Ocular toxicity associated with anti-HER2 agents in breast cancer: A pharmacovigilance analysis using the FAERS database.

Anti-human epidermal growth factor receptor 2 (HER2) agents have exhibited pronounced tumor-inhibitory activity, yet the accompanying ocular toxicity has frequently been underestimated. We aim to conduct a comprehensive comparative analysis of ocular toxicity risk related to various anti-HER2 agents. We executed a retrospective pharmacovigilance investigation based on the FDA Adverse Event Reporting System (FAERS) database, covering the period from Q2 2018 to Q1 2023. The disproportionality analysis was performed to assess ocular toxicity risk. Multivariate logistic regression was implemented to mitigate potential biases. Moreover, the time to onset of ocular toxicity was also evaluated. A total of 3467 ocular adverse event (AE) reports concerning anti-HER2 agents were collected. At the preferred term (PT) level, there were 69 positive signals, among which excessive eye blinking, abnormal sensation in the eye, and asthenopia presented a significant risk. In comparison to tyrosine kinase inhibitors (TKIs), antibody drugs were associated with a broader range of ocular disorders at Standardized MedDRA Queries (SMQ)levels, including conjunctival disorders, corneal disorders, ocular infections, ocular motility disorders, optic nerve disorders, and retinal disorders. In terms of onset time, pertuzumab displayed an earlier onset at 21.5 days, while trastuzumab deruxtecan had the latest at 91.5 days. In summary, our study reveals varying degrees of ocular toxicity related to anti-HER2 agents, with a significantly higher risk observed in antibody drugs. Additionally, novel ocular toxicity signals, not documented in product labels, have been detected. In the future, further research will be necessary to validate our findings.

The Involvement of Unfolded Protein Response in the Mechanism of Nitrogen Mustard-Induced Ocular Toxicity.

Nitrogen mustard (NM) is a known surrogate of sulfur mustard, a chemical-warfare agent that causes a wide range of ocular symptoms, from a permanent reduction in visual acuity to blindness upon exposure. Although it has been proposed that the two blistering agents have a similar mechanism of toxicity, the mode of NM-induced cell death in ocular tissue has not been fully explored. Therefore, we hypothesized that direct ocular exposure to NM in mice leads to retinal tissue injury through chronic activation of the unfolded protein response (UPR) PERK arm in corneal cells and VEGF secretion, eventually causing cell death. We topically applied NM directly to mice to analyze ocular and retinal tissues at 2 weeks postexposure. A dramatic decline in retinal function, measured by scotopic and photopic electroretinogram responses, was detected in the mice. This decline was associated with enhanced TUNEL staining in both corneal and retinal tissues. In addition, exposure of corneal cells to NM revealed 228 differentially and exclusively expressed proteins primarily associated with the UPR, ferroptosis, and necroptosis. Moreover, these cells exhibited activation of the UPR PERK arm and an increase in VEGF secretion. Enhancement of VEGF staining was later observed in the corneas of the exposed mice. Therefore, our data indicated that the mechanism of NM-induced ocular toxicity should be carefully examined and that future research should identify a signaling molecule transmitted via a prodeath pathway from the cornea to the retina. SIGNIFICANCE STATEMENT: This study demonstrated that NM topical exposure in mice results in dramatic decline in retinal function associated with enhanced TUNEL staining in both corneal and retinal tissues. We also found that the NM treatment of corneal cells resulted in 228 differentially and exclusively expressed proteins primarily associated with ferroptosis. Moreover, these cells manifest the UPR PERK activation and an increase in VEGF secretion. The latter was also found in the corneas of the cexposed mice.

Ocular toxicities in chimeric antigen receptor T-cell therapy: a real-world study leveraging FAERS database.

Aim: The purpose of this study was to comprehensively explore the ocular toxicity associated with chimeric antigen receptor (CAR) T-cell therapy. Materials & methods: Data were assembled from the US FDA's Adverse Event Reporting System (FAERS) database from 2017 to 2023. Information component and reporting odds ratio methods were used for signal detection in total/categorized CAR T-cell therapy. Results: A total of 17 positive signals (preferred term) were detected, yet none of them were documented in the product information. Some adverse events were with death outcomes and overlapped a lot with cytokine-release syndrome. Conclusion: The ocular adverse events associated with CAR-T cell therapy are noteworthy, and it is imperative to maintain increased alertness and institute early intervention strategies.

CAR-T-cell therapy is a highly effective treatment for blood cancers that has gained significant attention as a promising therapy in recent years. However, a complete analysis of its side effects on eyes has not been determined. In this study, we examined eye-related adverse events with five US Food and Drug Administration (FDA)-approved CAR T-cell therapies by using data from the FDA. We found that certain eye issues such as dilated pupils, impaired pupillary light reflex and eye surface bleeding deserve attention. Surprisingly, these problems were not mentioned in the product information. Since some adverse events can have severe outcomes, it is important to be vigilant and take early action.

Antibody-Drug Conjugates and Ocular Toxicity.

Antibody-drug conjugates (ADCs) are a growing class of chemotherapeutic agents for the purpose of treating cancers that often have relapsed or failed first- and second-line treatments. ADCs are composed of extremely potent cytotoxins with a variety of side effects, one of the most significant being ocular toxicity. The available literature describes these toxicities as varying in severity and in incidence, although with disparate methods of evaluation and management. Some of the most common toxicities include microcyst-like epithelial keratopathy and dry eye. We discuss proposed mechanisms of ocular toxicity and describe the reports that mention these toxicities. We focus on ADCs with the most published literature and the most significant effects on ocular tissue. We propose areas for further investigation and possible ideas of future management. We provide a comprehensive look at the reports of ADCs in current literature to better inform clinicians on an expanding drug class.

Ocular toxicities associated with antibody drug conjugates and immunotherapy in oncology: clinical presentation, pathogenesis, and management strategies.

INTRODUCTION: The development of molecularly targeted anticancer therapies and immunotherapy continues to revolutionize the treatment of cancer. FDA accelerated approvals of novel targeted therapies allowed for introduction of these agents into the clinic at a rapid rate. On-and off-target ocular toxicities are prevalent treatment-related adverse events of newer therapies including antibody drug conjugates (ADCs) and immunotherapy. Ocular toxicities associated with ADCs and immunotherapy have heterogeneous presentations and pathogenesis requiring unique and often complex monitoring, and management. AREAS COVERED: In this article, we provide an updated review of treatment-emergent ocular toxicity associated with new and novel oncologic therapies and summarize guidelines and best practice strategies for prevention, monitoring and management. A literature search was performed through PubMed, ClinicalTrials.gov, and FDA website (1 January 2017 to 10 May 2023) to identify relevant information. EXPERT OPINION: The implementation of a strategy for monitoring, prevention, and management of treatment-related ocular toxicities involves a multi-disciplinary, often cross-center approach. Communication with infusion nursing leadership, clinic staff, and eye care providers is crucial to the successful implementation of eye care plans to prevent and manage ocular toxicity.

Cyclopentenylcytosine (CPE-C): In Vitro and In Vivo Evaluation as an Antiviral against Adenoviral Ocular Infections.

Adenoviruses are the major cause of ocular viral infections worldwide. Currently, there is no approved antiviral treatment for these eye infections. Cyclopentenylcytosine (CPE-C) is an antiviral that has demonstrated activity against more than 20 viruses. The goals of the current study were to determine the in vitro and in vivo antiviral activity of CPE-C as well as its ocular toxicity. Antiviral activity was evaluated in vitro using standard plaque reduction assays to determine the 50% effective concentrations (EC50s) and in vivo in the Ad5/NZW rabbit ocular replication model. Ocular toxicity was determined in uninfected rabbit eyes following topical ocular application. The in vitro EC50s for CPE-C ranged from 0.03 to 0.059 µg/mL for nine adenovirus types that commonly infect the eye. Ocular toxicity testing determined CPE-C to be non-irritating or practically non-irritating by Draize scoring. In vivo, 3% CPE-C topically administered 4X or 2X daily for 7 days to adenovirus-infected eyes demonstrated effective antiviral activity compared with the negative control and comparable antiviral activity to the positive control, 0.5% cidofovir, topically administered twice daily for 7 days. We conclude CPE-C was relatively non-toxic to rabbit eyes and demonstrated potent anti-adenoviral activity in vitro and in vivo.

FDA Approval Summary: Mirvetuximab Soravtansine-Gynx for FRα-Positive, Platinum-Resistant Ovarian Cancer.

On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9-41.6] with a median duration of response of 6.9 months (95% CI, 5.6-9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx.

Management of Belantamab Mafodotin-Associated Keratopathy With Rigid Gas-Permeable Corneal Contact Lenses.

ABSTRACT: Belantamab mafodotin is a relatively new drug used in the treatment of relapsed or refractory multiple myeloma. Clinical studies have shown promising responses, but ocular toxicity remains a major challenge with dose reduction or therapy discontinuation being the only available treatment option. We report a clinical case of a patient with severe keratopathy under therapy with belantamab. The use of rigid gas-permeable corneal contact lenses led to a major visual improvement and enabled therapy continuation at full dose over several months. Although this strategy may not be suitable for all patients, it provides an additional option for the treatment of ocular toxicity of this promising agent.

Ocular toxicity of investigational anti-cancer drugs in early phase clinical trials.

Ocular toxicities arising from anti-cancer drugs occur sporadically and are sometimes underestimated because they are not life-threatening. Reports focusing on ocular toxicities from cancer therapy are limited. We investigated the detailed progress of ocular toxicities of anti-cancer drugs including first-in-class ones. A retrospective review of medical records was conducted for patients who were involved in early phase clinical trials with scheduled ophthalmologic examinations according to their protocols between January 2014 and August 2021. Patients with ocular toxicity suspected to be related to the investigational drugs in the ophthalmic examination were investigated in detail. In total, 37 ocular toxicities related to investigational drugs occurred in 7.6% of patients (33/434). The median age of the 33 patients was 61 years (range, 33-76 years), and 20 were male. Causal drugs with a high incidence of ocular toxicities were HSP90 inhibitors and FGFR inhibitors. Retinopathy was most frequent, while conjunctivitis, dry eye, keratitis, keratopathy, and uveitis were also observed. Dim vision as a subjective finding was a unique adverse event. Most patients developed ocular toxicities even though their dose was below the drug's maximum tolerated dose. Except for one case, all ocular toxicities occurred bilaterally. About 60% (22/37) of ocular toxicity cases needed a temporary hold of the drug. All except for three cases fully recovered. This study reported the risks and timing of the onset of a variety of ocular toxicities of anti-cancer drugs, which were fundamentally controllable. (Trial registration number. Retrospectively registered).

Ocular toxicity following carboplatin chemotherapy for neuroendocrine tumour of the bladder.

INTRODUCTION: Carboplatin is a commonly used platinum analogue chemotherapeutic agent that is similar to cisplatin but is known to be better tolerated. This case report outlines a case of ocular toxicity following carboplatin chemotherapy used for the management of a neuroendocrine tumour of the bladder. CASE REPORT: A 70-year-old man with a history of neuroendocrine bladder cancer underwent chemotherapy with carboplatin and etoposide. He presented 4 weeks following his fourth chemotherapy cycle with a 1-week history of right eye blurriness. The patient had suffered a similar episode 2 weeks following his third chemotherapy cycle in his left eye. Carboplatin-induced ocular toxicity was suspected and his vision remained stable following cessation of carboplatin chemotherapy. DISCUSSION: Current literature on carboplatin-induced ocular toxicity remains scanty, however, previous cases have reported symptoms beginning 5 days to 2 weeks following carboplatin use. Visual disturbance in the form of altered colour vision, blind spot, blurred vision and metamorphopsia have been reported by previous literature. This case report emphasised a case of bilateral sequential blurring of vision following carboplatin chemotherapy. CONCLUSION: It remains critical for ophthalmologists and oncologists to look out for ocular side effects of chemotherapy due to its devastating effects.

Bromelain protects against cisplatin-induced ocular toxicity through mitigating oxidative stress and inflammation.

The aim of this study was to investigate the molecular, biochemical, and histopathological effects of bromelain, which has antioxidant and anti-inflammatory properties, against cisplatin-induced ocular toxicity. The groups were designed as (1) Control, (2) Cisplatin (7 mg/kg, intraperitoneally), (3) Cisplatin + Bromelain (50 mg/kg, orally for 14 consecutive days), (4) Cisplatin + Bromelain (100 mg/kg, orally for 14 consecutive days). The activity of total antioxidant capacity (TAC) and total oxidant status (TOS) and levels of reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-1ß (IL-1ß), IL-10, nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α) and 8-OHdG were measured in ocular tissue. The mRNA expression of NF-κB and Caspase-3 was also evaluated. Also, ocular sections were evaluated histopathologically. Bromelain demonstrated a dose-dependent protective effect in cisplatin-induced toxicity by regulating oxidative stress, inflammation, and tissue damage. Our results suggested that bromelain may be a potential adjuvant that can protect the eye from cisplatin-induced toxicity.

Perillaldehyde Protects Against Aspergillus fumigatus Keratitis by Reducing Fungal Load and Inhibiting Inflammatory Cytokines and LOX-1.

PURPOSE: The purpose of this research was to explore the antifungal and anti-inflammatory effects of perillaldehyde (PAE) in Aspergillus fumigatus (A. fumigatus) keratitis and the underlying mechanism. METHODS: The biofilm formation, adherence assay, and propidium iodide uptake test were used to determine the possible mechanism of PAE in terms of antifungal effects in vitro. The severity of corneal infection was evaluated by clinical scores. The immunofluorescence staining (IFS) was adopted to detect the number of macrophages in infected corneas. Draize test was performed to assess the ocular toxicity of PAE. Real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Western blot reflected the expression of inflammatory cytokines and Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) in mice corneas and RAW264.7 cells. RESULTS: PAE was able to inhibit the formation of biofilm, reduce conidial adhesion, and damage the integrity of membranes to exert antifungal activity. In C57BL/6 mice models, PAE alleviated the severity of infected corneas, reduced the recruitment of macrophages and had low ocular toxicity. In addition, the mRNA and protein levels of TNF-α, CCL-2, and LOX-1 could be significantly decreased by the application of PAE after A. fumigatus infection in vivo and in vitro. CONCLUSION: Our study indicated that PAE protected against A. fumigatus keratitis by reducing fungal load, accumulation of macrophages, and inhibiting the expression of inflammatory cytokines.

Impact of belantamab mafodotin-induced ocular toxicity on outcomes of patients with advanced multiple myeloma.

Belantamab mafodotin (BLMF) is a B-cell maturation antigen-directed antibody-drug conjugate, recently approved for advanced multiple myeloma (MM). The impact of BLMF-induced ocular toxicity on patient outcomes is unknown. We studied a cohort of 38 consecutively seen patients treated with BLMF outside of trials. Of those, 75% experienced ocular toxicity, with 69% developing keratopathy. Among patients requiring ocular toxicity-related permanent BLMF discontinuation (14%) or dose reduction (11%), 70% had progression of MM within a median of 3 months (95% confidence interval: 0.2-not reached) following BLMF interruption or dose reduction. Ocular toxicity is a major deterrent to the continuous use of BLMF in routine clinical practice. Measures to successfully prevent and mitigate ocular toxicity should be developed to achieve the full potential of this agent.

Rare ocular toxicity induced by pertuzumab/QL1209 in healthy chinese subjects: case reports and whole-exome sequencing analysis.

Pertuzumab is a recombinant anti-HER2 humanized monoclonal antibody widely used for the adjuvant treatment of HER2-positive breast cancer. Its safety is well established with the most common adverse effects being diarrhea and rash. To our knowledge, severe pertuzumab-induced ocular adverse events have never been reported. Herein, we describe several cases of pertuzumab/QL1209 (pertuzumab biosimilar)-induced blurred vision in healthy Chinese male subjects after a single injection of 420 mg pertuzumab/QL1209. Persistent optic nerve damage and vision loss occurred in the most severe case even after ophthalmic treatment. We conducted whole-exome sequencing (WES) of DNA samples from 5 cases and 13 controls to analyze the potential genetic factors and identified some associated variants (rs80303690 in RBM24, rs117375173 in CASR, rs1805097 in IRS2, and rs1227049 in CDH23). Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) terms gene enrichment analyses were carried out for differentially expressed genes clustered in the PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways, which were exactly activated by HER2 phosphorylation. In summary, this is the first report describing the occurrence of ocular toxicity induced by pertuzumab in the Chinese population and exploring the possible genetic mechanisms. These findings could provide evidence for clinicians to raise concerns about the risk of ocular toxicity with the clinical use of pertuzumab.

[Ocular toxicity of targeted therapies with MEK inhibitors and BRAF inhibitors in the treatment of metastatic cutaneous melanoma]. / Toxicité oculaire des thérapies ciblées anti-MEK et anti-BRAF dans le traitement des mélanomes cutanés métastatiques.

INTRODUCTION: Cutaneous melanoma is a malignant tumor, which develops from dermal melanocytes. Targeted therapies have changed the therapeutic management of metastatic melanoma and improved the survival rate. Among the various targeted therapies, MEK inhibitors and BRAF inhibitors have demonstrated efficacy, but they may lead to ocular toxicity. The goal of this study was to assess the incidence of ocular complications caused by the use of MEK inhibitors and BRAF inhibitors and to report their clinical features and therapeutic management. MATERIAL AND METHODS: This retrospective, observational, descriptive, single center study was conducted between May 2015 and December 2019 and included all patients with metastatic cutaneous melanomas treated with MEK inhibitors and BRAF inhibitors in whom ophthalmic toxicity was suspected. The data collected were demographic data (age, sex), the type of MEK inhibitors and BRAF inhibitors used, the length of time from melanoma diagnosis, mean duration of ophthalmological follow-up, time differential between starting therapy and the emergence of ocular complications, initial and final logMAR visual acuity, biomicroscopic examination of the anterior segment, dilatated fundus examination, and treatment administered. RESULTS: Fifty-four eyes of 27 patients with a mean age of 61.3±14.3 were included. The mean time delay between melanoma diagnosis and initiation of treatment was 23.2±8 months. Twenty patients (74%) were treated with a combination of MEK inhibitors and BRAF inhibitors (trametinib/dabrafenib), 5 patients (19%) were treated with MEK inhibitor monotherapy (cobimetinib), and 2 patients (7%) were treated with BRAF inhibitor monotherapy (vemurafenib). The mean duration of ophthalmological follow-up was 77.8±29 days, and the delay between the start of therapy and the emergence of symptoms was 87.2±78 days. The mean initial visual acuity was 0.075±0.13 logMAR, and the final visual acuity was 0.01±0.03 logMAR. Twelve patients (44%) developed ocular complications due to the targeted therapy. In the patients who received combination trametinib/dabrafenib, 5 patients (18.5%) developed clinical signs of uveitis, from acute anterior uveietis to panuveitis, and 2 patients (7.4%) developed bilateral central serous chorioretinopathy; in the patients who received cobimetinib, 4 patients (14.8%) developed bilateral central serous chorioretinopathy; and one patient (3.7%) who received vemurafenib developed acute anterior uveitis. For these 12 patients with ophthalmic side effects, temporary discontinuation of therapy was chosen for six patients (22.2%), three patients (11.1%) received half the initial dose, and for three patients (11.1%), normal dosing was continued. CONCLUSION: The two main side effects of targeted therapies are uveitis for BRAF inhibitors and central serous chorioretinopathy for MEK inhibitors. A multidisciplinary approach including ophthalmologists, dermatologists and oncologists is essential in order to adapt treatment in the advent of these ocular complications.

Ocular Toxicity in Breast Cancer Management: Manual for The Oncologist.

Ocular adverse events are common to many antineoplastic agents, although often misunderstood. In most cases, they are easily manageable, but sometimes they require instrumental diagnostics and specific treatments. There are currently no international guidelines for the management of these toxicities. In this review we summarized the main ocular adverse events related to the antineoplastic agents used in the treatment of breast cancer, analyzing their clinical presentation and management, trying to provide a useful tool to be used in clinical practice.

Dramatic Improvement of Severe Cicatricial Ectropion after Discontinuing Long-Term Erlotinib Therapy in a Patient with Lung Cancer

There is no consensus on the choice of systemic and ophthalmic treatment for patients who develop ocular toxicity with erlotinib in the few cases reported previously. Various ocular complications related to erlotinib have been reported, with one of the most serious being corneal perforation. Our patient was at risk of potential corneal perforation because of severe cicatricial ectropion and diffuse punctate corneal epitheliopathy. Therefore, erlotinib treatment was temporarily discontinued with the approval of the oncology department and the patient was closely followed. She was prescribed steroid eye ointment, single-use preservative-free artificial tears, and eye lubricant gel to protect the ocular surface. On day 4 of treatment, the patient's findings were significantly improved. After 1 week, the cicatricial ectropion had dramatically improved and the patient's complaints were completely resolved. To our knowledge, there is no case report of a patient with both ocular toxicity after long-term use that shows dramatic improvement with drug cessation, and severe cicatricial ectropion affecting the entire lower eyelid. Here, we described a patient who used erlotinib for 3 years due to non-small cell lung cancer and developed severe cicatricial ectropion which improved dramatically within one week of temporarily discontinuing erlotinib and discussed the possible reasons. Although ocular complications with erlotinib are usually encountered early in treatment, it should be kept in mind that erlotinib-related ocular complications may also arise with long-term use.

High local control and low ocular toxicity using ultra-low-dose "boom-boom" radiotherapy for indolent orbital lymphoma.

BACKGROUND: The first line definitive treatment for early-stage indolent B-cell lymphoma is radiation therapy (RT). Due to the sensitivity of orbital structures to radiation, ultra-low-dose RT (4 Gy in 2 fractions, "boom-boom") has and been utilized as an attractive option for orbital lymphoma. In this retrospective study, we evaluated the outcome and toxicity of "boom-boom" RT for indolent orbital lymphoma with an emphasis on ophthalmologic toxicity. METHODS: This is a retrospective case series with 17 patients with orbital lymphoma who received boom-boom RT at a single tertiary referral center between January 2017 and June 2022. Medical records, imaging and radiation treatment plans were reviewed. Endpoints included response rate, progression, and ocular toxicity per oncologist and ophthalmology reports. RESULTS: A total of 17 patients (12 female and 5 male) with 19 indolent orbital lymphomas were included. Median follow-up was 39 months. Complete, partial, and stable response was achieved in 65%, 24%, and 12% of patients, respectively. Only 1 patient developed local recurrent 47 month after radiation treatment, and was successfully salvaged with standard dose radiation (24 Gy). Five-year distant progression rate is 18%. Oncologist-reported Common Terminology Criteria for Adverse Events (CTCAE) toxicity rates were 6% grade 1 and 0% grade 2+. Ophthalmologist reported 33.3% new post-RT toxicities including dry eye, cataract, and chorioretinal atrophy. There is no significant vision acuity change after RT. CONCLUSIONS: "Boom-Boom" RT (4 Gy in 2 fractions) provides excellent control for indolent orbital lymphoma. While minimal toxicity was documented by radiation oncologists, higher rates were noted by ophthalmologists, highlighting the radiosensitivity of orbital structures and potentially underreported ocular toxicity in "boom-boom" and standard regimens. Further prospective randomized studies are needed to better define the outcome and toxicity of ultra-low-dose (4 Gy) RT for ocular lymphoma.