this time.

Time Frame At diagnosis through 6 years after last patient enrollment
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[Not Specified]
Arm/Group Title Stratum A Stratum B Stratum C
Hide Arm/Group Description:
Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.
Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Advanced Unilateral Retinoblastoma. Research participants with unilateral (unifocal or multifocal) advanced (Reese-Ellsworth group IV or V) intraocular disease will undergo upfront enucleation. Adjuvant therapy was also indicated in certain cases.
Overall Number of Participants Analyzed 12 24 41
Overall Number of Units Analyzed
Type of Units Analyzed: Number of exams
33 152 122
Mean (Standard Deviation)
Unit of Measure: Maximum t-statistic (negative BOLD)
7.9  (6.9) 6.2  (3.9) 8.8  (4.7)
31.Post-Hoc Outcome
Title Number of Patients Recommended for and Utilizing Rehabilitation Services
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Participants were evaluated by Occupational Therapy at diagnosis, and at 3, 6, 9, and 12 months from diagnosis with a battery of standardized and non-standardized measures. Assessments including the Battelle Developmental Inventory, the Sensory Profile, the Oregon Project for Visually Impaired Preschoolers, Pediatric Evaluation of Disability Inventory, and the Greenspan Social Emotional Growth Scale were utilized for developing the participants plan of care and making referrals for services in the home community. Recommendations for rehabilitation services in the home community were made based on the results of the occupational therapists evaluation.

A subsequent review of February 2013 subgroup definitions resulted in the reclassification of evaluable participants and subgroups in May 2015. This reclassification applies to the data for this outcome only.

Time Frame At diagnosis, and at 3, 6, 9, and 12 months from diagnosis
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Objective was added after the protocol started. Due to the late start, 33 of the 105 overall participants were eligible. Of the 33, 1 family declined to participate; 1 was removed from the protocol, 5 were lost to follow-up, and 4 patients were unable to complete the developmental assessment. In total, 22 have complete data sets.
Arm/Group Title Occupational Therapy Recommended Rehabilitation Services Occupational Therapy Did Not Recommend Rehabilitation Services
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Occupational therapy evaluation recommended rehabilitation services.
Occupational therapy evaluation did not recommend rehabilitation services.
Overall Number of Participants Analyzed 16 6
Measure Type: Number
Unit of Measure: participants
Received rehabilitation services 12 1
Did not receive rehabilitation services 4 5
Time Frame Adverse events have been collected from study activation (February 2005) through June, 2011.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Stratum A Stratum B Stratum C
Hide Arm/Group Description Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. Advanced Unilateral Retinoblastoma. Research participants with unilateral (unifocal or multifocal) advanced (Reese-Ellsworth group IV or V) intraocular disease will undergo upfront enucleation. Adjuvant therapy was also indicated in certain cases.
All-Cause Mortality
Stratum A Stratum B Stratum C
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Stratum A Stratum B Stratum C
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/23 (4.35%)      9/27 (33.33%)      1/55 (1.82%)    
Ear and labyrinth disorders       
Hearing: patients with/without baseline audiogram and enrolled in a monitoring program * 1  0/23 (0.00%)  0 0/27 (0.00%)  0 1/55 (1.82%)  1
Gastrointestinal disorders       
Anorexia * 1  0/23 (0.00%)  0 2/27 (7.41%)  2 0/55 (0.00%)  0
Colitis * 1  0/23 (0.00%)  0 1/27 (3.70%)  1 0/55 (0.00%)  0
Diarrhea * 1  0/23 (0.00%)  0 2/27 (7.41%)  2 0/55 (0.00%)  0
Gastrointestinal - Other (Specify, __) * 1  1/23 (4.35%)  1 0/27 (0.00%)  0 0/55 (0.00%)  0
Vomiting * 1  0/23 (0.00%)  0 1/27 (3.70%)  1 0/55 (0.00%)  0
Immune system disorders       
Allergic reaction/hypersensitivity (including drug fever) * 1  0/23 (0.00%)  0 8/27 (29.63%)  9 0/55 (0.00%)  0
Infections and infestations       
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils * 1  0/23 (0.00%)  0 1/27 (3.70%)  1 0/55 (0.00%)  0
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, colon * 1  0/23 (0.00%)  0 2/27 (7.41%)  2 0/55 (0.00%)  0
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, cellulitis * 1  0/23 (0.00%)  0 1/27 (3.70%)  2 0/55 (0.00%)  0
Neutrophils/granulocytes (ANC/AGC) * 1  0/23 (0.00%)  0 4/27 (14.81%)  4 0/55 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Pulmonary/Upper Respiratory - Other (Specify, __) * 1  0/23 (0.00%)  0 1/27 (3.70%)  1 0/55 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE (3.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Stratum A Stratum B Stratum C
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   23/23 (100.00%)      27/27 (100.00%)      18/55 (32.73%)    
Blood and lymphatic system disorders       
Neutrophils/granulocytes (ANC/AGC) * 1  23/23 (100.00%)  161 26/27 (96.30%)  271 18/55 (32.73%)  69
Platelets * 1  9/23 (39.13%)  22 25/27 (92.59%)  86 10/55 (18.18%)  32
Hemoglobin * 1  10/23 (43.48%)  22 23/27 (85.19%)  72 14/55 (25.45%)  34
Leukocytes * 1  3/23 (13.04%)  5 20/27 (74.07%)  36 14/55 (25.45%)  23
Gastrointestinal disorders       
Anorexia * 1  1/23 (4.35%)  1 6/27 (22.22%)  9 0/55 (0.00%)  0
Dehydration * 1  3/23 (13.04%)  4 5/27 (18.52%)  5 0/55 (0.00%)  0
Diarrhea * 1  1/23 (4.35%)  1 7/27 (25.93%)  10 1/55 (1.82%)  1
Mucositis/stomatitis (clinical exam), Oral cavity * 1  0/23 (0.00%)  0 2/27 (7.41%)  2 1/55 (1.82%)  1
Vomiting * 1  3/23 (13.04%)  5 2/27 (7.41%)  2 1/55 (1.82%)  3
Infections and infestations       
Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented) * 1  2/23 (8.70%)  3 17/27 (62.96%)  30 3/55 (5.45%)  3
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, upper airway * 1  2/23 (8.70%)  2 4/27 (14.81%)  4 0/55 (0.00%)  0
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, cellulitis * 1  1/23 (4.35%)  2 4/27 (14.81%)  4 0/55 (0.00%)  0
Infection(documented clinically or microbiologically with Grade 3 or 4 neutrophils,catheter-related * 1  2/23 (8.70%)  2 3/27 (11.11%)  3 0/55 (0.00%)  0
Infection with normal ANC or Grade 1 or 2 neutrophils, Catheter-related * 1  2/23 (8.70%)  2 3/27 (11.11%)  3 0/55 (0.00%)  0
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L) * 1  0/23 (0.00%)  0 8/27 (29.63%)  8 0/55 (0.00%)  0
Metabolism and nutrition disorders       
Potassium, serum-low (hypokalemia) * 1  1/23 (4.35%)  1 3/27 (11.11%)  3 2/55 (3.64%)  3
Skin and subcutaneous tissue disorders       
Rash/desquamation * 1  0/23 (0.00%)  0 5/27 (18.52%)  8 0/55 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE (3.0)
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Ibrahim Qaddoumi MD
Organization: St. Jude Children's Research Hospital
Phone: 1-866-278-5833
EMail: info@stjude.org
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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT00186888     History of Changes
Other Study ID Numbers: RET5
P01CA023099 ( U.S. NIH Grant/Contract )
NCI-2011-01186 ( Registry Identifier: NCI Clinical Trial Registration Program )
First Submitted: September 12, 2005
First Posted: September 16, 2005
Results First Submitted: June 29, 2011
Results First Posted: August 30, 2011
Last Update Posted: February 15, 2019