Verteporfin and other Cytotoxics for the Eye

Cytotoxic drugs have a role in ophthalmology units in the treatment of a few conditions, examples of which are outlined below. As with other conditions requiring these drugs, therapy is initiated and monitored by specialists.

Age-related macular degeneration: verteporfin (Visudyne®)

• Action - this is a light-activated compound which selectively exerts its cytotoxic effects on the subretinal neovascular membrane found in wet age-related macular degeneration. It is preferentially taken up by rapidly dividing endothelial cells of the developing vessels; laser light is then applied. Its energy is taken up by the photosensitive verteporfin causing damage to the vascular endothelial cells and thrombotic occlusion of the blood vessels with the neovascular membrane.
• Administration - photodynamic therapy (PDT) is offered to those patients with a visual acuity of 6/60 or above. It is carried out in an outpatient setting: verteporfin is infused intravenously over 10 minutes and then 5 minutes later, a laser diode is applied to the target area on the retina. The treatment can be repeated at 3-monthly intervals.¹
• Ocular side-effects - visual disturbances, sub-retinal and vitreous haemorrhage are possible problems. Severe visual loss occurs in 1-4% of patients which may be permanent in a small proportion of these patients.²
• Systemic side-effects - photosensitivity: patients are advised to avoid bright light during treatment and for 48 hours thereafter. Hypersensitivity reactions, nausea, pruritus, fever, back pain, hypercholesterolaemia and reactions at the site of injection.

Age-related macular degeneration: anti-vascular endothelial growth factor treatment

• Action - these are agents that interfere with angiogenesis by binding to vascular endothelial growth factors (VEGFs) to prevent endothelial cell proliferation. Ranibizumab (Lucentis®) has recently been licensed for use in the UK.³ Pegaptanib (Macugen®) is not the recommended first line treatment but used by some.
• Administration - there are a number of specific criteria identified in a nationally-used protocol, prepared by the Royal College of Ophthalmologists and endorsed by NICE, guiding the administration ± discontinuation of this drug.³ It is administered directly into the vitreous of the eye under sterile conditions. Three doses are given at four-weekly intervals in the first instance and the patient's response is monitored according to strict protocols before further treatment is given.
• Ocular side-effects - these may be related to the procedure, which is invasive, or to the drug itself. Complications are uncommon but may include endophthalmitis, traumatic lens injury, retinal detachment, uveitis and periocular infections.^2,3
• Systemic side-effects - hypersensitivity reaction, thrombo-embolic phenomena.³
• New developments - Bevacizumab (Avastin®) - more commonly encountered in the treatment of metastatic colorectal cancer - is being assessed as another candidate drug; data is limited but promising so far,⁴ as are early results of trials combining these anti-VEGF drugs with PDT⁵ and other treatment modalities.²

Glaucoma: 5-fluorouracil, mitomycin C

• Action - 5-fluorouracil prevents normal cellular division by irreversible combination with cellular enzymes. Mitomycin C's alkylating properties inhibit DNA replication.
• Administration - subconjunctival injection during or soon after a trabeculectomy procedure to suppress episcleral fibrosis of the drainage bleb.
• Ocular side-effects - there may be local irritation and failure of action. Mitomycin C may increase the risk of cataract formation in the long-term.⁶
• Systemic side-effects - not seen with topical injection but, should the drug inadvertently enter the circulation, they include: oral mucositis, hyperuricaemia, nausea and vomiting, bone marrow suppression, alopecia and disruption of reproductive function. The very small quantities used are unlikely to cause these effects.

Other conditions

• PDT can be used for other conditions presenting with formation of a neovascular membrane, such as in the presence of retinal angioid streaks,⁷ ocular histoplasmosis syndrome and in Best's disease but verteporfin is not yet licensed for this in the UK.
• Von Hippel-Lindau syndrome, which gives rise to retinal capillary haemangiomas, can also be treated with photodynamic therapy,⁸ as can choroidal haemangiomas.⁹
• PDT has been used in the treatment of choroidal neovascularisation associated with high myopia.¹⁰
• Certain patients with severe or chronic uveitis associated with non-infectious, multi-system disease such as Behçet's disease and Vogt-Koyanagi-Harada syndrome show poor response to conventional steroids and eventually necessitate ciclosporin, azathioprine or chlorambucil.^8,11,12

• Tumours can arise within the globe (retina, choroids, iris), the optic nerve and the surrounding tissues (eyelid, conjunctiva, orbit) but can also be exogenous (chronic lymphocytic leukaemia), intraocular lymphoma.¹³
• Treatment of these lesions tends to revolve around radiotherapy, thermotherapy and surgery but chemotherapy finds a place in the treatment of metastatic disease, particularly in debulking large tumours, such as in the case of retinoblastoma.¹¹
• Topically applied chemotherapy can be used in more superficial lesions such as conjunctival melanomas and squamous cell carcinomas,^14,15 especially where there is poor definition of lesion margins. Otherwise, surgical excision is the mainstay of therapy.¹¹

1. The clinical effectiveness and cost effectiveness of photodynamic therapy for age related macular degeneration. NICE Technology Appraisal (September 2003).
2. Age related Macular Degeneration - Guidelines for Management, Royal College of Ophthalmologists (February 2009)
3. Royal College of Ophthalmologists; Ranibizmab: The Clinician’s Guide to commencing,continuing and discontinuing treatment (June 2008).
4. The Intravitreal use of Bevacizumab (Avastin) in Age Related Macular Degeneration, Royal College of Ophthalmologists (February 2009)
5. Kaiser PK, Boyer DS, Garcia R, et al; Verteporfin photodynamic therapy combined with intravitreal bevacizumab for neovascular age-related macular degeneration. Ophthalmology. 2009 Apr;116(4):747-55, 755.e1. Epub 2009 Feb 25. [abstract]
6. Wilkins M, Indar A, Wormald R; Intra-operative Mitomycin C for glaucoma surgery. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD002897. DOI: 10.1002/14651858.CD002897.pub2.
7. Abusamak M; Angioid Streaks. eMedicine, (October 2008).
8. Kunimoto DY, Kanitkar KD, Makar MS; The Wills Eye Manual, 4th Edition, 2004, Lippincott, Williams and Wilkins.
9. Boixadera A, Garcia-Arumi J, Martinez-Castillo V, et al; Prospective clinical trial evaluating the efficacy of photodynamic therapy for symptomatic circumscribed choroidal hemangioma. Ophthalmology. 2009 Jan;116(1):100-105.e1. Epub 2008 Oct 30. [abstract]
10. Lam DS, Chan WM, Liu DT, et al; Photodynamic therapy with verteporfin for subfoveal choroidal neovascularisation of pathologic myopia in Chinese eyes: a prospective series of 1 and 2 year follow up. Br J Ophthalmol. 2004 Oct;88(10):1315-9. [abstract]
11. Kanski J. Clinical Ophthalmology, A Systematic Approach, 5th Ed, 2003, Butterworth Heinemann.; Pages 193-269.
12. Arthritis Research and Therapy; 1st Workshop of the International Society for Behcet?s Disease (ISBD) on Pathophysiology and Treatment of Behcet?s Disease, April 2003 .
13. Finger PT; List of eye cancer conditions.
14. Finger PT, Czechonska G, Liarikos S; Topical mitomycin C chemotherapy for conjunctival melanoma and PAM with atypia. BJO 1998; 82: 476-479.
15. Midena E, Angeli CD, Valenti M et al.; Treatment of conjunctival squamous cell carcinoma with topical 5-fluorouracil. BJO 2000;84:268-272.

• Eye Cancer Network; Good overview with lots of patient information
• RNIB; Best's disease