Combination of Carboplatin and Bevacizumab Is an Efficient Therapeutic Approach in Retinoblastoma Patient-Derived Xenografts

PURPOSE: Retinoblastoma (Rb) is a rare childhood cancer of the retina with a survival rate of 95% in children living in high-income countries, after appropriate therapies such as chemotherapy, local ophthalmologic treatment, and radiotherapy. However, due to inactivation of the RB1 gene, all bilateral and almost 15% of unilateral retinoblastoma patients have a higher risk of s econdary cancers, especially sarcomas. Hence, new nonmutagen treatments are warranted. Therefore, we investigated the efficacy of therapy using anti-VEGF antibody bevacizumab, either alone or with carboplatin, in well-characterized Rb patient-derived xenografts (PDXs). METHODS: Three Rb PDXs previously established and characterized, RB102, RB111, and RB200, have been treated using carboplatin, bevacizumab, or carboplatin + bevacizumab. In order to define antitumor responses, various quantitative PCR and histopathologic analyses have then been performed on tumors collected at the end of experiments. RESULTS: In all treated PDX models, we have observed a high and significant improvement of chemotherapy-induced in vivo efficacy by the antiangiogenic antibody. The overall response rate, lower than -0.5, was 48%, 27%, and 86% after carboplatin, bevacizumab, and carboplatin + bevacizumab, respectively (carboplatin versus carboplatin + bevacizumab; P < 10-2; bevacizumab versus carboplatin + bevacizumab; P < 10-3). In the Rb200 PDX, such a result was also observed when bevacizumab was combined with lower doses of carboplatin. Quantitative PCR and histopathologic analyses have been performed and confirmed the impact of the bevacizumab-based treatments on various angiogenic markers. CONCLUSIONS: Overall, our in vivo results confirm the interest in antiangiogenic therapy for the treatment of Rb in combination with carboplatin and provide a robust rationale for testing this combination in the clinical setting for Rb patients.