Intravitreal chemotherapy in the management of retinoblastoma in a resource-limited setting

Intravitreal chemotherapy (IVitC) in the management of retinoblastoma has increased the rate of globe salvage, specifically in patients with recurrent disease and associated vitreous seeds. A significant number of children with retinoblastoma in developing countries present late, resulting in higher intraocular tumour-stage at presentation. Treatment requirements for such tumours usually include intravenous chemotherapy (IVC) and/or intra-arterial chemotherapy (IAC). While IVC has a long usage track record and a good efficacy, it has been reported to be associated with higher recurrence rates in a significant number of patients. Intra-arterial chemotherapy has the advantage of lower recurrence rates but requires personnel with advanced interventional radiology skills and has limited efficacy in treating intravitreal seeds. Intravitreal chemotherapy has gained popularity recently, largely because of its superior efficacy in the management of vitreous seeds, subretinal seeds and recurrent retinal tumour. An 8-month-old male infant initially presented with bilateral retinoblastoma, International Classification System for Intraocular Retinoblastoma (ICRB) Group E in the right eye and Group B on the left eye. The right eye was enucleated and currently has a prosthesis. The left eye had tumours that initially responded to brachytherapy and transpupillary thermotherapy (TTT). Approximately two years later his tumours recurred with vitreous seeds and were successfully managed with the use of cryotherapy and intravitreal chemotherapy. The simplicity of the technique of IVitC and its efficacy in controlling vitreous seeds and recurrent retinal tumours makes this route of regional chemotherapy a viable one in areas with limited expertise and resources such as South Africa.

A Rare Case of Acute Hemorrhagic Retinopathy Following Intravitreal Melphalan Injection for Persistent Vitreous Seeds in Retinoblastoma

Purpose: This report describes a case of acute occlusive hemorrhagic complication after intravitreal melphalan for vitreous seeds in retinoblastoma. Methods: A case report is presented. Results: Intravitreal melphalan has been used extensively for vitreous seeds in retinoblastoma. Although melphalan is relatively safe at optimal doses, it can sometimes cause inadvertent complications like hemorrhagic events if the drug is administered close to the retina or in more pigmented eyes. We report a case of a 5-month-old patient with bilateral retinoblastoma who underwent enucleation of the right eye and 2 intravitreal melphalan injections in the left eye (20 µg/0.02 mL) at a 1-month interval for persistent vitreous seeds. After the second injection, there was a sudden decrease in the child’s visual acuity in the left eye, and the retina showed multiple intraretinal hemorrhages and diffuse chorioretinal atrophy. Conclusion: Intravitreal melphalan may cause acute hemorrhagic complications after intravitreal use for retinoblastoma seeds, especially in pigmented eyes.

Safety and Efficacy of Intravitreal Chemotherapy (Melphalan) to Treat Vitreous Seeds in Retinoblastoma

Background: Active vitreous seeds in eyes with retinoblastoma (Rb) adversely affects the treatment outcome. This study aimed to investigate the safety and efficacy of intravitreal melphalan chemotherapy (IViC) as a treatment for recurrent and refractory vitreous seeds in patients with Rb.Methods: We used a retrospective non-comparative study of patients with intraocular Rb who had vitreous seeds and were treated by IViC (20–30 μg of melphalan) using the safety-enhanced anti-reflux technique. Tumor response, ocular toxicity, demographics, clinical features, and survival were analyzed.Results: In total, 27 eyes were treated with 108 injections for recurrent (16 eyes) or refractory (11 eyes) vitreous seeds after failed systemic chemotherapy. A total of 15 (56%) were males, and 20 (74%) had bilateral disease. At diagnosis, the majority (n = 21) of the injected eyes were group D, and n = 6 were group C. Vitreous seeds showed complete regression in 21 (78%) eyes; 100% (n = 10) for eyes with focal seeds; 65% (n = 11/17 eyes) for eyes with diffuse seeds (p = 0.04); 7 (64%) eyes with refractory seeds; and 14 (87%) eyes with recurrent seeds showed complete response (p = 0.37). In total, 16 (59%) eyes developed side effects: retinal toxicity (48%), pupillary synechiae (15%), cataracts (30%), iris atrophy (7%), and retinal and optic atrophy (4%). Only one child was lost to follow-up whose family refused enucleation and none developed orbital tumor recurrence or distant metastasis.Conclusion: IViC with melphalan is effective (more for focal than diffuse seeding) and a relatively safe treatment modality for Rb that can improve the outcomes of eye salvage procedures. However, unexpected toxicity can occur even with the standard dose of 20–30 μg.

Evaluation of intravitreal topotecan dose levels, toxicity and efficacy for retinoblastoma vitreous seeds: a preclinical and clinical study

BackgroundCurrent 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.MethodsRabbit 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. Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.ResultsIntravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 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.ConclusionsTaken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

Vitreous Seed Classification and Regression Patterns in Eyes With Retinoblastoma

Purpose: This work subclassifies retinoblastoma vitreous seeds and evaluates the efficacy, regression patterns, and adverse effects of combination intravitreal melphalan and topotecan chemotherapy for resistant and recurrent vitreous seeds. Methods: A retrospective review of medical records was conducted of patients with retinoblastoma and resistant or recurrent vitreous seeds who were treated with intravitreal melphalan and topotecan injections from August 2014 to July 2018. Main outcome measures included regression pattern, time for regression, time for recurrence of seeds, treatment outcomes, and ocular toxicity. Results: Nineteen eyes received 138 intravitreal injections over 74 treatment sessions (mean, 7.26 injections per eye); vitreous seeds regressed in 18 eyes. Of cloud vitreous seeds, curvilinear (n = 2) and sphero-linear (n = 2) subtypes were observed. During regression, some sphere seeds showed an intermediary streak-like pattern and took longer to regress (mean, 11.13 ± 14.05 months and 11.67 ± 8.62 injections) than those without the intermediary streak-like pattern (mean, 3.55 ± 2.57 months and 4.2 ± 1.87 injections). Mean follow-up was 34.87 ± 21.09 months (median, 35 months; range, 11-96 months). Anterior segment toxicity was seen in 10 (53%) eyes and posterior segment toxicity in 5 (26%) eyes. Kaplan-Meier survival estimates for globe salvage at 2 years was 94% and 73% at 5 years. Kaplan-Meier survival for vitreous seed–free status was 94% at 2 years and 65% at 5 years. Conclusions: An expanded vitreous seed classification system that further subcategorizes hitherto unrecognized vitreous seed morphology is needed. An intermediate streaking process results in a prolonged regression time for sphere vitreous seeds.

Is intravitreal topotecan toxic to retinal function?

BackgroundIntravitreal injections of topotecan are used in the management of retinoblastoma with vitreous seeds. This study evaluated whether intravitreal topotecan was associated with retinal toxicity.MethodsRetrospective cohort study of patients with retinoblastoma who were treated with intravitreal topotecan at Memorial Sloan Kettering Cancer Center between December 2014 and May 2019. Electroretinogram (ERG) responses under anaesthesia were measured immediately before treatment with intravitreal topotecan and at the next visitor approximately one-month. Ocular toxicity was defined by a decrease in the ERG response at 30 Hz at follow-up.ResultsOcular toxicity was evaluated by ERG on 50 evaluable injections administered to 28 eyes. 22 (44.0%) injections were performed with concurrent intravitreal melphalan. The median time to ERG measurement following an injection was 27 days. By using a paired t-test, intravitreal topotecan combined with melphalan (n=22) at a dose of 25 μg or 30 μg was associated with a significant decrease in ERG amplitude at follow-up (p=0.046, 95% CI −20.4 μV to −0.2 μV). Among eyes that only received topotecan (n=28) at doses of 20 μg or 30 μg, there was not a significant difference in ERG amplitude measured (p=0.85, 95% CI −7.0 μV to 5.8 μV).ConclusionIntravitreal topotecan combined with intravitreal melphalan was associated with a decrease in ERG amplitude; there was not a significant decrease in ERG amplitude observed in patients who received topotecan alone. These findings suggest that intravitreal topotecan injections at doses of 20 μg or 30 μg are not associated with retinal toxicity in patients with retinoblastoma.