Treatment of ocular metastasis with anti-VEGF: A literature review and case report Haley Augustine, MScOT,* Monique Munro, MD,† Feisal Adatia, MD, FRCSC,† Marc Webster, MD, PhD, FRCPC,‡ Michael Fielden, MD, FRCSC§ ABSTRACT ● RÉSUMÉ Purpose: This is the first case report where 1.25 mg intravitreal bevacizumab (IVB) correlated with choroidal mass resolution from metastatic breast cancer given concurrently with chemotherapy demonstrating, at best, disease stability in other organs. Study design: Case report. Methods: Upon confirmation of choroidal, liver and bone metastasis from breast carcinoma, a 72-year-old female received four intravitreal bevacizumab 1.25 mg injections based on the presence of subretinal and intraretinal fluid. Visual outcomes were analyzed by ophthalmologic evaluation, B-scan, fluorescein angiography, and optical coherence tomography. Results: After 3 treatments of 1.25 mg intravitreal bevacizumab, visual acuity improved from 20/125 OD to 20/30 OD. These results were maintained for 5 months, after which a 4th IVB injection was given to try to further improve visual outcomes. Following this, complete resolution of the mass was observed with remaining pigmentary changes and vision improved to 20/25 one month following this. IVB was administered concurrently to systemic chemotherapy that demonstrated at best disease stability in metastases in other organs. Conclusion: In this case 1.25 mg intravitreal bevacizumab proved to be a safe, effective and relatively easy treatment for choroidal metastasis from breast cancer. An important benefit of intravitreal bevacizumab therapy for choroidal metastasis is the ease of administration and minimal time commitment required as compared to other therapies. Further studies should be conducted to confirm the appropriate dosing and long-term outcomes of intravitreal bevacizumab to treat choroidal metastasis. Objet : Ceci est le premier compte-rendu selon lequel le bevacizumab intravitréen (BIV) de 1,25 mg qui, en relation avec la résolution d’une masse choroïdienne métastatique d'un cancer de sein simultanément avec la chimiothérapie, et démontrant, au mieux, la stabilité de la maladie dans d’autres organes. Nature : Compte rendu. Méthodes : Sur confirmation d’une métastase choroïdienne, du foie et des os, dus à un carcinome mammaire, une femme de 72 ans a reçu quatre injections intravitréennes de bevacizumab 1,25 mg, fondées sur la présence de fluide sous-rétinien et intrarétinien. Les résultats visuels ont été analysés par évaluation ophtalmologique, B-scan, angiographie à la fluorescéine et tomographie par cohérence optique. Résultats : Après 3 traitements de 1,25 mg de bevacizumab intravitréen, l’acuité visuelle s’est améliorée, de 20/125 OD à 20/30 OD. Ces résultats ont été maintenus 5 mois, après quoi une 4e injection de BIV a été administrée pour améliorer davantage les résultats visuels. Par la suite, la résolution entière de la masse a été observée selon les changements pigmentaires restants et l’amélioration de la vision à 20/25 le mois suivant. Le BIV a été administré en même temps que la chimiothérapie systémique, qui avait démontré, au mieux, la stabilité de la maladie dans les métastases des autres organes. Conclusion : Dans ce cas, 1,25 mg de bevacizumab intravitréen se sont avérés un traitement sécuritaire, efficace et relativement facile pour la métastase choroïdienne provenant du cancer du sein. Un avantage important de la thérapie du bevacizumab intravitréen pour la métastase choroïdienne est la facilité d’administration et le temps minime requis comparativement à d’autres thérapies. D’autres études devraient être effectuées pour confirmer la dose appropriée et les résultats à long terme du bevacizumab intravitréen pour traiter la métastase choroïdienne.

Ocular metastases occur secondary to a number of primary malignancies, causing reduced visual acuity (VA). Metastatic breast cancer to the choroid is the most common ocular metastasis and indicates poor outcomes, with a 10month median survival.1,2 The choroid is a vascular structure with no lymphatic drainage; therefore, tumours such as breast cancer metastasize via hematologic micrometastasis.3 The main symptoms reported by patients are blurred vision and decreased VA. Other symptoms include floaters, flashes, pain, metamorphopsia, and scotomas.4 This article reviews the literature regarding the use of

anti-vascular endothelial growth factor (anti-VEGF) for all ocular metastasis and presents a case report demonstrating the resolution of a choroidal breast metastatic lesion with intravitreal bevacizumab (IVB) concurrent with systemic chemotherapy.

From the *Dalhousie University, Halifax, N.S.; †University of Calgary; ‡Tom Baker Cancer Center; and §Calgary Retina Consultants, University of Calgary, Calgary, Alta.

Can J Ophthalmol 2014;49:458–463 0008-4182/14/$-see front matter & 2014 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

Originally received Jan. 16, 2014. Final revision Jun. 18, 2014. Accepted Jun. 26, 2014 Correspondence to Michael Fielden, MD, Calgary Retina Consultants, University of Calgary, 200, 5340 1st Street SW, Calgary AB, Canada T2H 0C8; mpfi[email protected]



LITERATURE REVIEW Bevacizumab (Avastin; Roche) is a monoclonal antibody against VEGF used to inhibit tumour angiogenesis and is approved for systemic use in various metastatic malignancies

Table 1—Individual characteristics of 20 cases identified in the literature review of patients with ocular metastasis receiving anti–vascular endothelial growth factor Primary Tumour Breast


Ocular Metastasis


Chemotherapy Treatment

Dose Bevacizumab (cycles)



Yao et al. (2010)10 Zako et al. (2012)11

Concurrent Concurrent þ letrozole

Amselem et al. (2007)8 Yokouchi et al. (2013)18 Bhattacharyya et al. (2013)16 Lai et al. (2012)17 D’Antonio et al. (2012)15

Choroid Choroid and optic disc Choroid Iris Choroid Choroid Choroid

2.5 mg PRN q4 wk (9 cycles) 2.5 mg (1 cycle) NR (1 cycle)

Previous Previous Concurrent Concurrent Concurrent

Kim et al. (2009)14 Maturu et al. (2014)13

Choroid Choroid


Nakashima et al. (2011) Singh et al. (2012)



Thyroid Colon

Detorakis et al. (2012)19 Fabrini et al. (2009)21 Lin et al. (2010)7

Nasal MM

Kuo et al. (2008)5 Detorakis et al. (2012)19 Zhou et al. (2013)22

VA Pretreatment

VA Post-treatment

Tumour Size



20/20 OS

20/40 OS



CF OS 20/40

20/30 OS 20/400 (optic neuritis 2 tamoxifen) 20/60 20/20 20/125 20/60 Improved VA

Decr. Decr.

Resolved Resolved

4 mg (1 cycle) 1.25 mg q4 wk (3 cycles) 2.5 mg q4 wk (5 cycles) 2.5 mg q2 wk (2 cycles) 1.25 mg q2 wk (14 cycles)

NR RD (resolved with chemotherapy) NR N/A RD (resolution NR) NR RD- resolved

Decr. Decr. NR Decr. Decr.

Decr. N/A NR Decr. Resolved

2.5 mg q6 wk (3 cycles) 1.25 mg q4 wk (4 cycles)

RD- resolved NR

20/40 20/63

Decr. Decr.

Resolved Decr.


Previous þ concurrent erlotinib Previous þ concurrent gefitinib Concurrent

1.25 mg q4 wk (3 cycles)

RD OD (resolution NR)



1.25 mg (1 cycle)


20/80 OD 20/125 OS NR

NR OD Incr. OS Decr.

NR OD Incr. OS N/A

Choroid Choroid Choroid Choroid Choroid OS Optic nerve OD Choroid Choroid Iris

Concurrent Concurrent Concurrent None Concurrent

1.25 mg q4 wk (7 cycles) 1.25 mg q4 wk (3 cycles) 0.5 RZB q6 wk (3 cycles)* NR (1 cycle) 4 mg (4 cycles)

RD- resolved RD- worsened NR RD- resolved RD OS (resolution NR)

1.25 mg q4 wk (3 cycles) 0.5 RZB q6 wk (3 cycles)* 1.25 mg q1 wk (2 cycles)


Decr. Incr. Decr. Stable Decr. OD Incr. OS Decr. Decr. Stable

NR Incr. Resolved Decr. NR

Previous Previous radiation Concurrent

20/400 OS Progression 20/32 OD 20/20 OD 20/20 OD HM OS 20/30 OS NR 20/50 OS

SRF, subretinal fluid; RD, retinal detachment; MM, multiple myeloma; NR, not reported; Decr., decreased; CF, counting fingers; N/A, not applicable; Incr., increased.

10/200 20/40 20/200 20/200 Blurred VA þ diplopia 20/200 CF 20/20 OD 20/63 OS 20/16 OD Blurred VA 20/600 OS HM OD 20/80 OD 20/25 OD 20/20 OD 20/400 OS HM OS CF 20/25 OS

Decr. NR N/A


Choroidal metastasis effectively treated with IVB—Augustine et al.

Mansour and Alameddine (2012)9

Retinal Detachment

Choroidal metastasis effectively treated with IVB—Augustine et al. Table 2—Pooled characteristics of 20 patients with ocular metastasis who received anti-VEGF Characteristic

Pooled Result

Average age Primary tumour site Lung Breast Colorectal Thyroid Nasal MM Ocular involvement Unilateral Bilateral Anatomical site of metastasis (n ¼ 22 eyes) Choroid Iris Optic nerve Chemotherapy Previous treatment Concurrent treatment Other IVB dosing 1.25 mg 2.5 4 mg 0.5 mg ranibizumab Not reported No cycles Average: 3.4 cycles Median: 3 cycles RD (n ¼ 22 eyes) Reported cases RD Improved RD Change RD not reported Visual acuity (n ¼ 22 eyes) Improved/Stabilized Worsened Not reported Tumor size (n ¼ 22 eyes) Decrease size/Stabilized Increased size Not specified SRF (n ¼ 22 eyes) Decreased SRF/resolved Increased SRF/SRF persisted Not reported/not applicable

53 years 55% 20% 10% 5% 5% 5%

(11/20) (4/20) (2/20) (1/20) (1/20) (1/20)

90% (18/20) 10% (2/20) 73% (18/22) 14% (3/22) 5% (1/22) 50% (10/20) 25% (5/20) 25% (5/20) 45% 25% 10% 10% 10%

(9/20) (5/20) (2/20) (2/20) (2/20)

Range: 1–14 cycles

9 56% (5/9) 33% (3/9) 59% (13/22) 32% (7/22) 9% (2/22) 77% (17/22) 14% (3/22) 9% (2/22) 45% (10/22) 14% (3/22) 41% (9/22)

The cases varied in treatment regimen. Fifty percent of cases used concurrent chemotherapy, and 25% had previous chemotherapy that was ineffective for treatment of the ocular metastasis. The most common anti-VEGF treatment was 1.25 mg IVB (range 1.25–4 mg IVB and 0.5 mg ranibizumab), and the average number of injections was 3.4 (range 1–14; Table 1 and 2). Similar to the literature presented, bevacizumab was successfully used in this case report. IVB correlated with choroidal mass resolution from metastatic breast cancer given concurrently with chemotherapy demonstrating minimal response in other organs.

CASE REPORT A 72-year-old postmenopausal female presented with progressive blurred vision in the right eye over 2 months. Her VA was 20/125 OD and 20/20 OS. Fundus examination revealed a creamy, yellowish submacular choroidal mass in the right eye with associated SRF and intraretinal fluid (IRF) highly suspicious for breast cancer metastases. Fluorescein angiography, B-scan, and optical coherence tomography (OCT) supported this diagnosis (Figs. 1, 2, and 5). The mass was irregularly shaped with low internal reflectivity with SRF and IRF on OCT. She was phakic with bilateral posterior vitreous detachment. Of note, she had a 3year history of daily hydroxychloroquine (200 mg) treatment for arthritis with no evidence of maculopathy. Relevant medical history included bilateral breast cancers. In 1995, she was diagnosed with ductal carcinoma in situ of her right breast and was treated with segmental resection and radiotherapy. In 1998, microscopic invasive carcinoma arose in her left breast and was treated with

MM, multiple myeloma; IVB, intravitreal bevacizumab; RD, retinal detachment; SRF, subretinal fluid.

including colorectal and renal cell carcinoma.5 IVB is also frequently used as off-label treatment for various retinal pathologies.6 Anti-VEGF therapies such as IVB have also been applied to mitigate retinal fluid and neovascularization of ocular tumours in patients with adenocarcinoma,5,7 breast cancer,8–11 lung cancer,12–20 thyroid cancer,21 multiple myeloma,22 and nasopharyngeal carcinomas.19 The choroid appears to be the most common site for ocular metastases,5,7,9–11,13–17,19,21 with lesions also occuring at the iris,12,18 optic nerve head,7,11 and ciliary body.22 There are multiple case reports demonstrating conflicting outcomes in terms of VA, tumour size, and resolution of subretinal fluid (SRF) with the use of anti-VEGF. Details of the current literature are provided in Table 1. In summary, anti-VEGF treatment improved VA in 59% of cases, decreased or stabilized tumour size in 77% of cases, and improved or resolved SRF in 77% of cases where it was reported (Table 2).



Fig. 1 — Pretreatment B-scan (10/23/12) demonstrating choroidal mass (2.39 mm height) with low internal reflectivity.

Choroidal metastasis effectively treated with IVB—Augustine et al.

Fig. 2 — Pretreatment optical coherence tomography (10/23/12) demonstrating choroidal tumour. Intraretinal fluid and subretinal fluid are evident together with the irregular surface of the underling choroidal metastasis.

segmental resection, postoperative radiotherapy, and 5 years of tamoxifen. In 2008, she experienced development of ductal carcinoma in her right breast (2.6 cm) and had a mastectomy, with sentinel node biopsy (1/5 positive nodes; sentinel node, 0.4 mm) staged at IIB (T2N1M0). This was followed by 3 cycles of FEC-100 and 9 weekly doses of paclitaxel, and sequential adjuvant letrozole. After the presumptive diagnosis of choroidal breast cancer metastases, further investigations were performed. Staging investigations included computed tomography scans of the head, chest, abdomen, and pelvis that revealed abnormal enhancement in the right globe, multiple hepatic metastases, solitary T6 vertebral lytic lesion, and indeterminate brain lesion. Biopsy of a hepatic lesion confirmed ductal breast carcinoma, with estrogen receptor 8/8, progesterone receptor 4/8, human epidermal growth factor receptor 2 normal by ratio (HER2 copy number ¼ 4.6, centromere enumerator probe for chromosome 17 ¼ 3.6, ratio 1.3). After diagnosis, she completed 3 cycles of paclitaxel/gemcitabine from November 2012 to January 2013 achieving minimal response. Paclitaxel/gemcitabine was discontinued because of intolerance and impaired performance status. During this treatment, the patient was recommended IVB injections to resolve SRF and visual loss related to the choroidal tumour. After discussing alternate therapies, the patient elected to undergo monthly 1.25 mg IVB injections adjuvant to chemotherapy for a total of 4 treatments from November 2013 to February 2013. As second-line chemotherapy, because of poor initial response to systemic chemotherapy, the patient commenced capecitabine, and because of equivocal HER2 status by copy number, trastuzumab was administered concurrently. The interval staging investigation while receiving secondline chemotherapy revealed disease stability. She currently remains on capecitabine, trastuzumab, and denosumab for a total of 4 cycles initiated on March 2013.

As demonstrated in Table 3 and Figures 1 through 5, the VA and anatomical outcomes improved during chemotherapy and adjuvant IVB. During the course of treatment, the SRF and IRF resolved and the choroidal mass shrank (Figs. 2–5). These results were maintained throughout the 8-month follow-up.

DISCUSSION Breast cancer is the most common cause of choroidal metastasis, followed by lung cancer.1,7 The incidence of choroidal metastasis from breast cancer has decreased over time as a result of more aggressive systemic adjuvant therapies eradicating micrometastasis.4,7 The traditional approach to choroidal metastasis is external beam radiation; however, there is some preliminary evidence supporting the use of anti-VEGF therapy.2,5,7,8,10,17 Anti-VEGF therapies have antiangiogenesis properties targeted at tumours.6 The dosing of IVB in previous case reports ranged from 1.25 to 4 mg. There are

Table 3—Timeline of intravitreal bevacizumab injections together with outcomes recorded Treatment Initial visit Baseline þ first IVB F/U þ second IVB F/U þ third IVB F/U þ four IVB F/U F/U F/U F/U

Date 10/23/12 11/21/12 12/05/12 01/02/13 02/07/13 03/07/13 04/03/13 05/15/13 07/10/13

VA OD VA OS 20/125 20/50 20/50 20/60 20/30 20/30 20/25 20/25 20/25

20/20 20/20 20/20 20/20 20/20 20/20 20/20 20/20 20/20

OCT: OD comment Choroidal mass, Choroidal mass, Choroidal mass, Choroidal mass, Choroidal mass, RPE irregularity RPE irregularity RPE irregularity RPE irregularity


VA, visual acuity; OCT, optical coherence tomography; SRF, subretinal fluid; IVB, intravitreal bevacizumab; IRF, intraretinal fluid; F/U, follow-up.



Choroidal metastasis effectively treated with IVB—Augustine et al.

Fig. 3 — Post-treatment optical coherence tomography (05/15/13) demonstrating resolved choroidal tumour with retinal pigment epithelium (RPE) changes.

4 previous case reports that specifically identify choroidal metastasis secondary to breast cancer treated with bevacizumab. The details of these are summarized in Table 1. In summary, each of these case reports identifies previous chemotherapy used to treat breast cancer and choroidal metastasis with no reported improvement of choroidal tumour size, SRF, and VA until bevacizumab therapy was initiated. The one exception is a case report by Zako11 that had concomitant retinal detachment (RD) and optic disc metastasis. In this case, the RD and SRF improved with initial chemotherapy followed by bevacizumab, but the optic disc metastasis did not demonstrate VA improvements until treatment with letrozole. In other cases of choroidal metastasis, Lai et al.17 used IVB as a palliative, vision-saving treatment after lung metastasis concurrent to systemic chemotherapy and

demonstrated improvements in VA within 2 weeks. Kuo et al.5 found IVB to be an effective treatment for choroidal metastasis from colorectal cancer after previous systemic chemotherapy. During IVB injections, the patient was receiving radiation to the brain, and after 5 days of treatment VA improved from hand motions to 20/40.5 In a case of bilateral choroidal tumours secondary to colon adenocarcinoma, it was found that 4 mg IVB concurrent to chemotherapy regressed 1 tumour and improved VA, but worsened the same outcomes in the other eye.7 These results suggested that IVB is more effective in smaller choroidal metastasis.7 There was only 1 case report with an adverse outcome, where 20 months after the first IVB injection an intravitreal hemorrhage occurred.21 As outlined in the review of the literature, evidence has been reported that irrespective of the primary cancer and

Fig. 4 — Pretreatment fundus photo (10/19/2012) demonstrating choroidal tumour.

Fig. 5 — Post-treatment fundus photo (05/15/13) demonstrating regressed choroidal tumour.



Choroidal metastasis effectively treated with IVB—Augustine et al. ocular metastasis site, anti-VEGF appears to improve VA, decrease tumour size, as well as improve SRF with the use of anti-VEGF in majority of cases. This case is another example of effective choroidal tumour regression secondary to breast cancer with IVB injections. It is possible that the systemic chemotherapy assisted in shrinking the choroidal mass despite achieving only a minimal response in other organs. An important benefit of IVB therapy for choroidal metastasis is the ease of administration and minimal time commitment required. Compared with radiation therapy, this allows more free time away from a medical setting. However, there are still many uncertainties with respect to the use of anti-VEGF for ocular metastasis including optimal dose, interval, and number of injections of antiVEGF treatments, the indications for use, and maintenance therapy.

CONCLUSIONS This article presents a review of the literature on antiVEGF treatment for ocular metastasis from other primary sources. It demonstrates that anti-VEGF is an effective and noninvasive treatment for ocular metastasis to improve outcomes such as VA, tumour size, and SRF. In this case study, we present a 72-year-old patient effectively treated with IVB for a choroidal tumour secondary to metastatic breast cancer. IVB demonstrated dramatic functional and anatomic improvements, whereas the initial concurrent systemic chemotherapy achieved minimal disease response in other organs. Similar to the current literature, this case supports the use of adjuvant IVB for choroidal tumours resulting from metastatic cancers.

Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. REFERENCES 1. Freedman MI, Folk JC. Metastatic tumors to the eye and orbit. Patient survival and clinical characteristics. Arch Ophthalmol. 1987;105:1215-9. 2. Wiegel T, Bottke D, Kreusel KM, et al. External beam radiotherapy of choroidal metastases—final results of a prospective study of the German Cancer Society (ARO 95-08). Radiother Oncol. 2002;64:13-8. 3. Stephens RF, Shields JA. Diagnosis and management of cancer metastatic to the uvea: a study of 70 cases. Ophthalmology. 1979;86:1336-49. 4. Jang R, Doherty M, Hopkins J, Warner E. A case of prolonged disease-free survival in a patient with choroidal metastasis from breast cancer. Nat Clin Pract Oncol. 2009;6:118-21.

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Treatment of ocular metastasis with anti-VEGF: a literature review and case report.

This is the first case report where 1.25mg intravitreal bevacizumab (IVB) correlated with choroidal mass resolution from metastatic breast cancer give...
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