Neoplasms

Eye Diseases

All Conditions

Diseases and Abnormalities at or Before Birth

Rare Diseases

Retinoblastoma

Retinal Neoplasms

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Eye Neoplasms

Eye Diseases, Hereditary

Retinal Diseases

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Carboplatin

Etoposide

Vincristine

Melphalan

Etoposide phosphate

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Immunosuppressive Agents

Immunologic Factors

Tubulin Modulators

Antimitotic Agents

Group 1 - Multicentric non randomised, phase II study for patients with retinoblastoma (unilateral group A,B according to age, group C according to the age and the vitreous seeding or bilateral groups A,B and C excluding the bilateral groups D or patients with bilateral macular threat).

Treatment by chemoreduction (VP16, carboplatin) followed by Carboplatin + laser day 1 (chemothermotherapy) without laser treatment at day 8 (decreasing laser sessions) combined to local treatments from third course (laser, cryoapplication, I125 radioactive plaques or intravitreal Melphalan).

Group 2 - Multicentric non randomised, phase II study for the patients with bilateral very asymmetric disease (group D retinoblastoma on one of the eye, and the other amenable to a local treatment without chemotherapy) or unilateral presentation group D and groups B/C according to the age and vitreous seeding.

Treatment by Melphalan chemotherapy administered by superselective catheterization of the ophthalmic artery and combined to local treatments (laser, cryoapplication, I125 radioactive plaques or intravitreal Melphalan).

Group 3 - Multicentric non randomised, phase II study for the patients with bilateral group D retinoblastoma or with a group D retinoblastoma on the only remaining eye. Treatment by 6 cycles of three drugs (VP16, carboplatin, vincristin) regimen combined to local treatments from the third cycle (laser, cryoapplication, I125 radioactive plaques or intravitreal Melphalan).

Systemic treatment : Intravenous injections, 2 cycles (21 days)

VP16, carboplatin

intraarterial injections, 3 to 6 cycles (1 month)

Systemic treatment : Intravenous injections, 6 cycles (21 days)

VP16, carboplatin, vincristin

Chemothermotherapy : Intravenous injection by carboplatin and Laser at day 1

Carboplatin + laser day 1 (chemothermotherapy)

Laser (local treatment)

cryoapplication (local treatment)

I125 radioactive plaques (local treatment)

intravitreal Melphalan (local treatment)

Isabelle Aerts, MD

Catherine Devoldere, MD

Isabelle Pellier, MD

Véronique Laithier, MD

Celine De Bouyn-Icher, MD

Liana-Stephania Carausau, MD

Damien BODET, MD

Justyna Kanold, MD

Claire Briandet, MD

Dominique Plantaz, Prof.

Hélène Sudour-Bonnange, MD

Christophe Piguet, MD

Cécile Faure Conter, MD

Carole Coze, MD

Nicolas Sirvent, MD

Ludovic Mansuy, MD

Estelle Thebaud, MD

Marilyne Dupuy-Poiree, MD

Frederic Millot, MD

Claire Pluchart, MD

chloé Puiseux, MD

Pascale Schneider, Prof.

Jean-Louis Stephan, Prof.

Natacha Entz-Werle, MD

Anne-Isabelle Bertozzi-Salamon, MD

Pascale BLOUIN, MD

Michel Piotin, MD

Conservative treatments of retinoblastoma (RETINO 2011)

1. -Multicentric non randomised, phase II study for the patients treated by chemoreduction (VP16, carboplatin) followed by chemothermotherapy without laser treatment at day 8
2. -Multicentric non randomised, phase II study for the patients with bilateral very asymmetric dis-ease (Group D eye on one of the eye) or unilateral presentation groups B/C/D according to the age and vitreous seeding
3. - Multicentric non randomised, phase II study for the patients treated by 6 cycles of three drugs regimen and local treatments for bilateral group D eyes or on the only eye.

Conservative Treatments of Retinoblastoma

Sponsor will share de-identified data sets. Documents generated under the project will be disseminated in accordance with Institut Curie policies.

Number of fundus examination positives without clinical symptoms and number of patients treated after fundus examination-related treatment with a controlled disease.

Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v4.0 and types of adverse events occuring in order to reassess the benefice-risk scale (by Independent Data Monitoring Committee), for each arm of the study and for the whole study.

Rate of patient with a progression disease and/or presenting a medium/long term adverse event(s) or a second cancer.

Number of patients with uncontrolled disease (progression) and/or presenting Adverse Event(s) as assessed by CTCAE v4.0, related to intravitreal chemotherapy by Melphalan.

Time of scopies during ophthalmic arterial catheterism, doses delivered by the machine, doses received on skin.

Fondation Rothschild Paris

Institut Curie

Central Nervous System Depressants

Antirheumatic Agents

Anti-Infective Agents

Anesthetics

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Topotecan

Lenograstim

Mesna

Anti-Bacterial Agents

Antibiotics, Antitubercular

Topoisomerase I Inhibitors

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

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.

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.

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.

Enucleation

(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.

Vincristine, Carboplatin

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.

Focal Therapies

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.

External Beam Radiation

(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.

Vincristine and Topotecan

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

Vincristine + Carboplatin + Etoposide

(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

vincristine, cyclophosphamide, and doxorubicin

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

Vincristine, Carboplatin and Etoposide

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.

Periocular carboplatin

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.

G-CSF

Ibrahim Qaddoumi, M.D.

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.

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 of Treatment for Patients With Cancer of the Eye -Retinoblastoma

Protocol for the Study and Treatment of Patients With Intraocular Retinoblastoma

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.

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

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.

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.

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

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.

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.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

National Cancer Institute (NCI)

St. Jude Children's Research Hospital

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

Stratum 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.

Stratum B

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.

Stratum C

Total

Age, Continuous

Sex: Female, Male

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

Tumor Laterality

Ibrahim Qaddoumi MD

Partial response

Progressive Disease or New Lesion

Failure due to Toxicity

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.

Stratum B Response to Window Therapy

Progressive Disease / New lesion

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.

Stratum B Response Rate of Early Stage Eyes to Window Therapy

CYP3A4\*1B: The null hypothesis is there is not a statistically significant difference between the genotype groups.

CYP3A5\*3: The null hypothesis is there is not a statistically significant difference between the genotype groups.

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.

Relationship Between Topotecan Clearance (CL) and CYP3A4/5 Genotype in Stratum B Participants.

BCRP 1143: The null hypothesis is there is not a statistically significant difference between the genotype groups.

BCRP 15622: The null hypothesis is there is not a statistically significant difference between the genotype groups.

BCRP Exon 2: The null hypothesis is there is not a statistically significant difference between the genotype groups.

BCRP Exon 5: The null hypothesis is there is not a statistically significant difference between the genotype groups.

Pgp Exon 21: The null hypothesis is there is not a statistically significant difference between the genotype groups.

Pgp Exon 26: The null hypothesis is there is not a statistically significant difference between the genotype groups.

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.

Relationship Between Topotecan Clearance (CL) and ABCG2/B1 Genotype in Stratum B Participants.

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

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.

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.

Event-free Survival of Stratum B Patients Responding to Window Treatment

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.

Ocular Survival of Stratum B Patients Responding to Window Treatment

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.

Event-free Survival of Eyes in Stratum B Patients Responding to Window Treatment

Ocular Survival of Eyes in Stratum B Patients Responding to Window Treatment

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.

Event-free Survival of Stratum B Patients Not Responding to Window Treatment

Ocular Survival of Stratum B Patients Not Responding to Window Treatment

Event-free Survival of Eyes in Stratum B Patients Not Responding to Window Treatment

Ocular Survival of Eyes in Stratum B Patients Not Responding to Window Treatment

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Conservative Treatments of Retinoblastoma	NCT02866136	Retinoblastoma Children Retinal Neoplas...	VP16, carboplat... Melphalan VP16, carboplat... Carboplatin + l... Laser (local tr... cryoapplication... I125 radioactiv... intravitreal Me...	- 6 Years	Institut Curie
Conservative Treatments of Retinoblastoma	NCT02866136	Retinoblastoma Children Retinal Neoplas...	VP16, carboplat... Melphalan VP16, carboplat... Carboplatin + l... Laser (local tr... cryoapplication... I125 radioactiv... intravitreal Me...	- 6 Years	Institut Curie
Study of Treatment for Patients With Cancer of the Eye -Retinoblastoma	NCT00186888	Retinoblastoma Retinal Neoplas...	Enucleation Vincristine, Ca... Focal Therapies External Beam R... Vincristine and... Vincristine + C... vincristine, cy... Vincristine, Ca... Periocular carb... G-CSF	-	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for retinal neoplasm