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

Sponsor

St. Jude Children's Research Hospital (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT00186888

Collaborator

National Cancer Institute (NCI) (NIH)

107

Enrollment

Location

Arms

224.8

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Retinoblastoma is a childhood cancer which affects the retina of the eye. The retina is the light sensitive layer of tissue that lines the back of the eyeball; sends visual messages through the optic nerve to the brain. When only one eye is affected, this is known as unilateral retinoblastoma and when both eyes are affected, it is called bilateral retinoblastoma. Treatment for retinoblastoma is individualized for each patient and is based on the form and the stage of the disease (inside the eye or has moved outside). The main goal is always to cure the cancer, and save the life of the child. Treatments are also designed with the hope of saving the vision, while completely destroying the tumor. Therapies may involve surgery, chemotherapy, radiation, and other treatments called focal treatments. Focal treatments may be laser therapy, freezing, or heat treatments meant to shrink and kill the tumor.

In this study, researchers want to investigate how different participants respond to different therapies that are individualized specifically for them. Participants will be divided into three main groups, depending on whether the disease is unilateral or bilateral, and the stage of the disease. One of the main objectives of the study is to investigate how advanced tumors in children with bilateral disease respond to a new combination of chemotherapy with topotecan and vincristine, with G-CSF support. In order to improve results, some children with very advanced disease may receive carboplatin chemotherapy given around the eye at the same time that they receive topotecan by vein. Also, because children with retinoblastoma are diagnosed so early in life and the vision may be significantly impaired, this study will investigate how children develop and how the brain adjusts and compensates for the visual deficits. Finally, this study also investigates the biology of retinoblastoma, in order to understand better how this cancer develops.

Condition or Disease	Intervention/Treatment	Phase
Retinoblastoma Retinal Neoplasm	Procedure: Enucleation Drug: Vincristine, Carboplatin Procedure: Focal Therapies Radiation: External Beam Radiation Drug: Vincristine and Topotecan Drug: Vincristine + Carboplatin + Etoposide Drug: vincristine, cyclophosphamide, and doxorubicin Drug: Vincristine, Carboplatin and Etoposide Procedure: Periocular carboplatin Other: G-CSF	Phase 3

Detailed Description

This study will determine the following:

PRIMARY OBJECTIVE:

To estimate the ocular survival and event-free 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.

SECONDARY OBJECTIVES:

To estimate the ocular survival of eye and event-free 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.
To estimate the ocular survival and 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.
To estimate the ocular survival and event free survival of 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.
To estimate the ocular survival and event-free survival of patients with early stage intraocular retinoblastoma (R-E I-III) with vincristine and carboplatin with intensive focal treatments.
To estimate the ocular survival of eye and event-free survival of eye of patients with early stage intraocular retinoblastoma (R-E I-III) with vincristine and carboplatin with intensive focal treatments.
To estimate the response rate of early stage eyes (R-E I-III) in patients with contralateral advanced disease treated with vincristine and topotecan.
To estimate the ocular survival and event-free survival of early stage eyes (R-E I-III) of patients with contralateral advanced disease treated with vincristine and topotecan.
To describe the outcome of intraocular retinoblastoma with respect to the new International Classification for Intraocular Retinoblastoma and the AJCC.
To describe primary visual cortex function in patients with unilateral and bilateral retinoblastoma.
To describe the cognitive, adaptive, and social/emotional development of children with retinoblastoma.
To describe changes in the pineal gland during treatment in patients with bilateral retinoblastoma.
To assess the relation between CYP3A4/5 genotype and the pharmacokinetics and pharmacodynamics of topotecan.
To assess the relation between ABCG2 genotype and the pharmacokinetics and pharmacodynamics of topotecan.
To determine if carboplatin can produce changes in cochlear function that are detectable with measurement of otoacoustic emissions.
To evaluate the need for and feasibility of starting early intervention support during the first year after the diagnosis of retinoblastoma.

EXPLORATORY OBJECTIVES:

To provide insight into molecular pathogenesis of retinoblastoma.
To describe the incidence and type of germline mutations of the RB gene in patients with retinoblastoma.

Study Design

Study Type:

Interventional

Actual Enrollment :

107 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Protocol for the Study and Treatment of Patients With Intraocular Retinoblastoma

Actual Study Start Date :

Apr 7, 2005

Actual Primary Completion Date :

Nov 1, 2013

Anticipated Study Completion Date :

Jan 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Other: Stratum A Patients with early bilateral or unilateral, or patients with bilateral that have already had the advanced eye enucleated. Treatment included vincristine and carboplatin for 8 courses, given at 3-4 week intervals. Focal therapies any time after second course can include cryotherapy, laser photocoagulation, thermotherapy, and plaque radiotherapy	Procedure: Enucleation Enucleation (possibly associated with all treatment strata/arms. For Stratum A, patients with bilateral disease will have surgery to remove the advanced eye before chemotherapy, or patients that have disease progression after chemotherapy may have surgery to remove the affected eye. For Stratum B, Surgical removal of the affected eye may be required in cases of disease progression For Stratum C, first intervention is removal of the affected eye. Drug: Vincristine, Carboplatin (Stratum A subjects receive 8 courses every 3-4 weeks, Stratum B subjects receive this combination for Courses 3, 4, 6, 7, 9, and 10 after the window, if they respond to window therapy) Vincristine dosage< 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1. Other Names: Oncovin + Paraplatin Procedure: Focal Therapies Method will be at the discretion of the treating team, used after second course of chemotherapy. Cryotherapy- freezing of affected tissue, Laser photocoagulation- using lasers to destroy affected tissue, Thermotherapy and thermochemotherapy- using heat or heat/chemotherapy combination to destroy diseased tissue, and Episcleral plaque brachytherapy- radiation insertions in the diseased area to destroy affected tissue. Radiation: External Beam Radiation 44-46 Gy administered using standard practices , limiting dose to normal tissues to subjects with recurrent or progressive disease not considered controllable with focal treatments, Stratum B subjects with suspected active disease after completing therapy, or patients considered to have high-risk disease. Other: G-CSF G-CSF (5 mcg/kg/day), will be administered starting 24-36 hours after the completion of each course of chemotherapy, for 7 to 10 days, until ANC is > 2,000/mL in one occasion after the expected nadir. Other Names: Filgrastim Neupogen
Other: Stratum B Patients with bilateral disease (at least one advanced stage eye), candidate for conservative management. Treatment included window treatment with vincristine and topotecan, Followed by 3 more courses of vincristine-topotecan if they had a response to the window+ 6 courses of vincristine and carboplatin. If they do not respond to the window, they receive 6 courses of vincristine, carboplatin, and etoposide. Periocular carboplatin is also given three times, depending on whether they respond to window. External Beam Radiation 44-46 Gy administered using standard practices.	Procedure: Enucleation Enucleation (possibly associated with all treatment strata/arms. For Stratum A, patients with bilateral disease will have surgery to remove the advanced eye before chemotherapy, or patients that have disease progression after chemotherapy may have surgery to remove the affected eye. For Stratum B, Surgical removal of the affected eye may be required in cases of disease progression For Stratum C, first intervention is removal of the affected eye. Drug: Vincristine, Carboplatin (Stratum A subjects receive 8 courses every 3-4 weeks, Stratum B subjects receive this combination for Courses 3, 4, 6, 7, 9, and 10 after the window, if they respond to window therapy) Vincristine dosage< 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1. Other Names: Oncovin + Paraplatin Procedure: Focal Therapies Method will be at the discretion of the treating team, used after second course of chemotherapy. Cryotherapy- freezing of affected tissue, Laser photocoagulation- using lasers to destroy affected tissue, Thermotherapy and thermochemotherapy- using heat or heat/chemotherapy combination to destroy diseased tissue, and Episcleral plaque brachytherapy- radiation insertions in the diseased area to destroy affected tissue. Radiation: External Beam Radiation 44-46 Gy administered using standard practices , limiting dose to normal tissues to subjects with recurrent or progressive disease not considered controllable with focal treatments, Stratum B subjects with suspected active disease after completing therapy, or patients considered to have high-risk disease. Drug: Vincristine and Topotecan (Stratum B subjects receive two up-front courses of vincristine and topotecan, given in 21-day intervals, then those who respond receive 3 additional courses (courses 5, 8, and 11) after the window. Dosages are the same for both window and subsequent courses: Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Topotecan: TSE of 140 ± 20 ng/mlhr, daily for 5 consecutive days, infused over 30 minutes. Other Names: Oncovin + Hycamtin Drug: Vincristine + Carboplatin + Etoposide* Stratum B patients that do not respond to window receive 6 courses of this combination. Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1 Etoposide, < 12 months of age: 3.3 mg/kg/d i.v. days 1 - 3, ≥ 12 months of age: 100 mg/m2/d i.v. days 1 - 3 Other Names: Oncovin + Paraplatin + VP-16 Procedure: Periocular carboplatin Periocular (subtenon) carboplatin 20 mg, one injection, in courses 5, 8, and 11 in patients responding to the VT window, and in courses 1, 3, and 6 of VCE in patients not responding to the VT window, when active vitreous disease is present. Carboplatin 20 mg will be diluted in 2 mL of NS or D5W and given by subtenon administration while the patient is under general anesthesia. Other Names: Paraplatin Other: G-CSF G-CSF (5 mcg/kg/day), will be administered starting 24-36 hours after the completion of each course of chemotherapy, for 7 to 10 days, until ANC is > 2,000/mL in one occasion after the expected nadir. Other Names: Filgrastim Neupogen
Other: Stratum C Patients with advanced unilateral advanced intraocular disease. First intervention is enucleation. If enucleated eye does not have disease outside the retina (low risk), no additional treatment is given. For patients whose enucleated eye shows tumor outside the retina (intermediate risk), they will receive 4 courses of vincristine, cyclophosphamide, and doxorubicin followed by G-CSF. For patients with high risk disease (involvement of the sclera, optic nerve at the level of the cut-end), treatment after enucleation is 6 courses of alternating chemotherapy with vincristine, carboplatin, etoposide (VCE) to alternate with vincristine, cyclophosphamide, and doxorubicin (VCD). High risk patients also receive external-beam radiation therapy.	Procedure: Enucleation Enucleation (possibly associated with all treatment strata/arms. For Stratum A, patients with bilateral disease will have surgery to remove the advanced eye before chemotherapy, or patients that have disease progression after chemotherapy may have surgery to remove the affected eye. For Stratum B, Surgical removal of the affected eye may be required in cases of disease progression For Stratum C, first intervention is removal of the affected eye. Radiation: External Beam Radiation 44-46 Gy administered using standard practices , limiting dose to normal tissues to subjects with recurrent or progressive disease not considered controllable with focal treatments, Stratum B subjects with suspected active disease after completing therapy, or patients considered to have high-risk disease. Drug: vincristine, cyclophosphamide, and doxorubicin (High risk Stratum C patients in courses 2, 4, and 6 after enucleation, intermediate risk stratum C patients for four consecutive courses after enucleation) Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Cyclophosphamide: < 12 months of age: 40 mg/kg i.v. day 1, ≥ 12 months of age: 1,200 mg/m2 i.v. day 1, MESNA 200 mg/m2 at 0, 3, 6, and 9 hours Doxorubicin < 12 months of age: 1.5 mg/kg i.v. day 1, ≥ 12 months of age: 45 mg/m2 i.v. day 1 Other Names: Onconvin and Cytoxan and Adriamycin Drug: Vincristine, Carboplatin and Etoposide High risk Stratum C patients in courses 1, 3, and 5 after enucleation: Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1 Etoposide, < 12 months of age: 3.3 mg/kg/d i.v. days 1 - 3, ≥ 12 months of age: 100 mg/m2/d i.v. days 1 - 3 Other Names: Onconvin and Paraplatin and Vepesid Other: G-CSF G-CSF (5 mcg/kg/day), will be administered starting 24-36 hours after the completion of each course of chemotherapy, for 7 to 10 days, until ANC is > 2,000/mL in one occasion after the expected nadir. Other Names: Filgrastim Neupogen

Arm

Intervention/Treatment

Other: Stratum A

Patients with early bilateral or unilateral, or patients with bilateral that have already had the advanced eye enucleated. Treatment included vincristine and carboplatin for 8 courses, given at 3-4 week intervals. Focal therapies any time after second course can include cryotherapy, laser photocoagulation, thermotherapy, and plaque radiotherapy

Procedure: Enucleation

Enucleation (possibly associated with all treatment strata/arms. For Stratum A, patients with bilateral disease will have surgery to remove the advanced eye before chemotherapy, or patients that have disease progression after chemotherapy may have surgery to remove the affected eye. For Stratum B, Surgical removal of the affected eye may be required in cases of disease progression For Stratum C, first intervention is removal of the affected eye.

Drug: Vincristine, Carboplatin

(Stratum A subjects receive 8 courses every 3-4 weeks, Stratum B subjects receive this combination for Courses 3, 4, 6, 7, 9, and 10 after the window, if they respond to window therapy) Vincristine dosage< 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1.

Other Names:

Oncovin + Paraplatin

Procedure: Focal Therapies

Method will be at the discretion of the treating team, used after second course of chemotherapy. Cryotherapy- freezing of affected tissue, Laser photocoagulation- using lasers to destroy affected tissue, Thermotherapy and thermochemotherapy- using heat or heat/chemotherapy combination to destroy diseased tissue, and Episcleral plaque brachytherapy- radiation insertions in the diseased area to destroy affected tissue.

Radiation: External Beam Radiation

44-46 Gy administered using standard practices , limiting dose to normal tissues to subjects with recurrent or progressive disease not considered controllable with focal treatments, Stratum B subjects with suspected active disease after completing therapy, or patients considered to have high-risk disease.

Other: G-CSF

G-CSF (5 mcg/kg/day), will be administered starting 24-36 hours after the completion of each course of chemotherapy, for 7 to 10 days, until ANC is > 2,000/mL in one occasion after the expected nadir.

Other Names:

Filgrastim

Neupogen

Other: Stratum B

Patients with bilateral disease (at least one advanced stage eye), candidate for conservative management. Treatment included window treatment with vincristine and topotecan, Followed by 3 more courses of vincristine-topotecan if they had a response to the window+ 6 courses of vincristine and carboplatin. If they do not respond to the window, they receive 6 courses of vincristine, carboplatin, and etoposide. Periocular carboplatin is also given three times, depending on whether they respond to window. External Beam Radiation 44-46 Gy administered using standard practices.

Procedure: Enucleation

Drug: Vincristine, Carboplatin

Other Names:

Oncovin + Paraplatin

Procedure: Focal Therapies

Radiation: External Beam Radiation

Drug: Vincristine and Topotecan

(Stratum B subjects receive two up-front courses of vincristine and topotecan, given in 21-day intervals, then those who respond receive 3 additional courses (courses 5, 8, and 11) after the window. Dosages are the same for both window and subsequent courses: Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Topotecan: TSE of 140 ± 20 ng/ml*hr, daily for 5 consecutive days, infused over 30 minutes.

Other Names:

Oncovin + Hycamtin

Drug: Vincristine + Carboplatin + Etoposide

Stratum B patients that do not respond to window receive 6 courses of this combination. Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1 Etoposide, < 12 months of age: 3.3 mg/kg/d i.v. days 1 - 3, ≥ 12 months of age: 100 mg/m2/d i.v. days 1 - 3

Other Names:

Oncovin + Paraplatin + VP-16

Procedure: Periocular carboplatin

Periocular (subtenon) carboplatin 20 mg, one injection, in courses 5, 8, and 11 in patients responding to the VT window, and in courses 1, 3, and 6 of VCE in patients not responding to the VT window, when active vitreous disease is present. Carboplatin 20 mg will be diluted in 2 mL of NS or D5W and given by subtenon administration while the patient is under general anesthesia.

Other Names:

Paraplatin

Other: G-CSF

Other Names:

Filgrastim

Neupogen

Other: Stratum C

Patients with advanced unilateral advanced intraocular disease. First intervention is enucleation. If enucleated eye does not have disease outside the retina (low risk), no additional treatment is given. For patients whose enucleated eye shows tumor outside the retina (intermediate risk), they will receive 4 courses of vincristine, cyclophosphamide, and doxorubicin followed by G-CSF. For patients with high risk disease (involvement of the sclera, optic nerve at the level of the cut-end), treatment after enucleation is 6 courses of alternating chemotherapy with vincristine, carboplatin, etoposide (VCE) to alternate with vincristine, cyclophosphamide, and doxorubicin (VCD). High risk patients also receive external-beam radiation therapy.

Procedure: Enucleation

Radiation: External Beam Radiation

Drug: vincristine, cyclophosphamide, and doxorubicin

(High risk Stratum C patients in courses 2, 4, and 6 after enucleation, intermediate risk stratum C patients for four consecutive courses after enucleation) Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Cyclophosphamide: < 12 months of age: 40 mg/kg i.v. day 1, ≥ 12 months of age: 1,200 mg/m2 i.v. day 1, MESNA 200 mg/m2 at 0, 3, 6, and 9 hours Doxorubicin < 12 months of age: 1.5 mg/kg i.v. day 1, ≥ 12 months of age: 45 mg/m2 i.v. day 1

Other Names:

Onconvin and Cytoxan and Adriamycin

Drug: Vincristine, Carboplatin and Etoposide

High risk Stratum C patients in courses 1, 3, and 5 after enucleation: Vincristine: < 12 months of age: 0.05 mg/kg i.v. day 1, ≥ 12 months of age: 1.5 mg/m2 i.v. day 1 (max. dose 2 mg) Carboplatin will be administered i.v. to achieve an AUC of 6.5 mg/ml/min, day 1 Etoposide, < 12 months of age: 3.3 mg/kg/d i.v. days 1 - 3, ≥ 12 months of age: 100 mg/m2/d i.v. days 1 - 3

Other Names:

Onconvin and Paraplatin and Vepesid

Other: G-CSF

Other Names:

Filgrastim

Neupogen

Outcome Measures

Primary Outcome Measures

Stratum B Response to Window Therapy [Six weeks post window therapy]
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.

Secondary Outcome Measures

Stratum B Response Rate of Early Stage Eyes to Window Therapy [Six weeks post window therapy.]
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
Relationship Between Topotecan Clearance (CL) and CYP3A4/5 Genotype in Stratum B Participants. [Courses 1, 2, 5, and 8]
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.
Relationship Between Topotecan Clearance (CL) and ABCG2/B1 Genotype in Stratum B Participants. [Courses 1, 2, 5, and 8]
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.
Event-free Survival of Stratum B Patients Responding to Window Treatment [From date on-study to an event or last follow-up]
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.
Ocular Survival of Stratum B Patients Responding to Window Treatment [From date on-study to an event or last follow-up]
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
Event-free Survival of Eyes in Stratum B Patients Responding to Window Treatment [From date on-study to an event or last follow-up]
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.
Ocular Survival of Eyes in Stratum B Patients Responding to Window Treatment [From date on-study to an event or last follow-up]
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.
Event-free Survival of Stratum B Patients Not Responding to Window Treatment [From date on-study to an event or last follow-up]
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.
Ocular Survival of Stratum B Patients Not Responding to Window Treatment [From date on-study to an event or last follow-up]
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.
Event-free Survival of Eyes in Stratum B Patients Not Responding to Window Treatment [From date on-study to an event or last follow-up]
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
Ocular Survival of Eyes in Stratum B Patients Not Responding to Window Treatment [From date on-study to an event or last follow-up]
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
Event-free Survival of Stratum A Patients [From date on-study to an event or last follow-up]
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.
Ocular Survival of Stratum A Patients [From date on-study to an event or last follow-up]
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.
Event-free Survival of Eyes of Stratum B Patients [From date on-study to an event or last follow-up]
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.
Ocular Survival of Eyes of Stratum B Patients [From date on-study to an event or last follow-up]
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.
Event-free Survival of Eyes in Stratum A and Stratum B Patients Based on IC Classification [From date on-study to an event or last follow-up]
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.
Ocular Survival of Eyes in Stratum A and Stratum B Patients Based on IC Classification [From date on-study to an event or last follow-up]
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.
Event-free Survival Per Eye in Stratum A and Stratum B Patients Based on AJCC Classification [From date on-study to an event or last follow-up]
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
Ocular Survival Per Eye in Stratum A and Stratum B Patients Based on AJCC Classification [From date on-study to an event or last follow-up]
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
Change in Cognitive Functioning [Baseline (at study entry) and at ages 6 months, 1 year, 2 years, 3 years and 5 years]
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.
Change in Relevant Daily Living Skills [Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years]
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.
Change in Parent Report of Social-Emotional Factors [Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years]
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.
Change in Parenting Stress Index (PSI) [Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years]
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).
Assessment of School Readiness [Patients were assessed at 5 years of age]
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.
Number of Participants With Development of Pineal Cysts [At diagnosis through 6 years after last patient enrollment]
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.
Number of Participants With Change in Size of Pineal Gland [From diagnosis through 6 years after last patient enrollment]
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.
Change in Distortion Product Otoacoustic Emissions (DPOAEs) [From Diagnosis through 5 years after completion of therapy]
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.
Mean Primary Visual Cortex Function: Cluster Size [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.
Mean Primary Visual Cortex Function: Maximum T-value [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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Must have newly diagnosed intraocular retinoblastoma, previously untreated. Patients previously diagnosed with unilateral retinoblastoma treated surgically (or with focal therapies), who develop asynchronous involvement of the contralateral eye, will be eligible for study.
Must have a life expectancy of at least 8 weeks.
Must have Performance Status (ECOG) of 0-2.
Patients must have an adequate liver function, as defined by bilirubin less than or equal to 3 x normal, and SGOT and SGPT less than or equal to 3x normal.
Patients must have adequate renal function as defined by serum creatinine less than or equal to 3x normal for age.
Legal guardians must sign an informed consent indicating that they are aware of this study, its possible benefits, and toxic side effects. Legal guardians will be given a copy of the consent form.

Exclusion Criteria:

Previously treated patients
Presence of metastatic disease or orbital involvement
Patients must not have an invasive infection at time of protocol entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105

Sponsors and Collaborators

St. Jude Children's Research Hospital
National Cancer Institute (NCI)

Investigators

Principal Investigator: Ibrahim Qaddoumi, M.D., St. Jude Children's Research Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.

Responsible Party:

St. Jude Children's Research Hospital

ClinicalTrials.gov Identifier:

NCT00186888

Other Study ID Numbers:

RET5
P01CA023099
NCI-2011-01186

First Posted:

Sep 16, 2005

Last Update Posted:

Jan 19, 2022

Last Verified:

Jan 1, 2022

Keywords provided by St. Jude Children's Research Hospital

Cancer of the Eye

Eye Enucleation

Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details	107 patients were recruited between February, 2005 and June, 2010 (stratum B) and between February, 2005 and November, 2010 (strata A & C).The primary objective was designed only for stratum B patients who had advanced bilateral retinoblastoma and received the investigational window therapy.
Pre-assignment Detail	107 patients were enrolled on the study. Two patients were excluded as they were deemed to be ineligible after study enrollment. One patient was found to have retinal dysplasia rather than retinoblastoma and the other patient had retinoblastoma but did not fit into any of the defined treatment strata for this study.

Arm/Group Title	Stratum A	Stratum B	Stratum C
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.	Advanced Unilateral Retinoblastoma. Research participants with unilateral (unifocal or multifocal) advanced (Reese-Ellsworth group IV or V) intraocular disease will undergo upfront enucleation. Adjuvant therapy was also indicated in certain cases.
Period Title: Overall Study
STARTED	23	27	55
Window Therapy	0	27	0
COMPLETED	19	24	55
NOT COMPLETED	4	3	0

Baseline Characteristics

Arm/Group Title	Stratum A	Stratum B	Stratum C	Total
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.	Advanced Unilateral Retinoblastoma. Research participants with unilateral (unifocal or multifocal) advanced (Reese-Ellsworth group IV or V) intraocular disease will undergo upfront enucleation. Adjuvant therapy was also indicated in certain cases.	Total of all reporting groups
Overall Participants	23	27	55	105
Age (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	5.7 (3.6)	8.5 (4.6)	29.6 (22.1)	18.9 (19.7)
Sex: Female, Male (Count of Participants)
Female	11 47.8%	13 48.1%	28 50.9%	52 49.5%
Male	12 52.2%	14 51.9%	27 49.1%	53 50.5%
Tumor Laterality (Count of Participants)
Bilateral Tumor	3 13%	24 88.9%	0 0%	27 25.7%
Unilateral Tumor	9 39.1%	0 0%	41 74.5%	50 47.6%

Outcome Measures

1. Primary Outcome

Title	Stratum B Response to Window Therapy
Description	The primary outcome is to estimate the proportion of stratum B patients responding to 2 courses of window therapy consisting of vincristine and topotecan. Complete Response is the complete regression of all apparent tumor masses in the funduscopic examination and by MRI and ultrasound (US). Partial Response is defined as greater than 50% (but less than 100%) reduction of the tumor masses in the funduscopic examination and by US and MRI, without the appearance of any new lesions. The response must persist for at least 4 weeks. Stratum A and C did not receive window therapy.
Time Frame	Six weeks post window therapy

Outcome Measure Data

Analysis Population Description
The primary objective related to stratum B patients only, as these were the patients who were given window therapy consisting of 2 courses of vincristine and topotecan. Of the 27 stratum B patients enrolled, all were included in the analysis of the primary objective.

Arm/Group Title	Stratum B
Arm/Group Description	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Measure Participants	27
Partial response	24 104.3%
Progressive Disease or New Lesion	2 8.7%
Failure due to Toxicity	1 4.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum B
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Binomial Proportion
	Estimated Value	88.9
	Confidence Interval	(2-Sided) 95% 71.3 to 96.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Stratum B Response Rate of Early Stage Eyes to Window Therapy
Description	To estimate the proportion of early stage eyes defined as Reese-Ellsworth Group I, II, or III eyes, that responded to 2 courses of window therapy which consisted of vincristine and topotecan
Time Frame	Six weeks post window therapy.

Outcome Measure Data

Analysis Population Description
Among the 27 stratum B patients with 54 eyes with retinoblastoma, 12 eyes were early stage (Reese-Ellsworth group I, II, or III). The remaining 42 eyes were advanced stage and were not included in this analysis.

Arm/Group Title	Stratum B
Arm/Group Description	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Measure Participants	12
Partial response	11 47.8%
Progressive Disease / New lesion	0 0%
Failure due to Toxicity	1 4.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum B
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Binomial Proportion
	Estimated Value	91.7
	Confidence Interval	(2-Sided) 95% 65.1 to 99.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Relationship Between Topotecan Clearance (CL) and CYP3A4/5 Genotype in Stratum B Participants.
Description	Blood samples for pharmacokinetic studies were collected at 0 hour (pre-dose), 5 minutes, 1.5 and 2.5 hours after the end of topotecan dose on Course 1 Day 1, Course 2 Day 1, and if further studies were needed, Course 5 Day 1 and Course 8 Day 1. A blood sample for pharmacogenetic studies was collected during the course of therapy on protocol.
Time Frame	Courses 1, 2, 5, and 8

Outcome Measure Data

Analysis Population Description
Of the 107 participants enrolled in the overall study, analysis was performed for 19 participants who were enrolled on Stratum B AND who had results for both topotecan clearance and pharmacogenetic studies. Only wild-type was present in CYP3A5*6, therefore, statistical analysis was not done for these alleles.

Arm/Group Title	Stratum B
Arm/Group Description	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Measure Participants	19
Median (95% Confidence Interval) [Liters/hour/m^2]	18.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum B
	Comments	CYP3A4*1B: The null hypothesis is there is not a statistically significant difference between the genotype groups.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.452
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stratum B
	Comments	CYP3A5*3: The null hypothesis is there is not a statistically significant difference between the genotype groups.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.106
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Relationship Between Topotecan Clearance (CL) and ABCG2/B1 Genotype in Stratum B Participants.
Description	Blood samples for pharmacokinetic studies were collected at 0 hour (pre-dose), 5 minutes, 1.5 and 2.5 hours after the end of topotecan dose on Course 1 Day 1, Course 2 Day 1, and if further studies were needed, Course 5 Day 1 and Course 8 Day 1. A blood sample for pharmacogenetic studies was collected during the course of therapy on protocol.
Time Frame	Courses 1, 2, 5, and 8

Outcome Measure Data

Analysis Population Description
Of the 107 participants enrolled in the overall study, analysis was performed for 19 participants who were enrolled on Stratum B AND who had results for both topotecan clearance and pharmacogenetic studies. Only wild-type was present in BCRP 15994, therefore, statistical analysis was not done for these alleles.

Arm/Group Title	Stratum B
Arm/Group Description	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Measure Participants	19
Median (95% Confidence Interval) [Liters/hour/m^2]	18.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Stratum B
	Comments	BCRP 1143: The null hypothesis is there is not a statistically significant difference between the genotype groups.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.245
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Stratum B
	Comments	BCRP 15622: The null hypothesis is there is not a statistically significant difference between the genotype groups.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.297
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Stratum B
	Comments	BCRP Exon 2: The null hypothesis is there is not a statistically significant difference between the genotype groups.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.372
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Stratum B
	Comments	BCRP Exon 5: The null hypothesis is there is not a statistically significant difference between the genotype groups.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.844
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Stratum B
	Comments	Pgp Exon 21: The null hypothesis is there is not a statistically significant difference between the genotype groups.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.616
	Comments
	Method	ANOVA
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Stratum B
	Comments	Pgp Exon 26: The null hypothesis is there is not a statistically significant difference between the genotype groups.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments

Statistical Test of Hypothesis	p-Value	0.424
	Comments
	Method	ANOVA
	Comments

5. Secondary Outcome

Title	Event-free Survival of Stratum B Patients Responding to Window Treatment
Description	To estimate the 5-year event-free (EFS) survival of bilateral disease patients with advanced intraocular retinoblastoma in either eye (R-E IV-V) responding to the vincristine/topotecan window, with alternating cycles of vincristine and carboplatin with vincristine, topotecan, and periocular carboplatin, with intensive focal treatments. Event-free survival will be defined per patient as follows: for patients with one advanced stage eye, the time interval from date on study to date of first event (an event includes external beam radiation or enucleation) of advanced stage eyes, time to first event will be used for the analysis. Event-free survival will be estimated using the method of Kaplan and Meier.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
Of the total 27 eligible patients in stratum B, 3 patients were not responding to the window therapy; 1 withdrew the consent and was taken off the study, and 2 developed disease progression. Kaplan and Meier estimate of ocular survival was calculated for the remaining 24 patients.

Arm/Group Title	Stratum B
Arm/Group Description	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. Two patients (3 eyes) in stratum B received external beam radiation therapy (EBRT), and the same 2 patients later required enucleation of the treated eye, thus the failure (event number) and censoring status were not changed for the 2 patients.
Measure Participants	24
Number (95% Confidence Interval) [probability]	0.667

6. Secondary Outcome

Title	Ocular Survival of Stratum B Patients Responding to Window Treatment
Description	To estimate the 5-year ocular survival of bilateral disease patients with advanced intraocular retinoblastoma in either eye (R-E IV-V) responding to the vincristine/topotecan window, with alternating cycles of vincristine and carboplatin with vincristine, topotecan, and periocular carboplatin, with intensive focal treatments. Ocular survival will be defined per patient as follows: for patients with one advanced stage eye, the time interval from date on study to date of enucleation of advanced stage eye or date of last follow-up, for patients with two advanced stage eyes, the time to the first enucleation will be used for analysis. Ocular survival will be estimated using the method of Kaplan and Meier. Standard error is 5-year ocular survival
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
From the total of 27 eligible patients in stratum B, 3 patients were not responding to the window therapy; 1 withdrew the consent and was taken off the study, and 2 developed disease progression. Thus, the Kaplan and Meier estimate of ocular survival was calculated for the remaining 24 patients.

Arm/Group Title	Stratum B
Arm/Group Description	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Measure Participants	24
Number (95% Confidence Interval) [probability]	0.667

7. Secondary Outcome

Title	Event-free Survival of Eyes in Stratum B Patients Responding to Window Treatment
Description	To estimate the 5-year event-free survival (EFS) of eyes of bilateral disease patients with advanced intraocular retinoblastoma in either eye (R-E IV-V) responding to the vincristine/topotecan window, with alternating cycles of vincristine and carboplatin with vincristine, topotecan, and periocular carboplatin, with intensive focal treatments. Event-free survival of eye will be defined per eye as the time interval from date on study to date of first event (an event includes external beam radiation or enucleation) or to last follow-up date for eyes without events. Event-free survival of eye will be estimated using the method of Kaplan and Meier. Standard error is 5-year EFS.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
Of the 52 eyes (26 evaluable patients), 2 eyes (2 patients) were removed from analysis as they were not responsive to window therapy. In both cases, the contralateral eye was included in the analysis. One patient with upfront enucleation had only one eye for analysis. Eleven eyes were R-E Group I-III and were excluded. Total: 38 eyes for analysis.

Arm/Group Title	Stratum B
Arm/Group Description	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Measure Participants	25
Measure Eyes	38
Number (95% Confidence Interval) [probability]	0.763

8. Secondary Outcome

Title	Ocular Survival of Eyes in Stratum B Patients Responding to Window Treatment
Description	To estimate the 5-year ocular survival of eye of bilateral disease patients with advanced intraocular retinoblastoma in either eye (R-E IV-V) responding to the vincristine/topotecan window, with alternating cycles of vincristine and carboplatin with vincristine, topotecan, and periocular carboplatin, with intensive focal treatments. Ocular survival of eye will be defined per eye as the time interval from date on study to date of enucleation or date of last follow-up. Ocular survival of eye will be estimated using the method of Kaplan and Meier. Standard error is 5-year ocular survival.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
Of the 52 eyes (26 evaluable patients), 2 eyes (2 patients) were removed from analysis as they were not responsive to window therapy. In both cases, the contralateral eye was included in the analysis. One patient with upfront enucleation had only one eye for analysis. Eleven eyes were R-E Group I-III and were excluded. Total: 38 eyes for analysis.

Arm/Group Title	Stratum B
Arm/Group Description	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Measure Participants	25
Measure Eyes	38
Number (95% Confidence Interval) [probability]	0.763

9. Secondary Outcome

Title	Event-free Survival of Stratum B Patients Not Responding to Window Treatment
Description	To estimate the 5-year event free survival of patients with advanced intraocular retinoblastoma (R-E IV-V) not responding to the vincristine/topotecan window, with a combination of vincristine, carboplatin, etoposide, and periocular carboplatin, with intensive focal treatments.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
The study closed to enrollment early due to poor accrual, but it remains open to follow-up. Both patients who developed new lesions in one eye during window therapy had a good response in the contralateral eye, and they continued on protocol therapy with vincristine/topotecan. Therefore, no patients were treated with this combination therapy.

Arm/Group Title	Stratum B
Measure Participants	0

Arm/Group Title

Stratum B

Arm/Group Description

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

Measure Participants

10. Secondary Outcome

Title	Ocular Survival of Stratum B Patients Not Responding to Window Treatment
Description	To estimate the 5-year ocular survival of patients with advanced intraocular retinoblastoma (R-E IV-V) not responding to the vincristine/topotecan window, with a combination of vincristine, carboplatin, etoposide, and periocular carboplatin, with intensive focal treatments.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
The study closed to enrollment early due to poor accrual, but it remains open to follow-up. Both patients who developed new lesions in one eye during window therapy had a good response in the contralateral eye, and they continued on protocol therapy with vincristine/topotecan. Therefore, no patients were treated with this combination therapy.

Arm/Group Title	Stratum B
Measure Participants	0

Arm/Group Title

Stratum B

Arm/Group Description

Measure Participants

11. Secondary Outcome

Title	Event-free Survival of Eyes in Stratum B Patients Not Responding to Window Treatment
Description	To estimate the 5-year event free survival of the eye of patients with advanced intraocular retinoblastoma (R-E IV-V) not responding to the vincristine/topotecan window, with a combination of vincristine, carboplatin, etoposide, and periocular carboplatin, with intensive focal treatments
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
The study closed to enrollment early due to poor accrual, but it remains open to follow-up. Both patients who developed new lesions in one eye during window therapy had a good response in the contralateral eye, and they continued on protocol therapy with vincristine/topotecan. Therefore, no patients were treated with this combination therapy.

Arm/Group Title	Stratum B
Measure Participants	0

Arm/Group Title

Stratum B

Arm/Group Description

Measure Participants

12. Secondary Outcome

Title	Ocular Survival of Eyes in Stratum B Patients Not Responding to Window Treatment
Description	To estimate the 5-year ocular survival of the eye of patients with advanced intraocular retinoblastoma (R-E IV-V) not responding to the vincristine/topotecan window, with a combination of vincristine, carboplatin, etoposide, and periocular carboplatin, with intensive focal treatments
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
The study closed to enrollment early due to poor accrual, but it remains open to follow-up. Both patients who developed new lesions in one eye during window therapy had a good response in the contralateral eye, and they continued on protocol therapy with vincristine/topotecan. Therefore, no patients were treated with this combination therapy.

Arm/Group Title

Stratum B

Arm/Group Description

Measure Participants

13. Secondary Outcome

Title	Event-free Survival of Stratum A Patients
Description	To estimate the 5-year event-free survival of patients with early stage intraocular retinoblastoma (R-E I-III) with vincristine and carboplatin with intensive focal treatments. Event-free survival will be defined per patient as follows: for patients with one advanced stage eye, the time interval from date on study to date of first event (an event includes external beam radiation or enucleation) of advanced stage eyes, time to first event will be used for the analysis. Event-free survival will be estimated using the method of Kaplan and Meier.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

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

Arm/Group Title	Stratum A
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.
Measure Participants	23
Number (95% Confidence Interval) [probability]	0.688

14. Secondary Outcome

Title	Ocular Survival of Stratum A Patients
Description	To estimate the 5-year ocular survival of patients with early stage intraocular retinoblastoma (R-E I-III) with vincristine and carboplatin with intensive focal treatments. Ocular survival will be defined per patient as follows: for patients with one advanced stage eye, the time interval from date on study to date of enucleation of advanced stage eye or date of last follow-up, for patients with two advanced stage eyes, the time to the first enucleation will be used for analysis. Ocular survival will be estimated using the method of Kaplan and Meier.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

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

Arm/Group Title	Stratum A
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.
Measure Participants	23
Number (95% Confidence Interval) [probability]	0.688

15. Secondary Outcome

Title	Event-free Survival of Eyes of Stratum B Patients
Description	To estimate the 5-year event-free survival of early stage eyes (R-E I-III) of patients with contralateral advanced disease treated with vincristine and topotecan. Event-free survival of eye will be defined per eye as the time interval from date on study to date of first event (an event includes external beam radiation or enucleation) or to last follow-up date for eyes without events. Event-free survival of eye will be estimated using the method of Kaplan and Meier.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

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

Arm/Group Title	Stratum B
Arm/Group Description	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Measure Participants	11
Measure Eyes	11
Number (95% Confidence Interval) [probability]	1.0

16. Secondary Outcome

Title	Ocular Survival of Eyes of Stratum B Patients
Description	To estimate the 5-year ocular survival of early stage eyes (R-E I-III) of patients with contralateral advanced disease treated with vincristine and topotecan. Ocular survival will be defined per patient as follows: for patients with one advanced stage eye, the time interval from date on study to date of enucleation of advanced stage eye or date of last follow-up, for patients with two advanced stage eyes, the time to the first enucleation will be used for analysis. Ocular survival will be estimated using the method of Kaplan and Meier.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

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

Arm/Group Title	Stratum B
Arm/Group Description	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Measure Participants	11
Measure Eyes	11
Number (95% Confidence Interval) [probability]	1.0

17. Secondary Outcome

Title	Event-free Survival of Eyes in Stratum A and Stratum B Patients Based on IC Classification
Description	To describe the 5-year event-free survival of the eyes outcome of intraocular retinoblastoma with respect to the new International Classification (IC) for Intraocular Retinoblastoma and the AJCC. Patients were re-classified into 2 groups of early (IC groups A and B) and advanced (IC groups C, D, and E) retinoblastoma. Analysis was done at eye level since each eye in the same patient could be a different group. Patients from stratum A and B were analyzed separately. Three eyes (2 patients) in stratum B received external beam radiation therapy (EBRT) and were also coincident with enucleation surgery, so their event status was not changed. Although the 3 eyes had shorter EFS interval because EBRT occurred (less than 2 years) before the surgery, it did not change the 5-year survival probability.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
For the 23 stratum A patients, 35 eyes (12 bilateral patients, 11 unilateral patients) with IC grouping were analyzed. For 26 Stratum B patients, 1 eye with up-front surgery was excluded from analysis. 51 eyes with IC grouping were analyzed. Participants with bilateral disease may have one eye in each category.

Arm/Group Title	Stratum A-Early Disease	Stratum A-Advanced Disease	Stratum B-Early Disease	Stratum B-Advanced Disease
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. The patients were re-classified into 2 groups of early (IC Group=A and B) and advanced (IC Group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. The patients were re-classified into 2 groups of early (IC Group=A and B) and advanced (IC Group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. The patients were re-classified into 2 groups of early (IC Group=A and B) and advanced (IC Group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. The patients were re-classified into 2 groups of early (IC Group=A and B) and advanced (IC Group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.
Measure Participants	18	9	15	25
Measure Number of Eyes	26	9	16	35
Number (95% Confidence Interval) [probability]	0.839	0.667	1.0	0.743

18. Secondary Outcome

Title	Ocular Survival of Eyes in Stratum A and Stratum B Patients Based on IC Classification
Description	To describe the 5-year ocular survival of eyes outcome of intraocular retinoblastoma with respect to the new International Classification (IC) for Intraocular Retinoblastoma and the AJCC. Patients were re-classified into 2 groups of early (IC groups A and B) and advanced (IC groups C, D, and E) retinoblastoma. Analysis was done at eye level since each eye in the same patient could be a different group. Patients from stratum A and B were analyzed separately. Three eyes (2 patients) in stratum B received external beam radiation therapy (EBRT) and were also coincident with enucleation surgery, so their event status was not changed. Although the 3 eyes had shorter EFS interval because EBRT occurred (less than 2 years) before the surgery, it did not change the 5-year survival probability.
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
For the 23 stratum A patients, 35 eyes (12 bilateral patients, 11 unilateral patients) with IC grouping were analyzed.For 26 Stratum B patients, 1 eye with up-front surgery was excluded from analysis. 51 eyes with IC grouping were analyzed. Participants with bilateral disease may have one eye in each category.

Arm/Group Title	Stratum A-Early Disease	Stratum A-Advanced Disease	Stratum B-Early Disease	Stratum B-Advanced Disease
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. The patients were re-classified into 2 groups of early (IC group=A and B) and advanced (IC group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. The patients were re-classified into 2 groups of early (IC=A and B) and advanced (IC=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. The patients were re-classified into 2 groups of early (IC group=A and B) and advanced (IC group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. The patients were re-classified into 2 groups of early (IC group=A and B) and advanced (IC group=C, D, E) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.
Measure Participants	18	9	15	25
Measure Eyes	26	9	16	35
Number (95% Confidence Interval) [probability]	0.839	0.667	1.0	0.743

19. Secondary Outcome

Title	Event-free Survival Per Eye in Stratum A and Stratum B Patients Based on AJCC Classification
Description	To describe the 5-year event-free survival of eyes outcome of intraocular retinoblastoma with respect to the new classification of the American Joint Committee on Cancer (AJCC). For AJCC staging, the patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group. Patients from stratum A and B were analyzed separately
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
For the 23 stratum A patients, 35 eyes (12 bilateral patients, 11 unilateral patients) with IC grouping were analyzed. For 26 Stratum B patients, 1 eye with up-front surgery was excluded from analysis. Participants with bilateral disease may have one eye in each category.

Arm/Group Title	Stratum A-Early Disease	Stratum A-Advanced Disease	Stratum B-Early Disease	Stratum B-Advanced Disease
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.
Measure Participants	19	6	18	25
Measure Eyes	29	6	19	32
Number (95% Confidence Interval) [probability]	0.857	0.500	1.0	0.719

20. Secondary Outcome

Title	Ocular Survival Per Eye in Stratum A and Stratum B Patients Based on AJCC Classification
Description	To describe the 5-year ocular survival of eyes outcome of intraocular retinoblastoma with respect to the new classification of the American Joint Committee on Cancer (AJCC). For AJCC staging, the patients were classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma . The analysis was done at eye level since each eye in the same patient could be a different group. Patients from stratum A and B were analyzed separately
Time Frame	From date on-study to an event or last follow-up

Outcome Measure Data

Analysis Population Description
For the 23 stratum A patients, 35 eyes (12 bilateral patients, 11 unilateral patients) with IC grouping were analyzed. For 26 Stratum B patients, 1 eye with up-front surgery was excluded from analysis. Participants with bilateral disease may have one eye in each category.

Arm/Group Title	Stratum A-Early Disease	Stratum A-Advanced Disease	Stratum B-Early Disease	Stratum B-Advanced Disease
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A. The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan. The patients were re-classified into 2 groups of early (AJCC=1, 1a or 1b) and advanced (AJCC=2, 2a, 2b, 3, 3a, 3b) retinoblastoma. The analysis was done at eye level since each eye in the same patient could be a different group.
Measure Participants	19	6	18	25
Measure Number of Eyes	29	6	19	32
Number (95% Confidence Interval) [probability]	0.857	0.500	1.0	0.719

21. Secondary Outcome

Title	Change in Cognitive Functioning
Description	The Early Learning Composite was assessed with Mullen Scales of Early Learning, a measure of developmental functioning appropriate for use with children from birth through age 5. It is an examiner-administered instrument that uses toys, games, pictures, and other objects to elicit information about a child's language, fine and gross motor skills, and overall early learning capabilities. Raw scores are converted to an age-normed standard score (normative mean = 100, SD = 15) for the overall Early Learning Composite. This measure was given at all time points. Higher scores are indicative of better functioning, with scores from 85-115 in the average range.
Time Frame	Baseline (at study entry) and at ages 6 months, 1 year, 2 years, 3 years and 5 years

Outcome Measure Data

Analysis Population Description
Data was collected from 94 unique patients. All patients were included, regardless of treatment strata. If the patient age at study entry (baseline) was within the window of an identified time point, their information was included with that time point.

Arm/Group Title	Baseline	6 Months	1 Year	2 Years	3 Years	5 Years
Arm/Group Description	At study entry.	Participants at 6 months of age ±3 months.	Participant age was 1 year ±3 months.	Participant age was 2 years ±3 months.	Participant age was 3 years ±3 months.	Participant age was 5 years ±3 months.
Measure Participants	25	30	50	64	67	60
Mean (Standard Deviation) [units on a scale]	91.61 (16.93)	90.96 (17.66)	95.91 (17.98)	88.40 (18.72)	82.12 (19.75)	86.00 (15.31)

22. Secondary Outcome

Title	Change in Relevant Daily Living Skills
Description	The Adaptive Behavior composite was measured using the Vineland Scales of Adaptive Behavior (VABS) which is an examiner-administered semi-structured interview that assesses adaptive functioning from birth through adulthood. Subscales including motor skills, communication, socialization, and daily living skills combine into an overall adaptive behavior composite which is an age-normed standard score (normative mean = 100, SD = 15). This measure was given at all time points. Higher scores are indicative of better functioning, with scores from 85-115 in the average range.
Time Frame	Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years

Outcome Measure Data

Analysis Population Description
Data was collected from 94 unique patients. All patients were included, regardless of treatment strata. If the patient age at study entry (baseline) was within the window of an identified time point, their information was included with that time point.

Arm/Group Title	Baseline	6 Months	1 Year	2 Years	3 Years	5 Years
Arm/Group Description	At study entry.	Participants at 6 months of age ±3 months.	Participant age was 1 year ±3 months.	Participant age was 2 years ±3 months.	Participant age was 3 years ±3 months.	Participant age was 5 years ±3 months.
Measure Participants	25	30	50	64	67	60
Mean (Standard Deviation) [units on a scale]	97.48 (13.35)	104.73 (11.04)	106.06 (10.38)	94.22 (15.44)	96.45 (19.12)	93.03 (17.45)

23. Secondary Outcome

Title	Change in Parent Report of Social-Emotional Factors
Description	This outcome was measured using the Ages and Stages Questionnaire which is a parent-completed measure of a child's social-emotional functioning. Raw scores are calculated and compared to cut-off points by age (6 months = 45; 1 year = 48; 2 years = 50; 3 years = 59; 5 years =70). Higher scores are indicative of more problems with scores above the cut-off indicating significant concerns warranting additional follow-up. Possible scores range from 0 to 200+, depending on the number of items administered, which varies by the age of the child (19 to 33 items). However, the primary use of this tool is as a screener. Thus, typically, scores are interpreted as they compare to the identified cut-offs, with children who score above the cut-off referred for further evaluation. This measure was given at all time points.
Time Frame	Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years

Outcome Measure Data

Analysis Population Description
Data was collected from 94 unique patients. All patients were included, regardless of treatment strata. If the patient age at study entry (baseline) was within the window of an identified time point, their information was included with that time point.

Arm/Group Title	Baseline	6 Months	1 Year	2 Years	3 Years	5 Years
Arm/Group Description	At study entry.	Participants at 6 months of age ±3 months.	Participant age was 1 year ±3 months.	Participant age was 2 years ±3 months.	Participant age was 3 years ±3 months.	Participant age was 5 years ±3 months.
Measure Participants	25	30	50	64	67	60
Mean (Standard Deviation) [units on a scale]	40 (31.12)	19.42 (14.02)	26.28 (13.93)	29.67 (20.83)	40.61 (37.76)	39.93 (34.03)

24. Secondary Outcome

Title	Change in Parenting Stress Index (PSI)
Description	The PSI is a commonly used measure of parenting stress. In 101 questions, the PSI delineates between stress as a function of child characteristics (e.g., adaptability, demandingness, mood; Child Domain) and stress as a function of parent characteristics (e.g., depression, sense of competence, social isolation; Parent Domain), as well as an overall stress score (Total Stress). Raw scores are calculated (normative means: Child Doman = 98.4; Parent Domain = 122.7; Total Stress Score = 221.1). This measure was given at all time points. Scores range from 131-320 for Total Stress, 69-188 for Parent Domain, and 50-145 for Child Domain, with higher scores indicative of greater stress (Total: >260; Parent: >153, Child: >122).
Time Frame	Baseline (at study entry), 6 months, 1 year, 2 years, 3 years, and 5 years

Outcome Measure Data

Analysis Population Description
Data was collected from 94 unique patients. All patients were included, regardless of treatment strata. If the patient age at study entry (baseline) was within the window of an identified time point, their information was included with that time point.

Arm/Group Title	Baseline	6 Months	1 Year	2 Years	3 Years	5 Years
Arm/Group Description	At study entry.	Participants at 6 months of age ±3 months.	Participant age was 1 year ±3 months.	Participant age was 2 years ±3 months.	Participant age was 3 years ±3 months.	Participant age was 5 years ±3 months.
Measure Participants	25	30	50	64	67	60
Child Domain	96.76 (20.91)	93.08 (15.98)	93.27 (14.86)	92.77 (16.23)	94.60 (18.69)	92.49 (19.02)
Parent Domain	109.38 (30.33)	101.56 (22.90)	105.84 (22.90)	105.84 (27.56)	105.92 (24.96)	102.74 (24.97)
Overall Total Stress	207.25 (47.07)	194.84 (23.36)	200.51 (35.98)	198.61 (38.52)	200.23 (40.21)	194.68 (39.84)

25. Secondary Outcome

Title	Assessment of School Readiness
Description	The Bracken Basic Concepts Scale was used to assess school readiness. It is an examiner-administered measure that assesses per-academic skills including letter and number recognition, shapes, colors, and understanding of sizes and comparisons. Raw scores are converted into age-normed scaled scores (normative mean = 10, SD = 3) for the School Readiness Composite. Higher scores are indicative of stronger pre-academic skills, with scores from 7 to 13 within the Average range.
Time Frame	Patients were assessed at 5 years of age

Outcome Measure Data

Analysis Population Description
All patients were included, regardless of treatment strata.

Arm/Group Title	5 Years
Arm/Group Description	Participant age was 5 years ±3 months.
Measure Participants	60
Mean (Standard Deviation) [units on a scale]	8.96 (3.10)

26. Secondary Outcome

Title	Number of Participants With Development of Pineal Cysts
Description	The MRI reports from bilateral patients were reviewed and data abstracted regarding pineal gland measurement and information about pineal cysts. The number of participants with change in primary visual cortex function from diagnosis through 6 years after last patient enrollment is reported here.
Time Frame	At diagnosis through 6 years after last patient enrollment

Outcome Measure Data

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

Arm/Group Title	Participants With Bilateral Retinoblastoma
Arm/Group Description	Results were analyzed for all participants regardless of stratum. All participants received chemotherapy (5 Stratum C, high risk; 11 Stratum A; 27 Stratum B).
Measure Participants	43
Developed new solitary cyst(s)	12 52.2%
Developed multiple new cysts	15 65.2%
Growth of pineal cyst	5 21.7%
Decrease in size (resolution) of pineal cyst	1 4.3%
No change	11 47.8%

27. Secondary Outcome

Title	Number of Participants With Change in Size of Pineal Gland
Description	The MRI reports from bilateral patients were reviewed and data abstracted regarding pineal gland measurement and information about pineal cysts. The number of participants with change in pineal gland size is reported here.
Time Frame	From diagnosis through 6 years after last patient enrollment

Outcome Measure Data

Analysis Population Description
Pineal gland size was measured during routine MRI screening. Measurements were compared over time to quantify any change in size. Measurements were compared with standard pediatric norms to determine "prominence" or "mild enlargement" (subjective comparison).

Arm/Group Title	Participants With Bilateral Retinoblastoma
Arm/Group Description	Results were analyzed for all participants regardless of stratum. All participants received chemotherapy (5 Stratum C, high risk; 11 Stratum A; 27 Stratum B).
Measure Participants	43
Prominent or mildly enlarged pineal glands	12 52.2%
Pineal growth over time	8 34.8%
No change in pineal gland size	23 100%

28. Secondary Outcome

Title	Change in Distortion Product Otoacoustic Emissions (DPOAEs)
Description	For DP_amplitude to be considered valid, a baseline DP_SNR (Distortion Product for Signal-to-noise ratio) for each frequency (1000-8000 Hz) and for each ear (left and right) must be = 6 dB. Any ear with invalid amplitude at baseline for each frequency should be excluded. The DPOAEs amplitude levels were averaged across the right and left ears at each frequency in the patients exhibiting valid DPOAE amplitudes in both ears, resulting in mean DPOAE levels. Subsequently, comparisons between baseline and most recent evaluation (collapsed across ears) for each frequency were made to evaluate if a significant decrease in DPOAE amplitude exists between the two time points.
Time Frame	From Diagnosis through 5 years after completion of therapy

Outcome Measure Data

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

Arm/Group Title	Baseline	Interim Evaluation	Additional Evaluation
Arm/Group Description	All Stratum B participants with non-missing observation values were included. Stratum B (Advanced Bilateral retinoblastoma) includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.	All Stratum B participants with non-missing observation values were included. Stratum B (Advanced Bilateral retinoblastoma) includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.	All Stratum B participants with non-missing observation values were included. Stratum B (Advanced Bilateral retinoblastoma) includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.
Measure Participants	13	12	4
1000 Hz	17.7 (16.6)	5.5 (2.5)	4.5 (1.7)
1400 Hz	16.6 (3.6)	9.4 (2.5)	8.2 (2.8)
2000 Hz	15.1 (1.7)	13.0 (1.8)	11.0 (1.4)
2800 Hz	11.6 (2.0)	12.2 (1.9)	8.4 (3.2)
4000 Hz	15.3 (4.8)	11.3 (1.9)	3.4 (6.6)
6000 Hz	13.3 (2.0)	12.9 (2.2)	5.7 (8.6)
8000 Hz	5.0 (1.9)	-2.0 (3.2)	-9.9 (6.0)

29. Secondary Outcome

Title	Mean Primary Visual Cortex Function: Cluster Size
Description	Functional magnetic resonance imagining (fMRI) was used to investigate primary visual cortex (V1) response to visual stimulation in 105 children being treated for intraocular retinoblastoma. Primary visual cortex activity was assessed in each subject using blood oxygenation level-dependent (BOLD) signal. The BOLD signal was analyzed via a general linear model using Statistical Parametric Mapping software (SPM, Wellcome Institute of Neuology, London). Voxel volume/peak BOLD response is a measurement of the volume of activation of the cortex. There is no known association with visual outcome at this time.
Time Frame	At diagnosis through 6 years after last patient enrollment

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Stratum A	Stratum B	Stratum C
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.	Advanced Unilateral Retinoblastoma. Research participants with unilateral (unifocal or multifocal) advanced (Reese-Ellsworth group IV or V) intraocular disease will undergo upfront enucleation. Adjuvant therapy was also indicated in certain cases.
Measure Participants	12	24	41
Measure Number of exams	33	152	122
Mean (Standard Deviation) [number activated voxels (negative BOLD)]	2372 (2640)	1080 (2916)	2105 (2476)

30. Post-Hoc Outcome

Title	Number of Patients Recommended for and Utilizing Rehabilitation Services
Description	Participants were evaluated by Occupational Therapy at diagnosis, and at 3, 6, 9, and 12 months from diagnosis with a battery of standardized and non-standardized measures. Assessments including the Battelle Developmental Inventory, the Sensory Profile, the Oregon Project for Visually Impaired Preschoolers, Pediatric Evaluation of Disability Inventory, and the Greenspan Social Emotional Growth Scale were utilized for developing the participants plan of care and making referrals for services in the home community. Recommendations for rehabilitation services in the home community were made based on the results of the occupational therapists evaluation. A subsequent review of February 2013 subgroup definitions resulted in the reclassification of evaluable participants and subgroups in May 2015. This reclassification applies to the data for this outcome only.
Time Frame	At diagnosis, and at 3, 6, 9, and 12 months from diagnosis

Outcome Measure Data

Analysis Population Description
Objective was added after the protocol started. Due to the late start, 33 of the 105 overall participants were eligible. Of the 33, 1 family declined to participate; 1 was removed from the protocol, 5 were lost to follow-up, and 4 patients were unable to complete the developmental assessment. In total, 22 have complete data sets.

Arm/Group Title	Occupational Therapy Recommended Rehabilitation Services	Occupational Therapy Did Not Recommend Rehabilitation Services
Arm/Group Description	Occupational therapy evaluation recommended rehabilitation services.	Occupational therapy evaluation did not recommend rehabilitation services.
Measure Participants	16	6
Received rehabilitation services	12 52.2%	1 3.7%
Did not receive rehabilitation services	4 17.4%	5 18.5%

31. Secondary Outcome

Title	Mean Primary Visual Cortex Function: Maximum T-value
Description	Functional magnetic resonance imagining (fMRI) was used to investigate primary visual cortex (V1) response to visual stimulation in 105 children being treated for intraocular retinoblastoma. Primary visual cortex activity was assessed in each subject using blood oxygenation level-dependent (BOLD) signal. The BOLD signal was analyzed via a general linear model using Statistical Parametric Mapping software (SPM, Wellcome Institute of Neurology, London). The maximum t-statistic in activated cluster (negative BOLD) is provided. Voxel volume/peak BOLD response is a measurement of the volume of activation of the cortex. There is no known association with visual outcome at this time.
Time Frame	At diagnosis through 6 years after last patient enrollment

Outcome Measure Data

Analysis Population Description
[Not Specified]

Arm/Group Title	Stratum A	Stratum B	Stratum C
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.	Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.	Advanced Unilateral Retinoblastoma. Research participants with unilateral (unifocal or multifocal) advanced (Reese-Ellsworth group IV or V) intraocular disease will undergo upfront enucleation. Adjuvant therapy was also indicated in certain cases.
Measure Participants	12	24	41
Measure Number of exams	33	152	122
Mean (Standard Deviation) [Maximum t-statistic (negative BOLD)]	7.9 (6.9)	6.2 (3.9)	8.8 (4.7)

Adverse Events

	Stratum A		Stratum B		Stratum C
Time Frame	Adverse events have been collected from study activation (February 2005) through June, 2011.
Adverse Event Reporting Description

Arm/Group Title	Stratum A		Stratum B		Stratum C
Arm/Group Description	Early Unilateral or Bilateral Retinoblastoma. Stratum A includes mainly patients with early stage (Reese-Ellsworth group I, II, or III) bilateral retinoblastoma. Patients with unilateral disease diagnosed at an early stage, and patients with early multifocal unilateral disease are rare, but these patients are also candidates for conservative management and were treated in stratum A.		Advanced Bilateral Retinoblastoma. Stratum B includes patients with at least one Reese-Ellsworth group IV or V eye that after careful evaluation by the treating team is considered not to require upfront enucleation. A proportion of patients treated on this stratum will not have advanced disease in both eyes. Only stratum B patients received window therapy consisting of 2 courses of vincristine and topotecan.		Advanced Unilateral Retinoblastoma. Research participants with unilateral (unifocal or multifocal) advanced (Reese-Ellsworth group IV or V) intraocular disease will undergo upfront enucleation. Adjuvant therapy was also indicated in certain cases.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Stratum A		Stratum B		Stratum C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/23 (4.3%)		9/27 (33.3%)		1/55 (1.8%)
Ear and labyrinth disorders
Hearing: patients with/without baseline audiogram and enrolled in a monitoring program	0/23 (0%)	0	0/27 (0%)	0	1/55 (1.8%)	1
Gastrointestinal disorders
Anorexia	0/23 (0%)	0	2/27 (7.4%)	2	0/55 (0%)	0
Colitis	0/23 (0%)	0	1/27 (3.7%)	1	0/55 (0%)	0
Diarrhea	0/23 (0%)	0	2/27 (7.4%)	2	0/55 (0%)	0
Gastrointestinal - Other (Specify, __)	1/23 (4.3%)	1	0/27 (0%)	0	0/55 (0%)	0
Vomiting	0/23 (0%)	0	1/27 (3.7%)	1	0/55 (0%)	0
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	0/23 (0%)	0	8/27 (29.6%)	9	0/55 (0%)	0
Infections and infestations
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils	0/23 (0%)	0	1/27 (3.7%)	1	0/55 (0%)	0
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, colon	0/23 (0%)	0	2/27 (7.4%)	2	0/55 (0%)	0
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, cellulitis	0/23 (0%)	0	1/27 (3.7%)	2	0/55 (0%)	0
Neutrophils/granulocytes (ANC/AGC)	0/23 (0%)	0	4/27 (14.8%)	4	0/55 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary/Upper Respiratory - Other (Specify, __)	0/23 (0%)	0	1/27 (3.7%)	1	0/55 (0%)	0
Other (Not Including Serious) Adverse Events
	Stratum A		Stratum B		Stratum C
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/23 (100%)		27/27 (100%)		18/55 (32.7%)
Blood and lymphatic system disorders
Neutrophils/granulocytes (ANC/AGC)	23/23 (100%)	161	26/27 (96.3%)	271	18/55 (32.7%)	69
Platelets	9/23 (39.1%)	22	25/27 (92.6%)	86	10/55 (18.2%)	32
Hemoglobin	10/23 (43.5%)	22	23/27 (85.2%)	72	14/55 (25.5%)	34
Leukocytes	3/23 (13%)	5	20/27 (74.1%)	36	14/55 (25.5%)	23
Gastrointestinal disorders
Anorexia	1/23 (4.3%)	1	6/27 (22.2%)	9	0/55 (0%)	0
Dehydration	3/23 (13%)	4	5/27 (18.5%)	5	0/55 (0%)	0
Diarrhea	1/23 (4.3%)	1	7/27 (25.9%)	10	1/55 (1.8%)	1
Mucositis/stomatitis (clinical exam), Oral cavity	0/23 (0%)	0	2/27 (7.4%)	2	1/55 (1.8%)	1
Vomiting	3/23 (13%)	5	2/27 (7.4%)	2	1/55 (1.8%)	3
Infections and infestations
Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented)	2/23 (8.7%)	3	17/27 (63%)	30	3/55 (5.5%)	3
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, upper airway	2/23 (8.7%)	2	4/27 (14.8%)	4	0/55 (0%)	0
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils, cellulitis	1/23 (4.3%)	2	4/27 (14.8%)	4	0/55 (0%)	0
Infection(documented clinically or microbiologically with Grade 3 or 4 neutrophils,catheter-related	2/23 (8.7%)	2	3/27 (11.1%)	3	0/55 (0%)	0
Infection with normal ANC or Grade 1 or 2 neutrophils, Catheter-related	2/23 (8.7%)	2	3/27 (11.1%)	3	0/55 (0%)	0
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	0/23 (0%)	0	8/27 (29.6%)	8	0/55 (0%)	0
Metabolism and nutrition disorders
Potassium, serum-low (hypokalemia)	1/23 (4.3%)	1	3/27 (11.1%)	3	2/55 (3.6%)	3
Skin and subcutaneous tissue disorders
Rash/desquamation	0/23 (0%)	0	5/27 (18.5%)	8	0/55 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title	Ibrahim Qaddoumi MD
Organization	St. Jude Children's Research Hospital
Phone	1-866-278-5833
Email	info@stjude.org

Responsible Party:

St. Jude Children's Research Hospital

ClinicalTrials.gov Identifier:

NCT00186888

Other Study ID Numbers:

RET5
P01CA023099
NCI-2011-01186

First Posted:

Sep 16, 2005

Last Update Posted:

Jan 19, 2022

Last Verified:

Jan 1, 2022

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

Study Details

Study Description

Brief Summary

Detailed Description

This study will determine the following:

PRIMARY OBJECTIVE:

SECONDARY OBJECTIVES:

EXPLORATORY OBJECTIVES:

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

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Additional Information:

Publications

Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Outcome Measure Data

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Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

Limitations/Caveats

More Information

Certain Agreements

Results Point of Contact