Abstract
Purpose. To measure the chemotherapeutic effects of focal melphalan (intravitreal and subconjunctival) on tumor burden, hypoxia, and vasculature in LHBETATAG murine retinoblastoma model. Methods. LHBETATAG transgenic mice were treated with a single 1 mcg intravitreal injection of melphalan, 100 mcg subconjunctival injection, or semiweekly 10 mcg subconjunctival injections for 3 weeks. At 1 or 3 weeks, eyes were enucleated, serially sectioned, and processed with haematoxylin and eosin (H&E) for tumor burden measurements and probed with immunofluorescence to analyze tumor hypoxia and vasculature. Results. Focal melphalan significantly reduced retinal tumor size (P < 0.02) when given intravitreally or subconjunctivally. Eyes treated with a one-time intravitreal injection of 1 mcg melphalan had significantly smaller tumors at both 1 week (P = 0.017) and at 3 weeks after injection (P = 0.005). Intratumoral hypoxia showed a significant decline in hypoxia at 1 week following intravitreal injection and after maximum dosage of subconjunctival melphalan. Total vasculature was not significantly affected following intravitreal administration. Conclusion. Focal delivery of melphalan via intravitreal or subconjunctival injection has a significant effect on reducing tumor burden, hypoxia, and vasculature, in the treatment of murine retinoblastoma tumors.
Highlights
Over the past decade, systemic chemotherapy combined with focal consolidative treatment has gained popularity as the initial treatment of choice for retinoblastoma, due to the benefits of globe preservation and the potential to maintain some functional vision—an important factor given the long remaining lifespan of retinoblastoma survivors [1, 2]
Histopathologic examination at 1 week and 3 weeks after treatment revealed that intravitreal melphalan 1 μg/2 uL significantly reduced tumor burden compared to untreated control eyes (Figure 1)
One week after intravitreal melphalan therapy, tumor burden was significantly reduced by 85% compared to control (P = 0.017); three weeks after treatment with a single injection, tumor burden remained significantly reduced by 83% (P = 0.0048)
Summary
Systemic chemotherapy combined with focal consolidative treatment has gained popularity as the initial treatment of choice for retinoblastoma, due to the benefits of globe preservation and the potential to maintain some functional vision—an important factor given the long remaining lifespan of retinoblastoma survivors [1, 2]. Local treatment forms include subconjunctival (subTenons’) injections [6], intravitreal injections [7,8,9,10], and intra-arterial administration [11,12,13]. Melphalan is already being used in the clinical setting in the form of intraarterial delivery and intravitreal injections for treatment of retinoblastoma, and preliminary studies have shown promise [14]. One of the largest studies on intra-arterial chemotherapy included 95 eyes with retinoblastoma. The authors report globe salvage of 70% for all eyes at 2 years, with eyes treated with intra-arterial chemotherapy as primary management having a higher success rate (81.7%) compared to salvage (58.4%) [11]. A recent study by Munier et al [14] reported on the efficacy of intravitreal melphalan for advanced retinoblastoma with
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