Although malignancies involving the vitreous are relatively uncommon, intravitreal chemotherapeutics are a key component of the treatment for these disease entities. Knowledge of the indications and side effects of these medications is useful for retina specialists treating, counseling, or comanaging these patients with ocular oncologists. Primary intraocular lymphoma, a tumor of B-cell in origin that is often considered a subset of primary central nervous system lymphoma, is the most common primary vitreous tumor in adults.1,2 Intravitreal chemotherapeutics are a key modality used to treat this disease, in addition to their use in the treatment of much rarer secondary intraocular lymphomas such as T-cell lymphoma. They are also used as adjuncts for the treatment of choroidal metastasis and for the treatment of vitreous seeding in retinoblastoma.
Intravitreal chemotherapeutics have also been used for a number of nononcologic indications including choroidal neovascularization, cystoid macular edema, noninfectious posterior uveitis, and proliferative vitreoretinopathy.3-5 While the injection technique for some of these medications is similar to that used for routine intravitreal injection for more common indications such as diabetic retinopathy and exudative age-related macular degeneration, the dosing, administration, and side-effect profiles of these medications for use in patients with ocular malignancies are unique. This review will focus primarily on the agents bevacizumab (Avastin; Genentech), methotrexate, and rituximab (Rituxan; Genentech), which are used more commonly in the adult population, in addition to the agents melphalan and topotecan, which are primarily used in pediatric patients to treat retinoblastoma with vitreous seeds.
Bevacizumab is a monoclonal antibody that binds to all isoforms of vascular endothelial growth factor A (VEGF-A).6 Most retina specialists are familiar with its use for the treatment of diabetic retinopathy and macular degeneration. However, for patients with choroidal melanoma receiving treatments such as plaque brachytherapy or proton beam therapy, bevacizumab is used to both prevent and treat radiation retinopathy.7-9 The most commonly used dose is the standard 1.25 mg/0.05 mL concentration, though other dosing strategies have been attempted with variable efficacy.8,9 Bevacizumab offers the advantage of treating radiation retinopathy while avoiding the risks of steroid response and accelerated cataract formation that can occur with intravitreal steroid injection. However, some patients become recalcitrant to intravitreal anti-VEGF therapy and ultimately require intravitreal steroids and/or laser treatment to control their radiation retinopathy.10
Although intravitreal bevacizumab may have a role in the treatment of choroidal metastasis in some patients who have failed systemic chemotherapy, other work has suggested that it is not highly effective as monotherapy for controlling choroidal metastasis.11,12 Bevacizumab may be used as an adjunct to reduce subretinal fluid and improve vision in patients with choroidal metastasis from a variety of primary tumors while definitive management with external beam radiation, plaque brachytherapy, or systemic chemotherapy is initiated.11,12 Bevacizumab may also be used as an adjunct for treating cystoid macular edema and subretinal fluid associated with vascular tumors such as vasoproliferative tumor and retinal capillary hemangioma.13 Given the large excess of VEGF production in patients with von Hippel Lindau syndrome, bevacizumab is not often effective as monotherapy, but may be used in combination with laser and photodynamic therapy in an effort to reduce subretinal and intraretinal fluid.14,15
The injection technique for bevacizumab in the setting of patients with ocular malignancies is similar to standard pars plana injection protocols for other indications with potential complications of corneal abrasion and irritation, endophthalmitis, cataract, and retinal tear or detachment.9,16 However, for patients with previously treated uveal melanoma or other intraocular solid neoplasms, care should be taken to avoid the site of the tumor and areas of previously irradiated sclera when selecting the injection site.
Methotrexate is a dihydrofolate reductase inhibitor that exerts cytotoxic activity through inhibition of nucleotide synthesis.17 Methotrexate offers the advantage of efficacy in treating both B-cell and T-cell lymphoma with vitreous involvement, as opposed to rituximab, which is limited to use in neoplasms of B-cell origin. For treatment of primary vitreoretinal lymphoma, most protocols have used a dose of 400 µg/0.10 mL; however, the frequency of injections for induction and maintenance has varied.18,19 Most protocols incorporate induction, consolidation, and maintenance regimens such as 2 times weekly for 4 weeks, 1 time weekly for 8 weeks, followed by monthly maintenance injections.18,20 Close communication with medical oncology is important because many patients receive systemic or intrathecal chemotherapy and radiation to the brain; and treatment of the patient’s ocular disease must be tailored to each patient’s clinical scenario.19,21,22 External-beam radiation to the globes may be favored over intravitreal injections on rare occasions.23
Keratitis is one of the most common side effects of intravitreal methotrexate, and patients should be counseled regarding the need for aggressive ocular surface lubrication while on therapy.20,24,25 Other reported complications have included progression of cataract, maculopathy, vitreous hemorrhage, and sterile endophthalmitis.20 Patients undergoing frequent intravitreal methotrexate injections should be monitored for these complications and counseled appropriately to call with problems after injections.
Intravitreal methotrexate has also been used in smaller case series and individual cases for the treatment of choroidal neovascularization, cystoid macular edema, noninfectious uveitis, and proliferative vitreoretinopathy, with variable efficacy.26-28 Larger, randomized studies are needed to determine the precise role that methotrexate may play in the treatment of these disorders.
The injection technique for methotrexate is similar to that for injection of other intravitreal agents with standard sterile techniques being employed. Consideration of inferotemporal injection with coverage of the injection site by a sterile, cotton-tipped applicator to prevent medication reflux may be considered to minimize corneal toxicity. Anterior-chamber paracentesis may also be required for intraocular pressure lowering, given the 0.10-mL volume administered at most centers, and this may be performed before injection to minimize reflux.19 Some centers may require that any wasted medication be disposed of in a chemotherapy-specific container.
Rituximab is an anti-CD20 antibody that targets B-cells, so it is limited in use to B-cell lymphomas.25,29 Intravitreal rituximab is usually administered at a dose of 1 mg/0.10 mL and offers the advantage of less corneal toxicity with better tolerance compared to methotrexate.25 Dosing regimens have also varied with rituximab, with weekly injections for 4 weeks followed by monthly injections thereafter being a more commonly used regimen.23,25,30 Rituximab may also be used in combination with methotrexate in some instances or alternated with methotrexate to avoid toxicity.19,30 Although some patients do show good response to rituximab, there are more reported treatment failures with rituximab monotherapy, and treatment regimens may ultimately require a change to methotrexate, combination therapy, or radiation in refractory cases.25,30 More common reported side effects of intravitreal rituximab are elevated intraocular pressure and anterior-segment inflammation.25,30 Injection technique is the same as that described for other intravitreal agents with attention to the potential of intraocular pressure spike with the 0.10 mL volume.
In children with retinoblastoma and vitreous seeding, intravitreal agents are generally used in combination with focal consolidation, systemic chemotherapy, or intra-arterial chemotherapy. Melphalan is an alkylating agent that results in cell death by causing DNA damage and has been used with efficacy as an adjunct in this setting.31 The typical melphalan dose is 20-30 µg/0.10 mL. Dosing frequency varies between centers and according to patient response.32 Side effects have included cataract, chorioretinal atrophy, iris atrophy, uveitis, and vitreous hemorrhage.32-34 The ERG response has also been noted to diminish in patients requiring multiple injections, and there may be an increased risk of toxicity in patients with more heavily pigmented eyes.31 A small case series has also suggested that intravitreal melphalan may have a role in the treatment of refractory primary intraocular lymphoma.35
In the setting of retinoblastoma, intravitreal injections are generally performed in the operating room. Cryotherapy is performed at the injection site to prevent extraocular extension of tumor, and care must be taken to avoid solid tumors to select the correct distance from the limbus given the difference in pars plana location among children of different ages.32
Topotecan is a topoisomerase inhibitor that exerts is chemotherapeutic activity by interfering with DNA synthesis.36 It has shown efficacy in treating vitreous seeds in patients with retinoblastoma, usually at a dose of 20-30 µg/0.10 mL.31,32,34,37 Topotecan has been used both as monotherapy to avoid toxicity in individuals with darkly pigmented eyes or patients with melphalan allergy, and it is also used in concert with melphalan in patients with slow melphalan response or a large amount of vitreous seeds.31,32,34 Intravitreal topotecan has been reported to be well tolerated with fewer of the inflammatory side effects that have been reported with melphalan.21,37 The injection technique is similar to that described for intravitreal melphalan above.
Intravitreal injection of chemotherapeutic agents has become an increasingly important tool for managing patients with intraocular malignancies. Specific knowledge of the disease, the location of the tumor within the globe, and the specific anatomy of the eye are vital to placing the needle and the agent in the proper location for optimal therapy, and to minimize complications. The dosing, indications, and potential side effects of these agents are unique, and the treating retina specialist or ocular oncologist must take these into consideration when treating and counseling patients. Good communication among the teams of retina specialists, ocular oncologists, medical oncologists, and radiation oncologists treating patients with ocular malignancies is imperative to high-quality care. RP
- Mochizuki M, Singh AD. Epidemiology and clinical features of intraocular lymphoma. Ocul Immunol Inflamm. 2009;17(2):69-72.
- Sagoo MS, Mehta H, Swampillai AJ, et al. Primary intraocular lymphoma. Surv Ophthalmol. 2014;59(5):503-516.
- Maass J, Matthe E. [Intravitreal methotrexate for treatment of uveitic cystoid macular edema]. Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft. 2018;115(7):595-597.
- Khalil HE, El Gendy HA, Youssef HA, Haroun HE, Gheita TA, Bakir HM. The effectiveness of intraocular methotrexate in the treatment of posterior uveitis in Behcet’s disease patients compared to retrobulbar steroids injection. J Ophthalmol. 2016;2016:1678495.
- Mateo-Montoya A, Baglivo E, de Smet MD. Intravitreal methotrexate for the treatment of choroidal neovascularization in multifocal choroiditis. Eye (Lond). 2013;27(2):277-278.
- Shojaei F, Ferrara N. Antiangiogenesis to treat cancer and intraocular neovascular disorders. Lab Invest. 2007;87(3):227-230.
- Shah SU, Shields CL, Bianciotto CG, et al. Intravitreal bevacizumab at 4-month intervals for prevention of macular edema after plaque radiotherapy of uveal melanoma. Ophthalmology. 2014;121(1):269-275.
- Mashayekhi A, Rojanaporn D, Al-Dahmash S, Shields CL, Shields JA. Monthly intravitreal bevacizumab for macular edema after iodine-125 plaque radiotherapy of uveal melanoma. Eur J Ophthalmol. 2014;24(2):228-234.
- Finger PT, Chin KJ, Semenova EA. Intravitreal anti-VEGF therapy for macular radiation retinopathy: a 10-year study. Eur J Ophthalmol. 2016;26(1):60-66.
- Kaplan RI, Chaugule SS, Finger PT. Intravitreal triamcinolone acetate for radiation maculopathy recalcitrant to high-dose intravitreal bevacizumab. Br J Ophthalmol. 2017;101(12):1694-1698.
- Maudgil A, Sears KS, Rundle PA, Rennie IG, Salvi SM. Failure of intravitreal bevacizumab in the treatment of choroidal metastasis. Eye (Lond). 2015;29(5):707-711.
- Fenicia V, Abdolrahimzadeh S, Mannino G, Verrilli S, Balestrieri M, Recupero SM. Intravitreal bevacizumab in the successful management of choroidal metastases secondary to lung and breast cancer unresponsive to systemic therapy: a case series. Eye (Lond). 2014;28(7):888-891.
- Rogers C, Damato B, Kumar I, Heimann H. Intravitreal bevacizumab in the treatment of vasoproliferative retinal tumours. Eye (Lond). 2014;28(8):968-973.
- Agarwal A, Kumari N, Singh R. Intravitreal bevacizumab and feeder vessel laser treatment for a posteriorly located retinal capillary hemangioma. Int Ophthalmol. 2016;36(5):747-750.
- Mennel S, Meyer CH, Callizo J. Combined intravitreal anti-vascular endothelial growth factor (Avastin) and photodynamic therapy to treat retinal juxtapapillary capillary haemangioma. Acta Ophthalmol. 2010;88(5):610-613.
- Falavarjani KG, Nguyen QD. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: a review of literature. Eye (Lond). 2013;27(7):787-794.
- Cronstein BN, Bertino JR. Milestones in drug therapy. Basel, Switzerland: Birkhauser Verlag; 2000.
- Frenkel S, Hendler K, Siegal T, Shalom E, Pe’er J. Intravitreal methotrexate for treating vitreoretinal lymphoma: 10 years of experience. Br J Ophthalmol. 2008;92(3):383-388.
- Chan CC, Rubenstein JL, Coupland SE, et al. Primary vitreoretinal lymphoma: a report from an International Primary Central Nervous System Lymphoma Collaborative Group symposium. Oncologist. 2011;16(11):1589-1599.
- Smith JR, Rosenbaum JT, Wilson DJ, et al. Role of intravitreal methotrexate in the management of primary central nervous system lymphoma with ocular involvement. Ophthalmology. 2002;109(9):1709-1716.
- Abu Samra K, Oray M, Ebrahimiadib N, Lee S, Anesi S, Foster CS. Intraocular lymphoma: descriptive data of 26 patients including clinico-pathologic features, vitreous findings, and treatment outcomes. Ocul Immunol Inflamm. 2018;26(3):347-352.
- Akiyama H, Takase H, Kubo F, et al. High-dose methotrexate following intravitreal methotrexate administration in preventing central nervous system involvement of primary intraocular lymphoma. Cancer Sci. 2016;107(10):1458-1464.
- Pe’er J, Hochberg FH, Foster CS. Clinical review: treatment of vitreoretinal lymphoma. Ocul Immunol Inflamm. 2009;17(5):299-306.
- Sahay P, Maharana PK, Temkar S, Chawla R. Corneal epithelial toxicity with intravitreal methotrexate in a case of B-cell lymphoma with ocular involvement. BMJ Case Rep. 2018;2018.
- Hashida N, Ohguro N, Nishida K. Efficacy and complications of intravitreal rituximab injection for treating primary vitreoretinal lymphoma. Transl Vis Sci Technol. 2012;1(3):1.
- Sadaka A, Sisk RA, Osher JM, Toygar O, Duncan MK, Riemann CD. Intravitreal methotrexate infusion for proliferative vitreoretinopathy. Clin Ophthalmol. 2016;10:1811-1817.
- Taylor SR, Habot-Wilner Z, Pacheco P, Lightman SL. Intraocular methotrexate in the treatment of uveitis and uveitic cystoid macular edema. Ophthalmology. 2009;116(4):797-801.
- Tsui E, Fern CM, Goldberg NR. Treatment of refractory tubercular serpiginous-like choroiditis with intravitreal methotrexate. Retin Cases Brief Rep. 2018. [Epub ahead of print]
- Scott SD. Rituximab: a new therapeutic monoclonal antibody for non-Hodgkin’s lymphoma. Cancer Pract. 1998;6(3):195-197.
- Larkin KL, Saboo US, Comer GM, et al. Use of intravitreal rituximab for treatment of vitreoretinal lymphoma. Br J Ophthalmol. 2014;98(1):99-103.
- Francis JH, Brodie SE, Marr B, Zabor EC, Mondesire-Crump I, Abramson DH. Efficacy and toxicity of intravitreous chemotherapy for retinoblastoma: four-year experience. Ophthalmology. 2017;124(4):488-495.
- Shields CL, Douglass AM, Beggache M, Say EA, Shields JA. Intravitreous chemotherapy for active vitreous seeding from retinoblastoma: outcomes after 192 consecutive injections. The 2015 Howard Naquin Lecture. Retina. 2016;36(6):1184-1190.
- Smith SJ, Smith BD, Mohney BG. Ocular side effects following intravitreal injection therapy for retinoblastoma: a systematic review. Br J Ophthalmol. 2014;98(3):292-297.
- Rao R, Honavar SG, Sharma V, Reddy VAP. Intravitreal topotecan in the management of refractory and recurrent vitreous seeds in retinoblastoma. Br J Ophthalmol. 2018;102(4):490-495.
- Shields CL, Sioufi K, Mashayekhi A, Shields JA. Intravitreal melphalan for treatment of primary vitreoretinal lymphoma: a new indication for an old drug. JAMA Ophthalmol. 2017;135(7):815-818.
- Newton MW, Wetzstein G, Sullivan D. Cancer management in man: chemotherapy, biological therapy, hyperthermia, and supporting measures. New York: Springer; 2011.
- Schaiquevich P, Carcaboso AM, Buitrago E, et al. Ocular pharmacology of topotecan and its activity in retinoblastoma. Retina. 2014;34(9):1719-1727.