melphalan and Retinal-Diseases

To evaluate clinical outcomes and enucleation rates after intravitreal melphalan (IVM) alone and after IVM combined with intravitreal topotecan (IVT) for the treatment of vitreous disease, and to a lesser extent subretinal and retrohyaloid seeds, in patients with retinoblastoma.. A retrospective analysis of 77 eyes of 72 consecutive patients.. Demographic data, classification of tumors, seed type (dust, sphere or cloud) before injection and at the end of follow-up, injection type (IVM or IVM+IVT), doses of IVM and IVT, number of injections, follow-up time, enucleation status and side effects were recorded. Cox regression analysis and log-rank test for Kaplan-Meier curves were performed.. Of 77 eyes, 40 received IVM alone (group 1) and 37 received IVM+IVT (group 2). Enucleation rates were 62.5% (n=25) in group 1 and 10.8% (n=4) in group 2 (p=0.001). Median eye survival was 23.6 months in group 1 and 25.6 months in group 2. Mantel-Cox test revealed statistically significant differences between Kaplan-Meier curves of group 1 and 2 (p=0.022). Multiple Cox regression analysis showed a significantly elevated enucleation rate associated with: IVM only treatment group (p=0.019) and pre-injection cloud type of seeding (p=0.014).. The combined use of intravitreal melphalan and topotecan provides significantly better results in terms of avoiding enucleation and vitreal and subretinal seed control.

Topics: Antineoplastic Agents, Alkylating; Child, Preschool; Drug Therapy, Combination; Eye Diseases; Eye Enucleation; Female; Follow-Up Studies; Humans; Infant; Intravitreal Injections; Kaplan-Meier Estimate; Male; Melphalan; Neoplasm Seeding; Proportional Hazards Models; Retinal Diseases; Retinal Neoplasms; Retinoblastoma; Retrospective Studies; Topoisomerase I Inhibitors; Topotecan; Treatment Outcome; Vitreous Body

To determine whether treatment order affects ophthalmic vascular event rates after intra-arterial chemotherapy (IAC) for retinoblastoma.. Patients who received IAC as primary or secondary treatment for retinoblastoma from January 2009 to January 2018 were included. All eyes were imaged with fundus photography and fluorescein angiography. Patient characteristics and vascular event rates were compared using t-test and Fisher's exact test.. There were 196 patients treated with 682 infusions of IAC, divided into primary (no previous therapy, 98 eyes of 98 patients, 328 infusions) and secondary (after other therapy, 105 eyes of 98 patients, 354 infusions) treatment. Overall, ophthalmic vascular events were found after 5% of infusions (17% eyes). A comparison of ophthalmic vascular events (primary vs. secondary IAC), with mean three infusions per eye (median 3, range 1-7), revealed no difference in overall percentage of eyes affected (18% vs. 15%, P = 0.57). Adverse vascular events per eye included retinal vasculature attenuation (1% vs. 0%, P = 0.99), peripheral retinal pruning (1% vs. 0%, P = 0.99), branch retinal artery occlusion (0% vs. 1%, P = 0.99), central retinal artery occlusion (0% vs. 1%, P = 0.99), macular ischemia (0% vs. 2%, P = 0.51), vitreous hemorrhage (2% vs. 3%, P = 0.92), subretinal hemorrhage (1% vs. 0%, P = 0.99), retinal pigment epithelium atrophy (6% vs. 3% P = 0.43), choroidal atrophy (4% vs. 2%, P = 0.92), optic disk pallor (1% vs. 0%, P = 0.99), and ophthalmic artery occlusion (9% vs. 6%, P = 0.35).. Ophthalmic vascular events after IAC for retinoblastoma affect only 5% of eyes per infusion (17% of treated eyes). Vascular event risk per eye is similar when using IAC as primary or secondary treatment.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Choroid; Female; Fluorescein Angiography; Humans; Infant; Infant, Newborn; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmic Artery; Retinal Diseases; Retinal Neoplasms; Retinal Vessels; Retinoblastoma; Retrospective Studies; Topotecan; Young Adult

To use our intra-arterial chemotherapy (IAC) rabbit model to assess the impact of IAC procedure, drug, dose, and choice of technique on ocular structure and function, to study the nature and etiology of IAC toxicity, and to compare to observations in patients.. Rabbits received IAC melphalan (0.4-0.8 mg/kg), carboplatin (25-50 mg), or saline, either by direct ophthalmic artery cannulation, or with a technique emulating nonocclusion. Ocular structure/function were assessed with examination, electroretinography (ERG), fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography, prior to and 5 to 6 weeks after IAC. Blood counts were obtained weekly. We reviewed our last 50 IAC treatments in patients for evidence of ocular or systemic complications.. No toxicity was seen in the saline control group. With standard (0.4 mg/kg) melphalan, no vascular/microvascular abnormalities were seen with either technique. However, severe microvascular pruning and arteriolar occlusions were seen occasionally at 0.8 mg/kg doses. ERG reductions were dose-dependent. Histology showed melphalan dose-dependent degeneration in all retinal layers, restricted geographically to areas of greatest vascular density. Carboplatin caused massive edema of ocular/periocular structures. IAC patients experienced occasional periocular swelling/rash, and only rarely experienced retinopathy or vascular events/hemorrhage in eyes treated multiple times with triple (melphalan/carboplatin/topotecan) therapy. Transient neutropenia occurred after 46% of IAC procedures, generally after triple therapy.. IAC toxicity appears to be related to the specific drug being used and is dose-dependent, rather than related to the IAC procedure itself or the specific technique selected. These rabbit findings are corroborated by our clinical findings in patients.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Carboplatin; Dose-Response Relationship, Drug; Electroretinography; Female; Fluorescein Angiography; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Models, Animal; Ophthalmic Artery; Rabbits; Retina; Retinal Diseases; Retinal Neoplasms; Retinal Vessels; Retinoblastoma; Retrospective Studies; Tomography, Optical Coherence

To assess risk factors for ophthalmic vascular events after intra-arterial chemotherapy (IAC) for retinoblastoma.. Retrospective cohort study.. Patients who received unilateral IAC as primary treatment for retinoblastoma from January 1, 2009, to November 30, 2017, at a single center.. Records were reviewed for patient demographics, tumor features, IAC parameters, and treatment-related vascular events in the early IAC era (2009-2011) compared with the recent era (2012-2017) using the t test and Fisher exact test. Change in event rates over time was assessed using Poisson regression analysis, with Spearman's rho used to test correlation.. Rate of IAC-induced ophthalmic vascular events.. There were 243 chemotherapy infusions in 76 eyes of 76 patients, divided into early (22 eyes, 57 infusions) and recent (54 eyes, 186 infusions) eras. Intra-arterial chemotherapy consisted of melphalan (243 infusions), topotecan (124 infusions), and carboplatin (9 infusions). A comparison (early vs. recent era) revealed fewer mean number of infusions (2.6 vs. 3.4, P = 0.02) with similar mean patient age and presenting tumor features. Event rates decreased over time (P < 0.01), with fewer ophthalmic vascular events (early era vs. recent era) in the recent era (59% vs. 9% per eye, 23% vs. 3% per infusion, P < 0.01), including peripheral retinal nonperfusion (5% vs. 2% per eye, P = 0.50), vitreous hemorrhage (9% vs. 2%, P = 0.20), subretinal hemorrhage (0% vs. 2%, P = 0.99), branch retinal vein occlusion (5% vs. 0%, P = 0.29), choroidal ischemia (14% vs. 4%, P = 0.14), and ophthalmic artery spasm/occlusion (27% vs. 0%, P < 0.01). Events did not correlate to patient age (P = 0.75), tumor diameter (P = 0.32), tumor thickness (P = 0.59), or cumulative dosage of melphalan (P = 0.13) or topotecan (P = 0.59). There were no IAC-induced vascular events in 72 infusions of 21 consecutively treated eyes in 2016 to 2017.. Ophthalmic vascular events after IAC have decreased from the early era (2009-2011) through the current era (2012-2017) at this center. Experience performing this highly specialized procedure could be an important factor predicting IAC-related vascular events.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Child; Child, Preschool; Female; Fluorescein Angiography; Humans; Infant; Infusions, Intra-Arterial; Male; Melphalan; Ophthalmoscopy; Retinal Diseases; Retinal Neoplasms; Retinal Vessels; Retinoblastoma; Retrospective Studies; Risk Factors; Topotecan; Ultrasonography; Young Adult

To report real-time ophthalmoscopic findings during superselective intraophthalmic artery chemotherapy (SSIOAC) in a nonhuman primate model.. Six adult male Rhesus macaques (Macacca mulatta) were randomly assigned to 1 of 2 treatment cohorts: melphalan (5 mg/30 mL) or carboplatin (30 mg/30 mL). Each animal underwent 3 separate SSIOAC procedures at 3-week intervals. Digital retinal images were obtained during each infusion. Intravenous fluorescein angiography was performed immediately after each procedure.. All SSIOAC procedures were successfully completed. Toxicities were equally distributed between drug cohorts. Systemic toxicities included mild bone marrow suppression in all animals and anorexia in 1. One animal had greater than 50% narrowing of the treated ophthalmic artery after its second infusion. All 18 procedures (100%) resulted in pulsatile optic nerve and choroid blanching, retinal artery narrowing, and retinal edema. Of the 18 procedures, retinal artery sheathing was found during 17 (94%), and retinal artery precipitates were seen in 10 (56%); choroidal hypoperfusion was seen by fluorescein angiogram in 18 (100%).. Real-time ophthalmic investigations are useful and, in our nonhuman primate model, indicate prevalent, acute ocular vascular toxicities during SSIOAC.. Real-time retinal imaging is feasible in a nonhuman primate model of SSIOAC. Application to SSIOAC in children may shed insight into reported vascular toxicities.

Topics: Angiography; Animals; Antineoplastic Agents, Alkylating; Carboplatin; Chemotherapy, Cancer, Regional Perfusion; Fluorescein Angiography; Fluoroscopy; Macaca mulatta; Male; Melphalan; Ophthalmic Artery; Ophthalmoscopy; Retinal Diseases

To investigate the toxic effects of perfusion of intravitreal melphalan during vitrectomy on the rabbit retina.. We performed electoretinography (ERG) in 18 eyes of 18 healthy albino rabbits before and after intraocular melphalan perfusion at concentrations of 5-, 10-, and 20-microg/ml during pars plana vitrectomy. Fellow eyes that underwent vitrectomy without melphalan served as controls. The histopathologic retinal changes were observed in both eyes of two rabbits from each group.. In the 5-microg/ml perfusion group, the ERGs and histology showed no substantial changes compared with control fellow eyes during 28 days postoperatively. In the 10- and 20-microg/ml groups, the mean a-wave amplitude decreased to 52% and 31% respectively of the fellow eye; the mean b-wave amplitude decreased to 52% and 19% respectively. However, the peak implicit time of the a- and b-waves did not significantly differ in the 10- and 20-microg/ml groups during 28 days postoperatively. Histologic sections showed necrosis of the inner nuclear layer and thinning of the outer nuclear layer in the 10-microg/ml group. Loss of the outer nuclear layer and the photoreceptor layer and necrosis of the inner nuclear layer were observed in the 20-microg/ml group.. The intravitreal 5-microg/ml melphalan perfusion during vitrectomy appears to be nontoxic to the retina. This therapeutic modality might be a potential treatment for retinoblastoma with vitreous seeding.

Topics: Animals; Antineoplastic Agents, Alkylating; Electroretinography; Infusions, Parenteral; Melphalan; Ophthalmoscopy; Rabbits; Retina; Retinal Diseases; Vitrectomy