Trial Outcomes & Findings for Study of Treatment for Patients With Cancer of the Eye -Retinoblastoma (NCT NCT00186888)

NCT ID: NCT00186888

Last Updated: 2025-09-04

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 107 participants
• Primary outcome timeframe: Six weeks post window therapy
• Results posted on: 2025-09-04

Participant Flow

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.

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.

Participant milestones

Measure	Stratum A 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.	Stratum B 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.	Stratum C 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 Study STARTED	23	27	55
Overall Study Window Therapy	0	27	0
Overall Study COMPLETED	19	24	55
Overall Study NOT COMPLETED	4	3	0

Reasons for withdrawal

Measure	Stratum A 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.	Stratum B 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.	Stratum C 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 Study Toxicity	0	1	0
Overall Study Relapse or progression of disease	4	2	0

Baseline Characteristics

Evaluable visual cortex (V1) activation for longitudinal analysis was detected in 77 patients.

Baseline characteristics by cohort

Measure	Stratum A n=23 Participants 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.	Stratum B n=27 Participants 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.	Stratum C n=55 Participants 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 n=105 Participants Total of all reporting groups
Age, Continuous	5.7 months STANDARD_DEVIATION 3.6 • n=23 Participants	8.5 months STANDARD_DEVIATION 4.6 • n=27 Participants	29.6 months STANDARD_DEVIATION 22.1 • n=55 Participants	18.9 months STANDARD_DEVIATION 19.7 • n=105 Participants
Sex: Female, Male Female	11 Participants n=23 Participants	13 Participants n=27 Participants	28 Participants n=55 Participants	52 Participants n=105 Participants
Sex: Female, Male Male	12 Participants n=23 Participants	14 Participants n=27 Participants	27 Participants n=55 Participants	53 Participants n=105 Participants
Tumor Laterality Bilateral Tumor	3 Participants n=12 Participants • Evaluable visual cortex (V1) activation for longitudinal analysis was detected in 77 patients.	24 Participants n=24 Participants • Evaluable visual cortex (V1) activation for longitudinal analysis was detected in 77 patients.	0 Participants n=41 Participants • Evaluable visual cortex (V1) activation for longitudinal analysis was detected in 77 patients.	27 Participants n=77 Participants • Evaluable visual cortex (V1) activation for longitudinal analysis was detected in 77 patients.
Tumor Laterality Unilateral Tumor	9 Participants n=12 Participants • Evaluable visual cortex (V1) activation for longitudinal analysis was detected in 77 patients.	0 Participants n=24 Participants • Evaluable visual cortex (V1) activation for longitudinal analysis was detected in 77 patients.	41 Participants n=41 Participants • Evaluable visual cortex (V1) activation for longitudinal analysis was detected in 77 patients.	50 Participants n=77 Participants • Evaluable visual cortex (V1) activation for longitudinal analysis was detected in 77 patients.

PRIMARY outcome

Timeframe: Six weeks post window therapy

Population: 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.

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.

Outcome measures

Measure	Stratum B n=27 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Stratum B Response to Window Therapy Progressive Disease or New Lesion	2 Participants	—	—	—	—	—
Stratum B Response to Window Therapy Partial response	24 Participants	—	—	—	—	—
Stratum B Response to Window Therapy Failure due to Toxicity	1 Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: Six weeks post window therapy.

Population: 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.

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

Outcome measures

Measure	Stratum B n=12 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Stratum B Response Rate of Early Stage Eyes to Window Therapy Partial response	11 Participants	—	—	—	—	—
Stratum B Response Rate of Early Stage Eyes to Window Therapy Progressive Disease / New lesion	0 Participants	—	—	—	—	—
Stratum B Response Rate of Early Stage Eyes to Window Therapy Failure due to Toxicity	1 Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: Courses 1, 2, 5, and 8

Population: 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.

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.

Outcome measures

Measure	Stratum B n=19 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Relationship Between Topotecan Clearance (CL) and CYP3A4/5 Genotype in Stratum B Participants.	18.8 Liters/hour/m^2 Interval 9.8 to 36.8	—	—	—	—	—

SECONDARY outcome

Timeframe: Courses 1, 2, 5, and 8

Population: 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.

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.

Outcome measures

Measure	Stratum B n=19 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Relationship Between Topotecan Clearance (CL) and ABCG2/B1 Genotype in Stratum B Participants.	18.8 Liters/hour/m^2 Interval 9.8 to 36.8	—	—	—	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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.

Outcome measures

Measure	Stratum B n=24 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Event-free Survival of Stratum B Patients Responding to Window Treatment	0.667 probability Interval 0.478 to 0.855	—	—	—	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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

Outcome measures

Measure	Stratum B n=24 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Ocular Survival of Stratum B Patients Responding to Window Treatment	0.667 probability Interval 0.478 to 0.855	—	—	—	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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.

Outcome measures

Measure	Stratum B n=38 Eyes 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Event-free Survival of Eyes in Stratum B Patients Responding to Window Treatment	0.763 probability Interval 0.628 to 0.898	—	—	—	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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.

Outcome measures

Measure	Stratum B n=38 Eyes 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Ocular Survival of Eyes in Stratum B Patients Responding to Window Treatment	0.763 probability Interval 0.628 to 0.898	—	—	—	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: All 23 stratum A patients received VC treatment and focal therapy.

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.

Outcome measures

Measure	Stratum B n=23 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Event-free Survival of Stratum A Patients	0.688 probability Interval 0.496 to 0.88	—	—	—	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: All 23 stratum A patients received VC treatment and focal therapy.

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.

Outcome measures

Measure	Stratum B n=23 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Ocular Survival of Stratum A Patients	0.688 probability Interval 0.496 to 0.88	—	—	—	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: The criteria considered eyes of all stratum B patients with R-E I-III (11 eyes in 11 patients).

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.

Outcome measures

Measure	Stratum B n=11 Eyes 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Event-free Survival of Eyes of Stratum B Patients	1.0 probability There is no event in the data, thus SE=0 and 95% CI is not available.	—	—	—	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: The criteria considered eyes of all stratum B patients with R-E I-III (11 eyes in 11 patients).

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.

Outcome measures

Measure	Stratum B n=11 Eyes 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Ocular Survival of Eyes of Stratum B Patients	1.0 probability There is no event in the data, thus SE=0 and 95% CI is not available.	—	—	—	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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.

Outcome measures

Measure	Stratum B n=26 Number of Eyes 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.	Stratum A-Advanced Disease n=9 Number of Eyes 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.	Stratum B-Early Disease n=16 Number of Eyes 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.	Stratum B-Advanced Disease n=35 Number of Eyes 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Event-free Survival of Eyes in Stratum A and Stratum B Patients Based on IC Classification	0.839 probability Interval 0.694 to 0.984	0.667 probability Interval 0.359 to 0.975	1.0 probability There is no event in the data, thus SE=0 and 95% CI is not available.	0.743 probability Interval 0.598 to 0.888	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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.

Outcome measures

Measure	Stratum B n=26 Eyes 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.	Stratum A-Advanced Disease n=9 Eyes 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.	Stratum B-Early Disease n=16 Eyes 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.	Stratum B-Advanced Disease n=35 Eyes 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Ocular Survival of Eyes in Stratum A and Stratum B Patients Based on IC Classification	0.839 probability Interval 0.694 to 0.984	0.667 probability Interval 0.359 to 0.975	1.0 probability There is no event in the data, thus SE=0 and 95% CI is not available.	0.743 probability Interval 0.598 to 0.888	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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

Outcome measures

Measure	Stratum B n=29 Eyes 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.	Stratum A-Advanced Disease n=6 Eyes 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.	Stratum B-Early Disease n=19 Eyes 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.	Stratum B-Advanced Disease n=32 Eyes 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Event-free Survival Per Eye in Stratum A and Stratum B Patients Based on AJCC Classification	0.857 probability Interval 0.726 to 0.987	0.500 probability Interval 0.1 to 0.9	1.0 probability There is no event in the data, thus SE=0 and 95% CI is not available.	0.719 probability Interval 0.563 to 0.875	—	—

SECONDARY outcome

Timeframe: From date on-study to an event or last follow-up

Population: 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.

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

Outcome measures

Measure	Stratum B n=29 Number of Eyes 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.	Stratum A-Advanced Disease n=6 Number of Eyes 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.	Stratum B-Early Disease n=19 Number of Eyes 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.	Stratum B-Advanced Disease n=32 Number of Eyes 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Ocular Survival Per Eye in Stratum A and Stratum B Patients Based on AJCC Classification	0.857 probability Interval 0.726 to 0.987	0.500 probability Interval 0.1 to 0.9	1.0 probability There is no event in the data, thus SE=0 and 95% CI is not available.	0.719 probability Interval 0.563 to 0.875	—	—

SECONDARY outcome

Timeframe: Baseline (at study entry) and at ages 6 months, 1 year, 2 years, 3 years and 5 years

Population: 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.

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.

Outcome measures

Measure	Stratum B n=25 Participants 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.	Stratum A-Advanced Disease n=30 Participants 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.	Stratum B-Early Disease n=50 Participants 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.	Stratum B-Advanced Disease n=64 Participants 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.	3 Years n=67 Participants Participant age was 3 years ±3 months.	5 Years n=60 Participants Participant age was 5 years ±3 months.
Change in Cognitive Functioning	91.61 units on a scale Standard Deviation 16.93	90.96 units on a scale Standard Deviation 17.66	95.91 units on a scale Standard Deviation 17.98	88.40 units on a scale Standard Deviation 18.72	82.12 units on a scale Standard Deviation 19.75	86.00 units on a scale Standard Deviation 15.31

SECONDARY outcome

Timeframe: Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years

Population: 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.

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.

Outcome measures

Measure	Stratum B n=25 Participants 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.	Stratum A-Advanced Disease n=30 Participants 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.	Stratum B-Early Disease n=50 Participants 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.	Stratum B-Advanced Disease n=64 Participants 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.	3 Years n=67 Participants Participant age was 3 years ±3 months.	5 Years n=60 Participants Participant age was 5 years ±3 months.
Change in Relevant Daily Living Skills	97.48 units on a scale Standard Deviation 13.35	104.73 units on a scale Standard Deviation 11.04	106.06 units on a scale Standard Deviation 10.38	94.22 units on a scale Standard Deviation 15.44	96.45 units on a scale Standard Deviation 19.12	93.03 units on a scale Standard Deviation 17.45

SECONDARY outcome

Timeframe: Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years

Population: 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.

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.

Outcome measures

Measure	Stratum B n=25 Participants 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.	Stratum A-Advanced Disease n=30 Participants 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.	Stratum B-Early Disease n=50 Participants 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.	Stratum B-Advanced Disease n=64 Participants 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.	3 Years n=67 Participants Participant age was 3 years ±3 months.	5 Years n=60 Participants Participant age was 5 years ±3 months.
Change in Parent Report of Social-Emotional Factors	40 units on a scale Standard Deviation 31.12	19.42 units on a scale Standard Deviation 14.02	26.28 units on a scale Standard Deviation 13.93	29.67 units on a scale Standard Deviation 20.83	40.61 units on a scale Standard Deviation 37.76	39.93 units on a scale Standard Deviation 34.03

SECONDARY outcome

Timeframe: Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years

Population: 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.

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).

Outcome measures

Measure	Stratum B n=25 Participants 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.	Stratum A-Advanced Disease n=30 Participants 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.	Stratum B-Early Disease n=50 Participants 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.	Stratum B-Advanced Disease n=64 Participants 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.	3 Years n=67 Participants Participant age was 3 years ±3 months.	5 Years n=60 Participants Participant age was 5 years ±3 months.
Change in Parenting Stress Index (PSI) Parent Domain	109.38 units on a scale Standard Deviation 30.33	101.56 units on a scale Standard Deviation 22.90	105.84 units on a scale Standard Deviation 22.90	105.84 units on a scale Standard Deviation 27.56	105.92 units on a scale Standard Deviation 24.96	102.74 units on a scale Standard Deviation 24.97
Change in Parenting Stress Index (PSI) Overall Total Stress	207.25 units on a scale Standard Deviation 47.07	194.84 units on a scale Standard Deviation 23.36	200.51 units on a scale Standard Deviation 35.98	198.61 units on a scale Standard Deviation 38.52	200.23 units on a scale Standard Deviation 40.21	194.68 units on a scale Standard Deviation 39.84
Change in Parenting Stress Index (PSI) Child Domain	96.76 units on a scale Standard Deviation 20.91	93.08 units on a scale Standard Deviation 15.98	93.27 units on a scale Standard Deviation 14.86	92.77 units on a scale Standard Deviation 16.23	94.60 units on a scale Standard Deviation 18.69	92.49 units on a scale Standard Deviation 19.02

SECONDARY outcome

Timeframe: Patients were assessed at 5 years of age

Population: All patients were included, regardless of treatment strata.

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.

Outcome measures

Measure	Stratum B n=60 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Assessment of School Readiness	8.96 units on a scale Standard Deviation 3.10	—	—	—	—	—

SECONDARY outcome

Timeframe: At diagnosis through 6 years after last patient enrollment

Population: A patient may be included in more than one category due to having more than one cyst.

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.

Outcome measures

Measure	Stratum B n=43 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Number of Participants With Development of Pineal Cysts Developed new solitary cyst(s)	12 Participants	—	—	—	—	—
Number of Participants With Development of Pineal Cysts Developed multiple new cysts	15 Participants	—	—	—	—	—
Number of Participants With Development of Pineal Cysts Growth of pineal cyst	5 Participants	—	—	—	—	—
Number of Participants With Development of Pineal Cysts Decrease in size (resolution) of pineal cyst	1 Participants	—	—	—	—	—
Number of Participants With Development of Pineal Cysts No change	11 Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: From diagnosis through 6 years after last patient enrollment

Population: 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).

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.

Outcome measures

Measure	Stratum B n=43 Participants 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.	Stratum A-Advanced Disease 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Number of Participants With Change in Size of Pineal Gland Prominent or mildly enlarged pineal glands	12 Participants	—	—	—	—	—
Number of Participants With Change in Size of Pineal Gland Pineal growth over time	8 Participants	—	—	—	—	—
Number of Participants With Change in Size of Pineal Gland No change in pineal gland size	23 Participants	—	—	—	—	—

SECONDARY outcome

Timeframe: From Diagnosis through 5 years after completion of therapy

Population: A total of 14 patients had "Incomplete data" and were not included in the analysis.

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.

Outcome measures

Measure	Stratum B n=13 Participants 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.	Stratum A-Advanced Disease n=12 Participants 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.	Stratum B-Early Disease n=4 Participants 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Change in Distortion Product Otoacoustic Emissions (DPOAEs) 1000 Hz	17.7 dB Standard Deviation 16.6	5.5 dB Standard Deviation 2.5	4.5 dB Standard Deviation 1.7	—	—	—
Change in Distortion Product Otoacoustic Emissions (DPOAEs) 1400 Hz	16.6 dB Standard Deviation 3.6	9.4 dB Standard Deviation 2.5	8.2 dB Standard Deviation 2.8	—	—	—
Change in Distortion Product Otoacoustic Emissions (DPOAEs) 2000 Hz	15.1 dB Standard Deviation 1.7	13.0 dB Standard Deviation 1.8	11.0 dB Standard Deviation 1.4	—	—	—
Change in Distortion Product Otoacoustic Emissions (DPOAEs) 2800 Hz	11.6 dB Standard Deviation 2.0	12.2 dB Standard Deviation 1.9	8.4 dB Standard Deviation 3.2	—	—	—
Change in Distortion Product Otoacoustic Emissions (DPOAEs) 4000 Hz	15.3 dB Standard Deviation 4.8	11.3 dB Standard Deviation 1.9	3.4 dB Standard Deviation 6.6	—	—	—
Change in Distortion Product Otoacoustic Emissions (DPOAEs) 6000 Hz	13.3 dB Standard Deviation 2.0	12.9 dB Standard Deviation 2.2	5.7 dB Standard Deviation 8.6	—	—	—
Change in Distortion Product Otoacoustic Emissions (DPOAEs) 8000 Hz	5.0 dB Standard Deviation 1.9	-2.0 dB Standard Deviation 3.2	-9.9 dB Standard Deviation 6.0	—	—	—

SECONDARY outcome

Timeframe: At diagnosis through 6 years after last patient enrollment

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.

Outcome measures

Measure	Stratum B n=33 Number of exams 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.	Stratum A-Advanced Disease n=152 Number of exams 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.	Stratum B-Early Disease n=122 Number of exams 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Mean Primary Visual Cortex Function: Cluster Size	2372 number activated voxels (negative BOLD) Standard Deviation 2640	1080 number activated voxels (negative BOLD) Standard Deviation 2916	2105 number activated voxels (negative BOLD) Standard Deviation 2476	—	—	—

SECONDARY outcome

Timeframe: At diagnosis through 6 years after last patient enrollment

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.

Outcome measures

Measure	Stratum B n=33 Number of exams 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.	Stratum A-Advanced Disease n=152 Number of exams 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.	Stratum B-Early Disease n=122 Number of exams 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Mean Primary Visual Cortex Function: Maximum T-value	7.9 Maximum t-statistic (negative BOLD) Standard Deviation 6.9	6.2 Maximum t-statistic (negative BOLD) Standard Deviation 3.9	8.8 Maximum t-statistic (negative BOLD) Standard Deviation 4.7	—	—	—

POST_HOC outcome

Timeframe: At diagnosis, and at 3, 6, 9, and 12 months from diagnosis

Population: 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.

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.

Outcome measures

Measure	Stratum B n=16 Participants 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.	Stratum A-Advanced Disease n=6 Participants 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.	Stratum B-Early Disease 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.	Stratum B-Advanced Disease 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.	3 Years Participant age was 3 years ±3 months.	5 Years Participant age was 5 years ±3 months.
Number of Patients Recommended for and Utilizing Rehabilitation Services Received rehabilitation services	12 participants	1 participants	—	—	—	—
Number of Patients Recommended for and Utilizing Rehabilitation Services Did not receive rehabilitation services	4 participants	5 participants	—	—	—	—

Adverse Events

Stratum A

Serious events: 1 serious events

Other events: 23 other events

Deaths: 0 deaths

Stratum B

Serious events: 9 serious events

Other events: 27 other events

Deaths: 0 deaths

Stratum C

Serious events: 1 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Measure	Stratum A n=23 participants at risk 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.	Stratum B n=27 participants at risk 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.	Stratum C n=55 participants at risk 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.
Immune system disorders Allergic reaction/hypersensitivity (including drug fever)	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	29.6% 8/27 • Number of events 9 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Gastrointestinal disorders Anorexia	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	7.4% 2/27 • Number of events 2 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Gastrointestinal disorders Colitis	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	3.7% 1/27 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Gastrointestinal disorders Diarrhea	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	7.4% 2/27 • Number of events 2 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Gastrointestinal disorders Gastrointestinal - Other (Specify, __)	4.3% 1/23 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/27 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Gastrointestinal disorders Vomiting	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	3.7% 1/27 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Ear and labyrinth disorders Hearing: patients with/without baseline audiogram and enrolled in a monitoring program	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/27 • Adverse events have been collected from study activation (February 2005) through June, 2011.	1.8% 1/55 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Infections and infestations Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	3.7% 1/27 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Infections and infestations Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, colon	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	7.4% 2/27 • Number of events 2 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Infections and infestations Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, cellulitis	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	3.7% 1/27 • Number of events 2 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Infections and infestations Neutrophils/granulocytes (ANC/AGC)	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	14.8% 4/27 • Number of events 4 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Respiratory, thoracic and mediastinal disorders Pulmonary/Upper Respiratory - Other (Specify, __)	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	3.7% 1/27 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.

Other adverse events

Measure	Stratum A n=23 participants at risk 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.	Stratum B n=27 participants at risk 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.	Stratum C n=55 participants at risk 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.
Blood and lymphatic system disorders Neutrophils/granulocytes (ANC/AGC)	100.0% 23/23 • Number of events 161 • Adverse events have been collected from study activation (February 2005) through June, 2011.	96.3% 26/27 • Number of events 271 • Adverse events have been collected from study activation (February 2005) through June, 2011.	32.7% 18/55 • Number of events 69 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Blood and lymphatic system disorders Platelets	39.1% 9/23 • Number of events 22 • Adverse events have been collected from study activation (February 2005) through June, 2011.	92.6% 25/27 • Number of events 86 • Adverse events have been collected from study activation (February 2005) through June, 2011.	18.2% 10/55 • Number of events 32 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Blood and lymphatic system disorders Hemoglobin	43.5% 10/23 • Number of events 22 • Adverse events have been collected from study activation (February 2005) through June, 2011.	85.2% 23/27 • Number of events 72 • Adverse events have been collected from study activation (February 2005) through June, 2011.	25.5% 14/55 • Number of events 34 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Blood and lymphatic system disorders Leukocytes	13.0% 3/23 • Number of events 5 • Adverse events have been collected from study activation (February 2005) through June, 2011.	74.1% 20/27 • Number of events 36 • Adverse events have been collected from study activation (February 2005) through June, 2011.	25.5% 14/55 • Number of events 23 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Infections and infestations Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented)	8.7% 2/23 • Number of events 3 • Adverse events have been collected from study activation (February 2005) through June, 2011.	63.0% 17/27 • Number of events 30 • Adverse events have been collected from study activation (February 2005) through June, 2011.	5.5% 3/55 • Number of events 3 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Infections and infestations Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, upper airway	8.7% 2/23 • Number of events 2 • Adverse events have been collected from study activation (February 2005) through June, 2011.	14.8% 4/27 • Number of events 4 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Infections and infestations Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, cellulitis	4.3% 1/23 • Number of events 2 • Adverse events have been collected from study activation (February 2005) through June, 2011.	14.8% 4/27 • Number of events 4 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Infections and infestations Infection(documented clinically or microbiologically with Grade 3 or 4 neutrophils,catheter-related	8.7% 2/23 • Number of events 2 • Adverse events have been collected from study activation (February 2005) through June, 2011.	11.1% 3/27 • Number of events 3 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Infections and infestations Infection with normal ANC or Grade 1 or 2 neutrophils, Catheter-related	8.7% 2/23 • Number of events 2 • Adverse events have been collected from study activation (February 2005) through June, 2011.	11.1% 3/27 • Number of events 3 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Infections and infestations Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	29.6% 8/27 • Number of events 8 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Gastrointestinal disorders Anorexia	4.3% 1/23 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.	22.2% 6/27 • Number of events 9 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Gastrointestinal disorders Dehydration	13.0% 3/23 • Number of events 4 • Adverse events have been collected from study activation (February 2005) through June, 2011.	18.5% 5/27 • Number of events 5 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Gastrointestinal disorders Diarrhea	4.3% 1/23 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.	25.9% 7/27 • Number of events 10 • Adverse events have been collected from study activation (February 2005) through June, 2011.	1.8% 1/55 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Gastrointestinal disorders Mucositis/stomatitis (clinical exam), Oral cavity	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	7.4% 2/27 • Number of events 2 • Adverse events have been collected from study activation (February 2005) through June, 2011.	1.8% 1/55 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Gastrointestinal disorders Vomiting	13.0% 3/23 • Number of events 5 • Adverse events have been collected from study activation (February 2005) through June, 2011.	7.4% 2/27 • Number of events 2 • Adverse events have been collected from study activation (February 2005) through June, 2011.	1.8% 1/55 • Number of events 3 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Skin and subcutaneous tissue disorders Rash/desquamation	0.00% 0/23 • Adverse events have been collected from study activation (February 2005) through June, 2011.	18.5% 5/27 • Number of events 8 • Adverse events have been collected from study activation (February 2005) through June, 2011.	0.00% 0/55 • Adverse events have been collected from study activation (February 2005) through June, 2011.
Metabolism and nutrition disorders Potassium, serum-low (hypokalemia)	4.3% 1/23 • Number of events 1 • Adverse events have been collected from study activation (February 2005) through June, 2011.	11.1% 3/27 • Number of events 3 • Adverse events have been collected from study activation (February 2005) through June, 2011.	3.6% 2/55 • Number of events 3 • Adverse events have been collected from study activation (February 2005) through June, 2011.

Additional Information

Ibrahim Qaddoumi MD

St. Jude Children's Research Hospital

Phone: 1-866-278-5833

Email: info@stjude.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place