Ophthalmic Surgery, Lasers and Imaging Retina

Case Report 

Successful Management of Choroidal Metastasis With Intravitreal Ranibizumab Injections

Efstathios T. Detorakis, MD, PhD; George Agorogiannis, MD; Eleni E. Drakonaki, MD, PhD; Miltiadis K. Tsilimbaris, MD, PhD; Ioannis G. Pallikaris, MD, PhD

Abstract

Uveal metastases are the most frequent intraocular malignancy in adults. Among various treatment modalities, previous studies have described intravitreal injections of bevacizumab to suppress tumor vascularity. Because of its smaller molecular size, compared to bevacizumab, ranibizumab may offer better tissue penetration and be more efficient in suppressing neovascularization in choroidal lesions. This report presents two cases of choroidal metastases from bronchial and nasopharyngeal carcinoma that were treated as a series of three intravitreal ranibizumab injections (0.5 mg each), showing definite signs of regression. The encouraging results imply that intravitreal ranibizumab may be effective in the management of choroidal metastases, but this finding will have to be confirmed by larger prospective studies.

Abstract

Uveal metastases are the most frequent intraocular malignancy in adults. Among various treatment modalities, previous studies have described intravitreal injections of bevacizumab to suppress tumor vascularity. Because of its smaller molecular size, compared to bevacizumab, ranibizumab may offer better tissue penetration and be more efficient in suppressing neovascularization in choroidal lesions. This report presents two cases of choroidal metastases from bronchial and nasopharyngeal carcinoma that were treated as a series of three intravitreal ranibizumab injections (0.5 mg each), showing definite signs of regression. The encouraging results imply that intravitreal ranibizumab may be effective in the management of choroidal metastases, but this finding will have to be confirmed by larger prospective studies.

From the Department of Ophthalmology, University Hospital of Heraklion, Crete, Greece.

The authors have no financial or proprietary interest in the materials presented herein.

Address correspondence to Efstathios T. Detorakis, MD, PhD, Department of Ophthalmology, University Hospital of Heraklion, 71110, Heraklion, Crete, Greece. E-mail: detorakis@hotmail.com

Received: March 15, 2012
Accepted: April 02, 2012
Posted Online: May 24, 2012

Introduction

Choroidal metastases are the most frequent intraocular tumors in the adult population.1 Until recently, the management options for such tumors were mainly based on the available modalities to treat primary intraocular tumors, such as brachytherapy, external beam radiotherapy, or transpupillary thermotherapy.2 The advent of medications able to suppress vascular endothelial growth factor (VEGF) activity, such as bevacizumab (Avastin; Genentech, Inc., San Francisco, CA), have revolutionized the management of a variety of ophthalmic conditions associated with neovascularization.3 Accordingly, intravitreal bevacizumab has also been used in the treatment of choroidal metastases.4,5 However, bevacizumab was not originally designed for ophthalmic use.6 Ranibizumab (Lucentis; Novartis AG, Basel, Switzerland) is a recombinant humanized monoclonal immunoglobulin G1 (IgG1) isotype antibody fragment that also inhibits human VEGF.6 Ranibizumab is designed for ophthalmic use, having different pharmacokinetic properties concerning retinal penetration and vitreal half-time compared with bevacizumab.6,7 In this report, we present two cases of choroidal metastasis from small cell bronchial carcinoma and nasopharyngeal carcinoma that were successfully managed with intravitreal ranibizumab injections.

Case Reports

Case 1

A 62-year-old man was referred to the Department of Ophthalmology, University Hospital of Heraklion due to impaired visual acuity to his left eye that had progressively worsened during the previous 2 to 3 weeks. Systemic history was significant for a recently diagnosed small cell lung cell carcinoma, being treated with systemic chemotherapy initiated 4 weeks earlier that included doxecatel and cisplatin. Previous ophthalmic history was noncontributory.

On examination, best-corrected visual acuity (BCVA) was 20/80 in the left eye and 20/20 in the right eye. Intraocular pressure was 14 mm Hg without treatment in both eyes. Slit-lamp biomicroscopy of the anterior segment was noncontributory. Funduscopy of the left eye was significant for a large prominent amelanotic choroidal mass, with prominent internal vascularity and dye leakage on fluorescein angiography, occupying the superior nasal quadrant of the posterior pole (Fig. 1). Ultrasound examination revealed low internal reflectivity and a maximal height of 5.79 mm (Fig. 2A). A small amount of subretinal fluid was present at the inferior border of the lesion, reaching the superior border of the macular area (Fig. 2B). Taking into account the history of the patient, the lesion was considered a choroidal metastasis and a series of three intravitreal ranibizumab injections (0.5 mg) at 6-week intervals was performed. Six months following the completion of the intravitreal ranibizumab injections, the lesion showed definite signs of regression, with a reduction in both elevation and internal vascularity and mottled pigment dispersion (Fig. 3). This was accompanied by a significant improvement in BCVA to 20/32.

(A) Choroidal mass occupying the superior quadrant of the posterior pole of the first patient’s left eye. The mass is mostly amelanotic with patchy hemorrhages and irregular borders. (B) Fluorescein leakage with areas of masking of choroidal fluorescence is noted on fluorescein angiography.

Figure 1. (A) Choroidal mass occupying the superior quadrant of the posterior pole of the first patient’s left eye. The mass is mostly amelanotic with patchy hemorrhages and irregular borders. (B) Fluorescein leakage with areas of masking of choroidal fluorescence is noted on fluorescein angiography.

(A) Ultrasonographic appearance of the mass presented in Figure 1. The dome-shaped lesion has a maximal elevation of 5.79 mm. (B) The mass is associated with the presence of local subretinal fluid.

Figure 2. (A) Ultrasonographic appearance of the mass presented in Figure 1. The dome-shaped lesion has a maximal elevation of 5.79 mm. (B) The mass is associated with the presence of local subretinal fluid.

Six months following the completion of three ranibizumab intravitreal injections (at 6-week intervals), the lesions show signs of regression with mottled pigment dispersion, resolution of subretinal fluid, as well as (A) decreased internal vascularity, and (B) decreased dye leakage.

Figure 3. Six months following the completion of three ranibizumab intravitreal injections (at 6-week intervals), the lesions show signs of regression with mottled pigment dispersion, resolution of subretinal fluid, as well as (A) decreased internal vascularity, and (B) decreased dye leakage.

Case 2

A 32-year-old woman was referred to the Department of Ophthalmology, University Hospital of Heraklion due to progressively worsening impaired visual acuity in her right eye. Systemic history was significant for nasopharyngeal carcinoma that had been treated by radiotherapy elsewhere. Previous ophthalmic history was noncontributory.

On presentation, BCVA was counting fingers in the right eye and 20/20 in the left eye. Intraocular pressure was 12 mm Hg in both eyes without treatment. Anterior segment biomicroscopy of both eyes was noncontributory. A positive relative afferent pupillary defect was noted in the right eye. Funduscopy of the left eye was noncontributory. Funduscopy of the right eye was significant for a large multi-lobulated amelanotic mass, occupying most of the posterior pole (Fig. 4A). Fluorescein angiography revealed prominent dye leakage (Fig. 4B). Magnetic resonance imaging scan was performed to assess the size, position, and multi-lobulated morphology of the lesion (Fig. 5). An Apparent Diffusion Coefficient magnetic resonance imaging sequence revealed an increased cell density within the mass (Fig. 6), compatible with a neoplastic condition. Taking into account the previous history of the nasopharyngeal carcinoma, the lesion was considered a metastasis and the patient was offered a series of three intravitreal ranibizumab (0.5 mg) injections at 6-week intervals. At the same time, she was referred to the Oncology Department for further treatment. Six months following the completion of the intravitreal injections, the lesion showed signs of regression with reduced elevation, reduced internal vascularity, and pigmentary changes at its borders (Fig. 7).

(A) Multi-lobulated elevated amelanotic choroidal mass occupying a large part of the posterior pole of the right eye of the second patient. (B) Fluorescein angiography dye leakage is noted.

Figure 4. (A) Multi-lobulated elevated amelanotic choroidal mass occupying a large part of the posterior pole of the right eye of the second patient. (B) Fluorescein angiography dye leakage is noted.

(A) Sagittal T1-weighted image and (B) coronal T1-weighted image of the right orbit showing the presence of multi-lobulated low signal intensity intraocular mass (asterisks).

Figure 5. (A) Sagittal T1-weighted image and (B) coronal T1-weighted image of the right orbit showing the presence of multi-lobulated low signal intensity intraocular mass (asterisks).

(A) Axial apparent diffusion coefficient value (ADC) map of the orbits showing an inhomogeneous low signal intensity intraocular mass (arrow) at the right eye. Low signal intensity corresponds to decreased ADC values reflecting the restriction of the motion of water molecules in a highly cellular malignant lesion. The areas with lower ADC values at the periphery of the lesion correspond to areas with higher cellularity (nuclear-to-cytoplasm ratio).(B) Axial T1-weighted image of the orbits after intravenous administration of gadolinium showing inhomogeneous enhancement of the intraocular mass with increased enhancement of the peripheral part of the lesion, corresponding to increased cellularity (arrow).

Figure 6. (A) Axial apparent diffusion coefficient value (ADC) map of the orbits showing an inhomogeneous low signal intensity intraocular mass (arrow) at the right eye. Low signal intensity corresponds to decreased ADC values reflecting the restriction of the motion of water molecules in a highly cellular malignant lesion. The areas with lower ADC values at the periphery of the lesion correspond to areas with higher cellularity (nuclear-to-cytoplasm ratio).(B) Axial T1-weighted image of the orbits after intravenous administration of gadolinium showing inhomogeneous enhancement of the intraocular mass with increased enhancement of the peripheral part of the lesion, corresponding to increased cellularity (arrow).

Six months following the completion of intravitreal ranibizumab injections, the mass shows signs of regression with reduced elevation and pigment dispersion at its borders in both (A) color photography and (B) fluorescein angiography.

Figure 7. Six months following the completion of intravitreal ranibizumab injections, the mass shows signs of regression with reduced elevation and pigment dispersion at its borders in both (A) color photography and (B) fluorescein angiography.

Discussion

Although metastatic tumors may occur anywhere in the uvea, most occur in the choroid.8 Choroidal metastases originate from a variety of primary sites, including the breast, lung, gastrointestinal tract, pancreas, and skin in women and the lung, gastrointestinal tract, pancreas, prostate, kidney, and skin in men.9,10 The decision to treat a patient with choroidal metastasis is affected by the site of the primary focus, the extent of metastatic disease (widely diffuse or focal), and the systemic condition of the patient.2,9,10 Because metastases, like solid tumors, are dependent on the development of new blood vessels (neovascularization), the inhibition of tumor-induced angiogenesis could reduce their growth.4,5 Bevacizumab is a humanized anti-VEGF monoclonal antibody that inhibits endothelial cells from responding to the angiogenic protein VEGF.7 Previous studies have reported the successful treatment of choroidal metastases from a variety of primary tumors, such as lung, colorectal, and breast carcinomas, by employing a series of intravitreal injections of bevacizumab (2.5 to 4 mg)4,5,11 that are sometimes combined with epidermal growth factor receptor inhibitors, such as oral erlotinib.11 In both cases presented, we decided to perform the series of intravitreal ranibizumab injections at 6-week intervals to allow for sufficient time to observe for the effects of injections on the size and vascularity of the lesions. Previous studies have also employed intravitreal bevacizumab injections for the treatment of choroidal metastasis from non-small-cell lung carcinoma at 6-week intervals.11

Our first patient had typical features of a unifocal choroidal metastasis from lung carcinoma. Previous studies have reported a favorable response of choroidal metastasis from non-small-cell lung cancer to systemic bevacizumab and chemotherapy.12 In our report, systemic chemotherapy had been initiated 4 weeks before the initiation of intravitreal injections. Because the patient was already receiving treatment with systemic chemotherapy at the time of the diagnosis of choroidal metastasis, the development of the latter was presumably not prevented or suppressed by systemic treatment. However, this possibility cannot be excluded based on the findings of this report. The fact that the vascularity of the choroidal lesion subsided in response to the intravitreal administration of ranibizumab, local anti-VEGF activity mediated by ranibizumab may be effective for the local control of choroidal metastases. Our second patient had also already been treated with radiotherapy elsewhere, and received the intravitreal ranibizumab injections before starting systemic chemotherapy. In both cases, intravitreal ranibizumab was the only ophthalmic therapeutic modality (it was not combined with oral erlotinib, as previous studies have reported for intravitreal bevacizumab). The smaller molecular size of ranibizumab (48 Kd), compared with bevacizumab (149 Kd), may be associated with an increased retinal permeability and increased effectiveness in suppressing choroidal neovascularization.6,7 This has been described in cases of age-related macular degeneration, but may also apply in the case of choroidal tumors.

The short follow-up of patients presented in this report limits the validity of findings. Furthermore, the intravitreal ranibizumab injections described are a palliative treatment for these patients at best and, as such, include the risk of recurrence with loss of function or even anatomical loss of the eye. Because the number of cases treated with either bevacizumab or ranibizumab is small and has a short follow-up, intravitreal injections with these agents could be compared with radiation, which is the standard treatment modality for choroidal metastasis. Once evidence and longer experience on the effectiveness of the intravitreal injections have been accumulated, a prospective head-to-head comparative study between bevacizumab and ranibizumab would be required to determine whether the latter is more effective in the form of intravitreal injections for the local control of choroidal metastases.

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Authors

From the Department of Ophthalmology, University Hospital of Heraklion, Crete, Greece.

The authors have no financial or proprietary interest in the materials presented herein.

Address correspondence to Efstathios T. Detorakis, MD, PhD, Department of Ophthalmology, University Hospital of Heraklion, 71110, Heraklion, Crete, Greece. E-mail: detorakis@hotmail.com

10.3928/15428877-20120517-03

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