Adjuvant Treatment in Extensive Unilateral Retinoblastoma Primary Enucleated (RB SFCE 2009)

Study Overview
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Brief Summary
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Postoperative Treatment of Unilateral Retinoblastoma After Primary Enucleation according to histopathological risk factors of the International Retinoblastoma Staging Working Group.

Detailed Description
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Post operative chemotherapy +/- radiotherapy according to histopathological risk factors of the International Retinoblastoma Staging Working Group. Low risk group : No optic nerve involvement. Intra and prelaminar involvement No choroidal involvement. Minimal superficial choroidal involvement . Intermediate risk group, 2 sub groups : Sub group 1 : Retrolaminar involvement without Invasion of surgical margin associated or not to massive choroidal involvement Anterior segment involvement. Intrascleral involvement. Sub Group 2 : Isolated massive choroidal involvement. High risk group : Invasion of the surgical margin of the optic nerve and/or microscopic extrascleral involvement Optic nerve meningeal sheat involvement .

Official Title
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Adjuvant Treatment in Extensive Unilateral Retinoblastoma Primary Enucleated

Conditions
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Retinoblastoma

Intervention / Treatment
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* Other: Observation
* Drug: Etoposide
* Drug: Vincristine
* Radiation: Orbital irradiation
* Drug: Carboplatin
* Drug: Vincristine
* Drug: Cyclophosphamide
* Drug: Carboplatin
* Drug: Etoposide
* Drug: Carboplatin
* Drug: Thiotepa
* Drug: Vincristine
* Drug: Cyclophosphamide
* Procedure: Cytapheresis
* Drug: Carboplatin
* Drug: Etoposide
* Drug: Thiotepa
* Procedure: Peripheral bood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent - a signed informed consent and/or assent (as age appropriate) will be obtained according to institutional guidelines; Male or female ≥2 months and <10 years of age at the time of signing the informed consent form; Diagnosis of non familial extensive unilateral retinoblastoma treated by primary enucleation In case of post operative chemotherapy, patients must have adequate organ function: Adequate hematopoietic function Neutrophils>1.0x109/l, Platelets >100 x 109/l. Adequate hepatic function: grade II NCI CTC Adequate renal function: serum creatinemia <1.5 x ULN for age with normal creatinine clearance estimated by SCHWARTZ formula Audiometry < Grade II de Brock. Echocardiography normal in case of high dose cyclophosphamide chemotherapy (3 g/m²). Patients affiliated to a Social Security Regimen or beneficiary of the same No chemotherapy or radiotherapy prior to administration of the first dose of study treatment for retinoblastoma or other tumor types Without medical cons-indication to study drugs. Exclusion Criteria: Bilateral and/or familial or trilateral retinoblastoma. Unilateral retinoblastoma with indication of primary chemotherapy before enucleation: One or several surgical risk factors Buphthalmia Exophthalmia. Peri ocular inflammatory signs. Extraocular extension : Radiological retrolaminar extension (more than 3 mm behind the lamina cribrosa) and or meningeal sheat optic nerve extension. Extrascleral extension Lymp nodes extension Unilateral retinoblastoma with possibility of conservative treatment: Metastatic extension at diagnosis One inclusion criteria non observed Uncontrolled medical conditions, psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low risk group<br> | Other: Observation<br>* no post operative chemotherapy<br>|
| Experimental: Intermediate risk sub group 1<br>2 cycles (4 courses): 2 courses of etoposide and Carboplatin from D1 to D5 and Vincristin at D22 and D26- Cyclophosphamide from D22 to D26. | Drug: Etoposide<br>* 100 mg/m²/d, IV (in the vein) from D1 to D5.<br>Drug: Carboplatin<br>* 160 mg/m²/d, IV from D1 to D5.<br>Drug: Vincristine<br>* 1,5 mg/m²/d, IV at D22 and D26<br>Drug: Cyclophosphamide<br>* 300 mg/m²/d, IV from D22 to D26.<br>|
| Experimental: Intermediate risk sub group 2<br>2 courses of Vincristin and Carboplatin | Drug: Vincristine<br>* 1, 5 mg/m²/d, IV at D1.<br>Drug: Carboplatin<br>* 560 mg/m²/d, IV at D1.<br>|
| Experimental: High risk group<br>Orbital irradiation 3 cycles of two different types of alternating chemotherapy courses (id 6 courses) : Etoposide (100 mg/m²/d) and Carboplatin (160 mg/m²/d) with intrathecal Thiotepa injection. Vincristin (1,5 mg/m²/d) - Cyclophosphamide (1000 mg/m²/d) Cytapheresis for peripheral blood stem cells collection after the primary or the secondary courses of Vincristine- Cyclophosphamide. High dose chemotherapy : Carboplatin (AUC : 7/d) - etoposide (250 mg/m²/d) - Thiotepa (300 mg/m²/d) Peripheral bood stem cell transplantation. | Radiation: Orbital irradiation<br>* 45 Grays (Standard or external beam radiotherapy).<br>Drug: Etoposide<br>* 100 mg/m²/d, IV from D1 to D5<br>Drug: Carboplatin<br>* 160 mg/m²/d,IV from D1 to D5<br>Drug: Thiotepa<br>* 15 mg, intrathecal Thiotepa injection at D1.<br>Drug: Vincristine<br>* 1,5 mg/m²/d), IV at D22<br>Drug: Cyclophosphamide<br>* 1000 mg/m²/d, IV from D22 à D24.<br>Procedure: Cytapheresis<br>* Cytapheresis for peripheral blood stem cells collection after the primary or the secondary courses of Vincristine- Cyclophosphamid.<br>Drug: Carboplatin<br>* AUC : 7/d, IV from D-8 to D-6.<br>Drug: Etoposide<br>* 250 mg/m²/d, IV from D -5 to D-3.<br>Drug: Thiotepa<br>* 300 mg/m²/d, IV from D-5 to D-3.<br>Procedure: Peripheral bood stem cell transplantation<br>* at D0<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of extra ocular relapses |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate long term and acute toxicities of adjuvant chemotherapy and orbital irradiation if necessary. | Number of participants with treatment-related Adverse Events as assessed by CTCAE v3.0. | 5 years | 
| Number of patient with secondary bilateralisation |  | 5 years | 
| Evaluate the different histopathological risk factors frequency | Number of patient in each histopathological risk group | 5 years | 
| To determine tumors genomic | Tumor genomic characterization in order to provide some new prognosis factors and better understanding of tumorigenesis by using of NGS (Next Generation Sequencing) techniques | at the inclusion | 
| Evaluate sensitivity of MRI in detecting extra ocular extension | Number of extra ocular extension detected by MRI | At the inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary enucleation, retinoblastoma