Intra-arterial Chemotherapy With Melphalan for the Treatment of Retinoblastoma (RTB) in Advanced Intraocular Stage

Study Overview
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Brief Summary
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For selected cases with advanced Retinoblastoma (RTB) intraocular involvement(stage V of the Reese-Ellsworth classification) in which enucleation would usually be the standard therapeutic approach, in this project the investigators propose an alternative conservative treatment using intra-arterial chemotherapy with melphalan, via direct administration by catheterization of the ophthalmic artery.

Detailed Description
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Retinoblastoma (RTB) is the most frequent tumour of the eye in early childhood and the commonest cancer in the first year of life. Approximately 60% of cases are sporadic and unilateral. Unilateral tumours are usually diagnosed in the advanced intraocular stage and the most frequent treatment prescribed is enucleation. This prevents disease progression but has an important visual risk, and also constitutes a mutilation, with potentially devastating psychological effects on patients and their relatives. At diagnosis, patients affected with RTB and their relatives are faced with the important effects of this disease, such as a threat to life, although rare in developed countries, and the risk of losing their sight, which depends on the uni- or bilateral nature of the tumour, the topography of the tumour or tumours, and the still prevalent need for enucleation as a treatment. In fact, almost all advanced stage unilateral RTBs are treated with enucleation. In addition to the risk to life and the patient's sight associated with this treatment, it is also important to take into account the risk to the eye itself. For selected cases with advanced intraocular involvement (stage V of the Reese-Ellsworth classification) in which enucleation would usually be the standard therapeutic approach, in this project we propose an alternative conservative treatment using intra-arterial chemotherapy with melphalan, via direct administration by catheterization of the ophthalmic artery. The treatment aims to preserve the eye ball and visual acuity as much as possible in these patients, and has been demonstrated to be extremely effective at achieving volumetric reduction of tumours, which permits, if necessary, the subsequent conservative treatment, mainly with brachytherapy for anterior tumours or thermotherapy with laser diode for posterior tumours. In cases of retinal detachment, significant volume reduction, such as that achieved after injection with melphalan would, in most cases, permit retinal reapplication that would favour visual prognosis. This technique was first described by David H. Abramson in the Sloan-Kettering Cancer Center Memorial Hospital of New York (A Phase I/II Study of direct Intra-arterial (Ophthalmic Artery) Chemotherapy with Melphalan for Intraocular Retinoblastoma). Here, in this study we propose using this technique for the first time outside New York city, in our own clinical setting (Retinoblastoma Unit, affiliated to the Oncology Development Department and the Ophthalmology Department of the Sant Joan de Déu Hospital in Barcelona). The attainment of positive results, in addition to those previously obtained by the New York project, could consolidate this treatment as an alternative to enucleation in most cases of advanced intraocular RTB, and open the way for the future indication of this technique in other stages of RTB.

Official Title
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An Open, Single-centre Non-randomized Phase II Clinical Trial on Intra-arterial Chemotherapy With Melphalan for the Treatment of Retinoblastoma (RTB) in Advanced Intraocular Stage

Conditions
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Retinoblastoma

Intervention / Treatment
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* Drug: Melphalan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with unilateral RTB. Patients with advanced intraocular involvement, corresponding to Stage D of the International Classification , selected by the Tumour Committee of the Retinoblastoma Unit. By contrast to most other cancers, histological confirmation is contraindicated in RTB prior to onset of treatment and, in our study, any biopsy of the tumour practiced was considered as an exclusion criterion. The only alternative to treatment is enucleation. Over six months old at diagnosis and younger than six years old. Informed consent of the parents or legal representative. Exclusion Criteria: Under 6 months old at diagnosis. Impaired kidney function, with creatinine clearance lower than 80 mL/min/1.73m2 or serum creatinine higher than 0.7 mg/dL. Impaired liver function, normal function being defined as presenting total bilirubin levels lower than 1.5 times the limit of normal for that age and ALT lower than 5 times the limit of normal for that age. Patients with some type of coagulation disorder that could contraindicate the procedure or with a previous diagnosis of any thrombotic condition. Congenital cerebral anomalies diagnosed previously or detected by angioresonance prior to treatment for extraocular involvement by RTB shown by image techniques, cerebrospinal fluid (CSF) cytology or cytomorphology of bone marrow aspirates (BMA), or positive expression of GD2 synthase in CSF or BMA. Patients with heart disease, arterial hypertension, or diseases of the nervous system not referred to in point 5, or with active infections that the Anaesthesiology Service responsible for the procedure have studied and consider to contraindicate the procedure. Not having been selected for intra-arterial chemotherapy through the ophthalmic artery for any other reason than those given by the Tumour Committee of the RTB Unit of the HSJD. Concurrent administration of any other anti-cancer treatment. Any surgical or non-surgical procedure that could have changed the structure of the eye and, therefore, facilitate risk of dissemination, including histological confirmation prior to treatment. Participation in another clinical trial.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 6 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Melphalan<br>Intra-arterial chemotherapy with melphalan, via direct administration by catheterization of the ophthalmic artery. Dosage range from 3 to 5 mg, depending of patient's weight and estimated tumour volume: a)3 mg for patients under 10 kg and tumour volume size under 1,5 cm3; b)5 mg for patients over 10 kg and tumour volume over 1,5 cm3; c)4 mg in all other situations(tumour volume over 1,5 cm3 in patients under 10 kg or tumour volume under 1,5 cm3 in patients over 10 kg). | Drug: Melphalan<br>* The usual number of chemotherapy cycles will be 3. First treatment with Melphalan will be initiated as soon as possible, once the patients are selected for the study. Once the first treatment has been completed, day 0, successive treatments will be considered, second and third (days 21 and 42). In those cases in which some patients could be considered for an additional treatments after the third cycle, these will be administrated in intervals at least of 21 days.Dosage range from 3 to 5 mg, depending of patient's weight and estimated tumour volume.<br>* Other names: Melfalan GlaxoSmithKline Inyectable;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the saving of eyes affected with RTB for patients who would have been candidates for enucleation. | The primary endpoint will be the objective response to treatment determined by funduscopy and RetCam explorations, recorded as a percentage of partial response (PR) or complete response (CR) to the treatment administered. | From V1 (Baseline) to V14 (1+ year after last treatment) | 
| The response will be evaluated as a function of tumoral volumetric size. | The response will be evaluated as a function of tumoral volumetric size by comparing images obtained in successive funduscopy and RetCam explorations. | From V1 (Baseline) to V14 (+1 year after last treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To preserve visual acuity, by studying the affected eye after the third cycle of treatment. | The secondary endpoint studied will correspond to changes in visual acuity of the affected eye after the third cycle of treatment, assessed by a visual acuity study. | V1 (Basal), V13 (day +52 to +60), V14 (+1 year after last treatment) | 
| To modify the result of electroretinographic studies and visual evoked potentials after the third cycle of treatment. | The secondary endpoint studied will correspond to changes in electroretinographic studies and visual evoked potentials after the third cycle of treatment | V1 (Basal), V13 (day +52 to +60), V14 (+1 year after last treatment dosage) | 
| To evaluate the safety of the technique and medicinal product used, by studying the ophthalmologic and systemic adverse events. | The secondary safety endpoints studied will correspond to analytical changes in the CBC (essentially in the number of absolute neutrophils) and biochemistry analysis after 10 days of each treatment, and potential ophthalmologic side effects. | Adverse events:on ongoing basis-assessed in each protocol visit / Laboratory test: V1 (Basal), V3&4 (day +1 to+10), V7&8 (day +22 to +31), V11&12 (day +43 to +52) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eye, Retinoblastoma, RTB, Ocular tumour, Melfalan, Enucleation, Tumor of the eye, Ocular cancer, Ocular chemotherapy, Ophthalmic artery, Intra-arterial chemotherapy