Ocular Toxicity Profile Research Articles

Ocular Toxicity Profile of Targeted Cancer Therapy (TCT) at a US Tertiary Cancer Center.

Targeted cancer therapy (TCT) is a significant advancement in oncology with promising survival improvement in patients with cancer and remarkable effects on various cancers. There is evidence suggesting a connection between specific TCT classes and the occurrence of immune-related adverse events (irAEs). Our study aims to investigate the potential ocular toxicities of different classes of TCT, provide a better understanding of these toxicities, and aid in the future development of screening and management recommendations for ocular irAEs. Retrospective observational case series. Only ocular immune-related AEs were included in the study; patients on TCT who received a new ophthalmic diagnosis were seen atthe MD Anderson Cancer Center. Between 2010 and 2019, we retrospectively reviewed the medical records of 6,354 patients on TCT at a large US tertiary cancer center. Results:The criteria for data analysis were met by 1861 patients. TCT was associated with a wide range of class-specific ocular irAEs. There was a statistically significant correlation between ocular toxicity with polytherapy with a p-value of <0.001. Furthermore, there was a statistically significant correlation between toxicity and BRAF, epidermal growth factor receptor (EGFR), and ICI <0.001, <0.001, and 0.006, respectively. Conclusion:Our cohort is the most extensive case series in English literature, demonstrating the increased risk of class-specific ocular toxicity associated with TCT, which sheds some light on the importance of developing standardized grading criteria and management guidelines.

Hydrocortisone loaded poly-(3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles for topical ophthalmic administration: Preparation, characterization and evaluation of ophthalmic toxicity.

Poly-(3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles (PHBV-NPs) to encapsulate hydrocortisone (HC) for topical ophthalmic administration were prepared and characterized. The technique used to prepare the nanoparticles (NPs) was emulsification/solvent evaporation. The obtained size was 237.3 ± 2.7 nm, suitable for topical ocular administration. The obtained results for the entrapment efficiency were between 1 and 2.5% and for the drug loading were around 0.5%. The release behaviour of HC from the PHBV-NPs was also analyzed, adjusting this to a Higuchi kinetic model. For the new drug delivery system developed the ocular toxicity profile was determined by viability studies carried out on bovine keratocytes, by a Hen's Egg Test - Chorioallantoic Membrane (HET-CAM) and by a Bovine Corneal Opacity and Permeability assay (BCOP). The obtained results concluded that the new system is no cytotoxic on bovine keratocytes and is neither irritating nor produces any alteration in the transparency and in the permeability of the cornea. Confocal studies were also performed and confirmed that PHBV-NPs are able to penetrate efficiently into the corneal tissue. This novel PHBV-based drug delivery system could be a good option for topical ophthalmic administration of drugs.

Erratum: Ocular toxicities associated with targeted anticancer agents: an analysis of clinical data with management suggestions.

[This corrects the article DOI: 10.18632/oncotarget.17634.].

Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors.

ST-162 and ST-168 are small-molecule bifunctional inhibitors of MEK and PI3K signaling pathways that are being developed as novel antitumor agents. Previous small-molecule and biologic MEK inhibitors demonstrated ocular toxicity events that were dose limiting in clinical studies. We evaluated in vitro and in vivo ocular toxicity profiles of ST-162 and ST-168. Photoreceptor cell line 661W and adult retinal pigment epithelium cell line ARPE-19 were treated with increasing concentrations of bifunctional inhibitors. Western blots, cell viability, and caspase activity assays were performed to evaluate MEK and PI3K inhibition and dose-dependent in vitro toxicity, and compared with monotherapy. In vivo toxicity profile was assessed by intravitreal injection of ST-162 and ST-168 in Dutch-Belted rabbits, followed by ocular examination and histological analysis of enucleated eyes. Retinal cell lines treated with ST-162 or ST-168 exhibited dose-dependent inhibition of MEK and PI3K signaling. Compared with inhibition by monotherapies and their combinations, bifunctional inhibitors demonstrated reduced cell death and caspase activity. In vivo, both bifunctional inhibitors exhibited a more favorable toxicity profile when compared with MEK inhibitor PD0325901. Novel MEK and PI3K bifunctional inhibitors ST-162 and ST-168 demonstrate favorable in vitro and in vivo ocular toxicity profiles, supporting their further development as potential therapeutic agents targeting multiple aggressive tumors.

Ocular toxicities associated with targeted anticancer agents: an analysis of clinical data with management suggestions.

Ocular toxicities are among the most common adverse events resulting from targeted anticancer agents and are becoming increasingly relevant in the management of patients on these agents. The purpose of this study is to provide a framework for management of these challenging toxicities based on objective data from FDA labels and from analysis of the literature. All oncologic drugs approved by the FDA up to March 14, 2015, were screened for inclusion. A total of 16 drugs (12 small-molecule drugs and 4 monoclonal antibodies) were analyzed for ocular toxicity profiles based on evidence of ocular toxicity. Trials cited by FDA labels were retrieved, and a combination search in Medline, Google Scholar, the Cochrane database, and the NIH Clinical Trials Database was conducted. The majority of ocular toxicities reported were low severity, and the most common were conjunctivitis and “visual disturbances.” However, severe events including incidents of blindness, retinal vascular occlusion, and corneal ulceration occurred. The frequency and severity at which ocular toxicities occur merits a more multidisciplinary approach to managing patients with agents that are known to cause ocular issues. We suggest a standardized methodology for referral and surveillance of patients who are potentially at risk of severe ocular toxicity.

Current treatment of lacrimal gland carcinoma.

The traditional treatment for lacrimal gland carcinoma is orbital exenteration followed by radiation therapy. However, orbital exenteration does not prevent distant relapse and death, and some patients experience local-regional recurrence after exenteration. More recently, eye-sparing surgery and adjuvant radiation therapy and chemotherapy have gained popularity in the treatment of lacrimal gland carcinoma. Preliminary studies show that these approaches are associated with reasonable local control rates and ocular toxicity profiles. In this review, we discuss recent studies of treatment of lacrimal gland carcinoma, including studies of potential molecular treatment targets. Recent studies suggest promising results for neoadjuvant intra-arterial chemotherapy followed by orbital exenteration and adjuvant intravenous chemotherapy, but only in patients with an 'intact lacrimal artery'. Recent studies of globe-sparing surgery followed by adjuvant proton radiation therapy or concurrent chemoradiation suggest good local control, reasonable rates of eye preservation, and low risk of serious ocular toxic effects. Larger tumor size and predominant basaloid histology seem to be associated with higher risk of local-regional recurrence and distant metastasis. One study showed oncogenic mutations in more than half of cases of lacrimal gland adenoid cystic carcinoma, with KRAS mutations in 10 of 24 patients, suggesting potential benefit of treatments targeting the EGFR-RAS-RAF cascade. In selected patients with lacrimal gland carcinoma, eye-sparing surgery with eye-sparing radiation therapy offers preservation of visual function with good local control and minimal radiation-induced ocular toxic effects. In patients with recurrent or metastatic disease, a search for actionable cancer-associated mutations may be prudent.

Toxicity of topical antifungal agents to stratified human cultivated corneal epithelial sheets.

Prolonged use of topical antifungal agents may compromise corneal epithelial integrity. Here, we used an in vitro model of human stratified corneal epithelium to compare the ocular toxicity profiles of 4 different antifungal eye drops. Human corneal epithelial cell sheets were cultured in a serum-free medium containing 0.1% micafungin, 1% voriconazole, 5% pimaricin, 0.1% amphotericin B, or controls (saline or 5% glucose). Cell viability and barrier function were measured by WST-1 assay and carboxyfluorescein permeability assay, respectively. Cell migration was measured on a wound healing assay. WST-1 assay and carboxyfluorescein permeability assay revealed that amphotericin B was the most toxic drug, followed by pimaricin, micafungin, and voriconazole. Cell migration on a wound healing assay was decreased in the following order, amphotericin B, pimaricin, micafungin, and voriconazole. Topical micafungin and voriconazole appeared to be the least toxic to the corneal epithelium. Drug prescription should consider not only fungal species and susceptibility but also ocular toxicity and stage of treatment.

Dye Solutions Based on Lutein and Zeaxanthin: In Vitro and In Vivo Analysis of Ocular Toxicity Profiles

Purpose: To study the safety profile of Lutein/Zeaxanthin(L/Z)-based natural dye solutions in in vitro and in vivo models.Material and methods: In vitro cytotoxicity and cellular growth experiments were carried out on ARPE-19 and human corneal epithelial (HCE) cell lines using different L/Z-based dye solutions, either alone or in association with brilliant blue (BB) or trypan blue (TB). Light and transmission electron microscopy studies were performed seven days after intravitreal injection of dye solutions in rabbits. Electroretinogram (ERG) recordings were taken at baseline and before histopathology.Results: In vitro cytotoxicity assays demonstrated that the different L/Z-based solutions (from 0.3 to 2%), either alone or in association with BB (0.025%) or TB (0.04%), did not significantly alter mitochondrial activity (≤15%) in the cell lines tested. In addition, in vitro cell growth was inhibited by up to 60% depending on the dye solution, and in direct proportion to the concentration assayed. There was no evidence of structural alterations in the neurosensory retina, retinal pigment epithelium (RPE), or choriocapillaris-choroidal complex. b-Wave ERG records showed no significant differences (±15.2%) in comparison with baseline.Conclusions: L/Z-based dye solutions demonstrated a safe profile in in vitro and in vivo models, and may be a useful tool for staining intraocular structures.

605 A Phase 1, Open-label, Dose-escalation Study of Oral Administration of the Investigational Agent MLN0128 in Combination with Paclitaxel (P) in Patients (pts) with Advanced Solid Malignancies

were mainly melanoma (n = 92) and colorectal cancer (n = 37). The MTD was defined for each schedule and the RP2D was determined (Table). Dose-limiting toxicities (DLTs) were mainly skin rash and ocular events. Adverse events (AEs) reported in 20% of pts were skin rash (66%), diarrhea (60%), ocular events (50%), asthenia (42%), peripheral edema (32%), nausea (32%) and vomiting (30%). Most ocular AEs were serous retinal detachment (SRD), with or without symptoms, and were reversible with or without treatment interruption. Only 2 SRDs were grade (G) 3 (S2 255mg and S4 75mg bid), both reversible. Retinal vein occlusion (RVO) was reported in 8 pts (3 pts in S1, 4 in S2 and 1 in S3) at high exposure. All but 1 pt (S2 195mg) had a favorable outcome with recovery of vision. With bid dosing, skin rash as well as diarrhea were more frequent but were manageable with supportive care and treatment interruptions/reductions and no RVO was observed. Based on an improved ocular toxicity profile (no RVO or G3 events) and signs of clinical activity, 60mg bid was defined as the RP2D. Clinical activity was observed in melanoma with durable responses in BRAF or NRAS mutated tumors. Conclusions: The safety of four dosing schedules (interrupted vs continuous, qd and bid dosing) of pimasertib was thoroughly evaluated. The main DLTs were skin rash and ocular AEs. The RP2D of pimasertib was 60mg bid continuous dosing. Phase II studies are ongoing.

Associating retinal drug exposure and retention with the ocular toxicity profiles of Hsp90 inhibitors.

3086 Background: In clinical trials certain Hsp90 inhibitors, including AUY922, SNX-5422, and 17-DMAG have caused visual symptoms suggesting retinal dysfunction; others, including ganetespib and 17-AAG, have not. Previous animal toxicology experiments have suggested that retinal changes may be linked to photoreceptor degeneration or cell death. Here histopathologic changes and/or exposure profiles of Hsp90 inhibitors with or without clinical reports of ocular toxicity were evaluated to understand the observed differences in toxicity profile between agents in this class. Methods: We reviewed visual symptoms among subjects administered ganetespib, a potent Hsp90 inhibitor currently in phase II trials; evaluated retinal morphology in rats and cyno monkeys given ganetespib; and compared TUNEL-positive photoreceptors and drug exposure profiles in the retina of rats treated with AUY922, 17-DMAG, and 17-AAG. Studies of ganetespib’s retinal pharmacokinetics and photoreceptor toxicity in rats are ongoing. Results: AUY922 and 17-DMAG induce visual disorders in the clinic. Both drugs induced marked photoreceptor cell death (increased TUNEL-positive cells) in rats with a high retina/plasma (R/P) exposure ratio, and a slow elimination rate (at 6 h post-dose, over 54% of AUY922 present at 30 min remained in the retina). In contrast, and consistent with an absence of clinical visual changes, 17-AAG at the maximum tolerated dose did not elicit photoreceptor injury. Further, retinal elimination was rapid (at 6 h post-dose, 94% of 17-AAG had been eliminated from the retina, resulting in a low R/P ratio). Ganetespib given by 1‑hour IV infusion on days 1 and 15 of four 21-day cycles did not cause histopathological changes in the retina of rats or cynos. This finding is consistent with very low rate (~3%) of drug-related visual symptoms observed among over 300 subjects to date that received ganetespib in the clinic. Conclusions: Unlike AUY922 and 17-DMAG, ganetespib is not associated with ocular toxicity in humans, primates, or rodents. The findings suggest that Hsp90 inhibitors may elicit visual disorders when associated with high retina/plasma exposure ratio and lower retinal elimination rate.