This protocol includes 2 independent studies. Both studies are multicenter studies, evaluating different therapeutic approaches in two different populations of patients:

• Study 1, a randomized phase-II study evaluating the efficacy of Intra-Arterial Chemotherapy (IAC) with melphalan and topotecan versus melphalan alone, both in association with ophthalmologic treatments.
• Study 2, a minimally invasive interventional study evaluating the results on visual function following reference treatment with intravenous (IV) chemotherapy in association with ophthalmologic or local ophthalmological treatment without IV chemotherapy.

Primary objective of the studies:

• Study 1: To evaluate the efficacy of IAC in term of local control of the disease in patients eligible for IAC (randomized phase II study);
• Study 2: To assess the visual function, based on World Health Organization (WHO) criteria, in patients eligible for other conservative treatments (IV chemotherapy in association with local ophthalmologic trématent or local ophthalmological treatment without IV chemotherapy; this is a minimally invasive interventional study).

Inclusion Criteria:

Overall study inclusion criteria:

1. Newly diagnosed retinoblastoma (RB).
2. Retinoblastoma with at least one eye eligible for conservative management.
3. Patients likely to be compliant with the study requirements and visits, including late follow-up.
4. Patients not previously treated with chemotherapy or radiotherapy for this or any other cancer.
5. Patients with no contraindication to the proposed treatments.
6. Informed consent signed by parents or legal representative.
7. French Social Security System coverage.

Study 1 inclusion criteria:

8.1. Children aged from 6 months to 6 years. 9. Retinoblastoma in at least one eye, deemed manageable with IAC in one side and without IV chemotherapy:

1. Unilateral Retinoblastoma classified as group B, C (if vitreous seeds < 3 mm), D or E with no invasion of the anterior segment, and without massive tumor of more than 2/3 of the eye, eligible for conservative management, or
2. Bilateral Retinoblastoma but with very unbalanced lesions between the two eyes: one eye group D or E without invasion of the anterior segment or massive tumor of more than 2/3 of the eye, eligible for IAC, and the other eye eligible for local treatment only (without IAC).

Study 2 inclusion criteria:

8.2. Retinoblastoma eligible for conservative management although not manageable with IAC:

1. Unilateral Retinoblastoma in children below 6 months of age, classified as Group A, B, C or D, with or without vitreous seeding, compatible with conservative management, or
2. Bilateral Retinoblastoma classified as group A, B, C D, or E without invasion of the anterior segment, and/or massive tumors of more than 2/3 of the eye and eligible for conservative management.

Exclusion Criteria:

Overall study non-inclusion criteria:

1. RB not eligible for conservative management :

   1. Extra-ocular extension of the disease, or
   2. Group E eyes with invasion of the anterior segment, and/or massive tumors of more than 2/3 of the eye.

2. Patient older than 6 years of age.

3. Patients with another associated disease contra indicating systemic chemotherapy.

4. Previously treated retinoblastoma by chemotherapy.

5. Patients already treated for another malignant disease.

6. Patient with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

7. Patients whose parents have not accepted the treatment regimen after explanation of it.

8. Contraindication to study drug mentioned in SmPC (Summary of Products Characteristics) of the study drugs.

9. Inclusion in another experimental anti-cancer drug therapy.

   Study 1 non-inclusion criteria:

10. Any contraindication or concomitant disease that would preclude the Study 1 treatment procedure and could delay treatment.

These patients should be eligible for Study 2.

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

Data requests can be submitted starting 9 months after last article publication and will be made accessible for up to 12 months.

Access to trial individual participant data can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a data sharing agreement (DSA).