Conservative Treatments of Retinoblastoma

Study Overview
=================
Brief Summary
-----------------
Conservative treatments of retinoblastoma (RETINO 2011) -Multicentric non randomised, phase II study for the patients treated by chemoreduction (VP16, carboplatin) followed by chemothermotherapy without laser treatment at day 8 -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 - 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.

Official Title
-----------------
Conservative Treatments of Retinoblastoma

Conditions
-----------------
Retinoblastoma, Children, Retinal Neoplasm

Intervention / Treatment
-----------------
* Drug: VP16, carboplatin
* Drug: Melphalan
* Drug: VP16, carboplatin, vincristin
* Drug: Carboplatin + laser day 1 (chemothermotherapy)
* Device: Laser (local treatment)
* Device: cryoapplication (local treatment)
* Radiation: I125 radioactive plaques (local treatment)
* Drug: intravitreal Melphalan (local treatment)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Study 1 inclusion criteria: Patients affected by unilateral retinoblastoma groups A, B (according to the age), group C (according to the age and vitreous seeding),or bilateral retinoblastoma groups A, B, C (excluding the eyes with macular threat and bilateral group D eyes or on the only remaining eye) amenable to a conservative treatment (at least on one eye in bilateral disease) but needing initial chemotherapy because of the location, the size of the lesion (more than 4 mm of diameter), a vision threat or risks of intravitreal relapse making those patients not amenable to chemothermotherapy first line. Patients less than six months of age with unilateral retinoblastoma groups B, C, D, or bilateral very asymmetric with one eye group D and the other amenable to local treatments without chemotherapy. Children from 0 to 6 years old. Study 2 inclusion criteria: Patients affected by unilateral or bilateral retinoblastoma group B (according to the age), group C (according to the age and vitreous seeding), or group D. Patients affected by bilateral retinoblastoma very asymmetric with a group D eye that can be treated by intraarterial chemotherapy by Melphalan and the other amenable to local treatments without chemotherapy. Children from 6 months to 6 years old. Study 3 inclusion criteria: Children affected of bilateral group D retinoblastoma or on the only eye amenable to conservative treatment. Children from 0 to 6 years old. Common inclusion criteria: Patients not previously treated by chemotherapy or radiotherapy for this tumour or another cancer. No contra-indications to the study treatments Possible long term follow-up. Written informed consent of the parents or the legal representative. Patients having social security cover. Exclusion Criteria: Study 1 exclusion criteria: Patients for whom a local treatment is possible without initial chemotherapy (tumour smaller than 4 mm and located far from optic nerve head or macula). Patients with an unilateral group D with massive tumour or group E eyes needing enucleation first line or after initial chemotherapy (in case of buphthalmia or suspected optic nerve invasion or extrascleral extension). Patients affected by bilateral retinoblastoma very asymmetric with a group D eye that can be treated by intraarterial chemotherapy by Melphalan and the other amenable to local treatments without chemotherapy. Patients with bilateral retinoblastoma and bilateral group D eyes or on the only remaining eye or presenting a bilateral macular threat requiring conservative treatment by a 6 cycles, three drugs regimen. Study 2 exclusion criteria: Patients with a unilateral group D (extensive) or B or C but covering the optic nerve head or group E eyes for which enucleation is warranted first line or after chemotherapy (in case of buphthalmia or suspected optic nerve invasion or extrascleral extension). Patients with unilateral group D eye with tumour volume of more than 50% of eye volume, for whom a massive choroidal invasion could be associated (on clinical or imaging criteria) and for which enucleation is warranted. Study 3 exclusion criteria: Patients for whom a local treatment is possible without chemoreduction (tumour smaller than 4 mm, distant from macula and from optic nerve head). Patients affected by bilateral retinoblastoma very asymmetric with a group D eye that can be treated by intraarterial chemotherapy by Melphalan and the other amenable to local treatments without chemotherapy. Patients with bilateral retinoblastoma without macular threat or groups A, B, C than can be treated with chemoreduction by VP16 and Carboplatin then chemothermotherapy without laser at day 8. Common exclusion criteria: Patients older than 6 years old. Patients with extraocular retinoblastoma. Patients with a disease being a contra-indication to chemotherapy. Patients anteriorly treated by chemotherapy. Patients anteriorly treated by external beam irradiation. Patients anteriorly treated for another cancer. Follow-up not possible due to geographic distance from the center or for social or psychological reasons. Parents not having accepted the therapeutic strategy after explanations by the investigator. Contra-indication to the use of one of the drugs used in the study.

Ages Eligible for Study
-----------------
Maximum Age: 6 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: (IV)Intravenous chemotherapy, laser diode<br>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). | Drug: VP16, carboplatin<br>* Systemic treatment : Intravenous injections, 2 cycles (21 days)<br>* Other names: etoposide, vepesid, chemotherapy;Drug: Carboplatin + laser day 1 (chemothermotherapy)<br>* Chemothermotherapy : Intravenous injection by carboplatin and Laser at day 1<br>* Other names: Carbo-laser, platinum-based chemotherapy;Device: Laser (local treatment)<br> <br> * Other names: Laser diode;Device: cryoapplication (local treatment)<br> <br> Radiation: I125 radioactive plaques (local treatment)<br> <br> Drug: intravitreal Melphalan (local treatment)<br> <br> |
| Other: (IA) Intraarterial Melphalan<br>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). | Drug: Melphalan<br>* intraarterial injections, 3 to 6 cycles (1 month)<br>* Other names: Alkeran, chemotherapy;Device: Laser (local treatment)<br> <br> * Other names: Laser diode;Device: cryoapplication (local treatment)<br> <br> Radiation: I125 radioactive plaques (local treatment)<br> <br> Drug: intravitreal Melphalan (local treatment)<br> <br> |
| Other: (IV-PM) Intravenous 3 drugs chemotherapy<br>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). | Drug: VP16, carboplatin, vincristin<br>* Systemic treatment : Intravenous injections, 6 cycles (21 days)<br>* Other names: etoposide, vepesid, leurocristine, Oncovin, chemotherapy;Device: Laser (local treatment)<br> <br> * Other names: Laser diode;Device: cryoapplication (local treatment)<br> <br> Radiation: I125 radioactive plaques (local treatment)<br> <br> Drug: intravitreal Melphalan (local treatment)<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of enucleation and external beam irradiation |  | From first day of treatment to 18 months after the end of treatments | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of relapses diagnosticated by fundus examination under general anesthesia until the age of 4 years, and without general anesthesia for older patients | Number of fundus examination positives without clinical symptoms and number of patients treated after fundus examination-related treatment with a controlled disease. | 5 years | 
| Prospective evaluation of the systemic, ocular and general sides effects (short term) of the intravenous chemotherapy, intraarterial chemotherapy, combined to the local treatments as well as the intravitreal injections of Melphalan | 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. | 5 years | 
| Prospective evaluation of the systemic, ocular and general sides effects (medium and long term) of the intravenous chemotherapy, intraarterial chemotherapy, combined to the local treatments as well as the intravitreal injections of Melphalan | Rate of patient with a progression disease and/or presenting a medium/long term adverse event(s) or a second cancer. | 5 years | 
| Response to intravitreal chemotherapy by Melphalan | 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. | 18 months | 
| Radiation doses received during intraarterial procedures | Time of scopies during ophthalmic arterial catheterism, doses delivered by the machine, doses received on skin. | 18 months | 
| Number of patients presenting a long term second tumour |  | until 20 years old |