Efficacy, Toxicity and Biodistribution of Intra-arterial vs. Intravenous Chemotherapy in a Rabbit Retinoblastoma Model

Abstract

Purpose : We previously described the first small animal model of intra-arterial chemotherapy (IAC) and our retinoblastoma xenograft rabbit model. Here, we directly compare pharmacokinetics following intravenous (IV) and IAC, their respective toxicities, and efficacy of each in treating retinoblastoma in vivo in rabbits.

Methods : Tissue drug levels were determined by serial sacrifice of rabbits following IAC or IV melphalan (0.4mg/kg) or carboplatin (50mg) (n=18 rabbits/drug/route). Toxicity was assessed (n=24 rabbits) by electroretinography, OCT, OCTA, fluorescein angiography, and histopathology, prior to and 5-weeks post-treatment with either IAC melphalan (0.4-1.2mg/kg), IV melphalan, or IV carboplatin/etoposide/vincristine, with weekly blood counts. Efficacy of each treatment was assessed against tumor xenografts in vivo in rabbits eyes by measuring induced apoptosis of tumor cells.

Results : Maximum carboplatin concentration (Cmax) in the treated eye was 1434.8μM for retina with IAC vs. 10.7μM with IV (134-fold, p<0.05 [Wilcoxon]), and in vitreous was 419.1μM with IAC vs. 1.02μM with IV (419-fold, p<0.05). Plasma Cmax was similar regardless of route (p=1.0) and Cmax in IAC-untreated (contralateral) eye was similar to IV treatment (p>0.1), suggesting drug enters the contralateral (“untreated”) eye by systemic recirculation following unilateral IAC. Areas-under-the-curve analyses, and results with IAC vs. IV melphalan, matched the above findings. IAC melphalan caused no evidence of vascular occlusions or retinal damage at standard doses. Electroretinographic reductions were dose dependent. With supratherapeutic melphalan (regardless of route), transient neutropenia occurred, but not at standard doses. Typical doses of IAC melphalan (3.6mg) caused apoptosis of tumor cells in vivo in our xenograft model (including vitreous seeds). IV chemotherapy was unable to treat retinoblastoma xenografts.

Conclusions : IAC achieves higher retinal and vitreous levels in the treated eye than does IV chemotherapy. However, plasma drug levels and drug levels in the contralateral eye are the same for IAC and IV, suggesting full systemic exposure to IAC drug. Toxicity is low at standard doses, and appears drug- and dose-specific, not related to the IAC procedure itself. Orthotopic retinoblastoma xenografts can be effectively treated by IAC in our model, paving the way for future drug discovery research.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.