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

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.

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.

(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.

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.

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.

(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.

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

(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

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

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.

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.

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.

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.

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.

King BA, Sahr N, Sykes A, Wilson MW, Brennan RC. Chemoreduction with topotecan and vincristine: Quantifying tumor response in bilateral retinoblastoma patients. Pediatr Blood Cancer. 2021 Apr;68(4):e28882. doi: 10.1002/pbc.28882. Epub 2021 Jan 28.