Ophthalmology & Visual Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Br J Ophthalmol. 2022 Feb;106(2):288-296. doi: 10.1136/bjophthalmol-2020-318529. Epub 2021 May 10.
Current melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.
Rabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction.
retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.
Intravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%-79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged.
Taken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.
目前基于美法仑的眼内玻璃体内RB 种子治疗方案会导致视网膜毒性。我们评估了拓扑替康单药治疗与美法仑在兔子模型和患者队列中的疗效和毒性。
兔子实验：在注射拓扑替康后确定经验性药代动力学。对于拓扑替康（15μg 或 30μg）、美法仑（12.5μg）或生理盐水，通过连续视网膜电图（ERG）和组织病理学评估毒性，并通过肿瘤细胞减少和凋亡诱导来测量对玻璃体内种子异种移植物的疗效。
接受 990 次眼内注射拓扑替康或美法仑的 235 例患者的回顾性队列研究。
眼内注射 30μg 拓扑替康（相当于人类的 60μg）达到了兔眼内的 IC。每周三次眼内注射 15μg 或 30μg 拓扑替康不会引起兔子的视网膜毒性，而美法仑 12.5μg（相当于人类的 25μg）可使 ERG 幅度降低 42%-79%。眼内注射 15μg 拓扑替康与美法仑治疗兔 WERI-Rb1 细胞异种移植物同样有效（拓扑替康与盐水相比减少 96%（p=0.004），美法仑与盐水相比减少 88%（p=0.004），拓扑替康与美法仑相比，p=0.15）。在我们的临床研究中，患者接受了 881 次单药注射（48 次拓扑替康，833 次美法仑）。接受 20μg 或 30μg 拓扑替康的患者未见明显的 ERG 降低；美法仑导致每次注射 25μg（p=0.03）或 30μg（p<0.001）的 ERG 降低 7.6μV。大多数接受眼内注射拓扑替康治疗的患者在治疗过程中的某个时间点也接受了眼内注射美法仑。在仅接受拓扑替康单药治疗的眼中，所有的眼睛都被挽救了。
综上所述，这些实验表明，眼内注射拓扑替康单药治疗 RB 玻璃体内种子是无毒且有效的。
