Systemic bevacizumab treatment of a juxtapapillary retinal haemangioma

Abstract

A 49-year-old man presented in our clinic with reduced vision in his right eye. On fundus biomicroscopy a solitary red−orange lesion with lipid exudation extending into the macula and associated serous detachment were seen (Fig. 1A). Fluorescein angiography (Fig. 1B, C) revealed a juxtapapillary hyperfluorescent vascular lesion, and due to the typical filling pattern, a diagnosis of a retinal capillary haemangioma (RCH) was established. The growth pattern appeared sessile. The subject's family history was negative for von Hippel−Lindau syndrome (VHL) and other VHL manifestations were excluded. Given the large size and juxtapapillary location of the tumour, a decision was made to treat the patient with photodynamic therapy (PDT) in an attempt to preserve adjacent retinal tissue. Photodynamic therapy with verteporfin was delivered to the tumour using the typical protocol (6 mg/m2 body surface area infused over 10 mins and at a spot duration of 83 seconds). A diode laser emitting at 689 nm and an irradiance of 600 mW/cm2 was used for photoactivation, applying a total light dose of 50 J/cm2. A single exposure and a single spot were directed on the tumour prominence, sparing the central vascular stem. Subsequently, triamcinolone acetonide 4 mg/0.1 ml (Kenalog®; Bristol-Myers Squibb, Uxbridge, UK) was injected intravitreally. Tumour activity and exudative detachment increased and a portion of lipid exudates moved inferiorly (Fig. 2A−C). A second injection of intravitreal triamcinolone acetonide (IVTA) administered 4 months later at the same dosage again showed a limited therapeutic effect, with somewhat decreased tumour activity (Fig. 3A−C). Exudation persisted and visual acuity declined from 0.3 (20/60) to hand motions. We gained the informed consent of the patient and the approval of the local ethics committee to administer six cycles of bevacizumab (6 mg/kg body weight) every second week from November 2004 to February 2005. Four months after the last bevacizumab cycle, lipid exudates and tumour activity were seen to have decreased and central subretinal fibrotic alterations were observed (Fig. 4A−C). Together with the angiographic findings, we interpreted these changes as reflecting reduced tumour activity, transient regression and partial therapeutic effect. However, associated serous retinal detachment of the macula and cystoid oedema were still present and vision remained unchanged. One year after treatment, severe progression of retinal detachment was found and the patient refused further treatment. (A) Fundus photograph, (B) early- and (C) late-phase fluorescein angiograms of the patient's right eye, showing the juxtapapillary capillary retinal haemangioma (arrow) before any treatment, with massive lipid exudates and associated exudative retinal detachment. (A) Fundus photograph, (B) early- and (C) late-phase fluorescein angiograms of the patient's right eye 12 weeks after combined photodynamic therapy and intravitreal triamcinolone acetonide, showing movement of lipid exudates inferiorly (asterisk), but increased tumour activity (arrow), leakage and exudative detachment. (A) Fundus photograph, (B) early- and (C) late-phase fluorescein angiograms of the patient's right eye 4 weeks after intravitreal triamcinolone acetonide and prior to bevacizumab treatment, showing reduced perivascular leakage and a slight decrease in tumour activity (arrow). (A) Fundus photograph, (B) early- and (C) late-phase fluorescein angiograms of the patient's right eye 4 months after six cycles of bevacizumab, showing partial regression of lipid exudates (asterisk), reduced tumour activity (arrow) and central subretinal fibrotic alterations. Solitary retinal haemangiomas of the optic nerve head are usually unilateral and imply a poor visual prognosis (Garcia-Arumi et al. 2000; Schmidt-Erfurth et al. 2002). Loss of central vision is a substantial threat in patients with juxtapapillary RCHs, particularly those located temporally. Small and peripherally located RCHs can be easily treated with traditional laser photocoagulation or cryotherapy, but larger juxtapapillary tumours are difficult to treat. Multiple sessions are usually necessary and can increase the extent of exudative detachment. Moreover, RCHs are located within the retinal layers and effective laser photocoagulation of a juxtapapillary lesion will therefore inevitably lead to visual deterioration. Various therapies, such as transpupillary thermal therapy, brachytherapy or vitrectomy, have shown unsatisfactory results (Garcia-Arumi et al. 2000). Photodynamic therapy has been reported to achieve a thrombotic effect and fibrosis in some patients with juxtapapillary RCHs (Schmidt-Erfurth et al. 2002). It has been shown that highly vascularized tumours such as haemangiomas are dependent on vascular endothelial growth factor (VEGF) and that an overproduction of VEGF leads to haemangioma-like lesions. In order to reduce the expression of VEGF and leakage of endothelial tight junctions, PDT was combined with IVTA. As the effect was limited and RCH is a vascular tumour, a systemic VEGF-targeted strategy seemed reasonable. Three publications have reported promising results in patients with retinal haemangiomas, all of which were associated with VHL and all of which were treated with the VEGF-receptor-inhibitor SU5416. Aiello et al. (2002) described visual recovery, Girmens et al. (2003) reported a decrease in associated macular oedema, and Madhusudan et al. (2004) demonstrated a complete regression of a retinal haemangioma. Inspired by these case reports, we decided to apply a systemic anti-VEGF therapy using bevacizumab. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that links to human VEGF and inhibits its biological activity by preventing the interaction of VEGF with its receptors Flt-1 and KDR on the surface of endothelial cells. At the time antiangiogenic treatment was chosen, no anti-VEGF drug was available for intravitreal use. Therefore we decided to treat the patient with the bevacizumab treatment protocol approved for patients with metastatic colorectal cancer. By contrast with the promising results achieved with the VEGF-receptor-inhibitor SU 5416 in patients with RCH associated with VHL (Aiello et al. 2002), systemic bevacizumab failed to have a significant effect on the solitary juxtapapillary RCH. Whereas bevacizumab is a recombinant VEGF antibody that inhibits binding between VEGF and its receptors, SU 5416 is a VEGF receptor 2-inhibitor. The different entity of disease as well as the different antiangiogenic pathways of the respective substances may be responsible for the reduced treatment response. The close time relationship between treatment and the reduction of lipid exudates is interpreted as an intermediate treatment benefit and justifies further study. However, it should be remembered that little is known of the natural course of RCHs and the changes we observed may have been spontaneous. Moreover, bevacizumab was used as a third-line therapy after PDT/IVTA and IVTA alone. Therefore, no final conclusion can be drawn about its efficiency, although this did appear to be better than that of PDT and IVTA. Intravitreal application of the antiangiogenic drugs available now may be more effective in this otherwise incurable disease. However, as in other retinal disorders, the effect is likely to be typically transient and to wane when antiangiogenic treatment is discontinued. Therefore, laser photocoagulation is still the treatment with the best-evidenced efficacy, despite its destructive properties and unfavourable functional results.