Int Ophthalmol (2015) 35:441–444 DOI 10.1007/s10792-015-0059-5
CASE REPORT
Rescue therapy with intravitreal aflibercept for choroidal neovascularization secondary to choroidal osteoma nonresponder to intravitreal bevacizumab and ranibizumab Andrea Saitta • Michele Nicolai • Piergiorgio Neri Michele Reibaldi • Alfonso Giovannini • Cesare Mariotti
•
Received: 10 January 2015 / Accepted: 7 March 2015 / Published online: 12 March 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract To investigate the effect of aflibercept in a rare case of choroidal neovascularization (CNV) secondary to choroidal osteoma (CO) and refractory to ranibizumab and bevacizumab. A 45-year-old male with CO-related CNV in his left eye received prior two intravitreal 1.25 mg bevacizumab injections and three intravitreal 0.5 mg ranibizumab injections without visual and anatomic improvement. Best-corrected visual acuity assessment, ophthalmic examination, fundus photography, and optical coherence tomography (OCT) were performed. Switching to intravitreal injection of 2.0 mg aflibercept was performed. After three loading doses of intravitreal aflibercept, visual acuity of the left eye improved from 20/50 to 20/32. Resolution of the persistent subfoveal fluid and reduction of retinal hemorrhage were confirmed according to ophthalmoscopy and OCT findings. No serious adverse events were observed. The treatment effect persisted during a 10-month follow-up period. In choroidal osteoma, switching to intravitreal aflibercept injection may be an effective therapeutic option
A. Saitta (&) M. Nicolai P. Neri A. Giovannini C. Mariotti Ophthalmology Department, Polytechnic University of Marche, Via Conca 71, 60020 Ancona, Italy e-mail: [email protected] M. Reibaldi Ophthalmology Department, University of Catania, Catania, Italy
for treatment of CNV refractory to ranibizumab and bevacizumab. Keywords Aflibercept Choroidal osteoma Switching Non-responder Anti-VEGF therapy
Introduction Choroidal osteoma (CO) is a rare, benign, choroidal tumor, which is composed by mature bone cells, involving mostly young healthy females in the second decade of life [1, 2]. CO is unilateral in approximately 75 % of cases and tends to be located in the juxtapapillary or peripapillary area, often with extension into the macula [3]. Choroidal neovascularization (CNV) is the most frequent complication of CO, leading to severe visual impairment [4]. Intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents, such as ranibizumab (Lucentis; Genentech, Inc, South San Francisco, CA, USA) and bevacizumab (Avastin; Genentech, Inc), can be an effective therapeutic option for CO-associated CNV, particularly when subfoveal [5–10]. Recently, a new anti-VEGF agent, aflibercept (Eylea; Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA), has shown promising efficacy for those patients non-responder to ranibizumab and bevacizumab in CNV associated with age-related macular degeneration (AMD) [11– 14]. We report a case of CO-related CNV resistant to
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other anti-VEGF agents which was successfully treated with aflibercept intravitreal injection.
Case report A 45-year-old man with CNV secondary to CO in his left eye (LE) was referred to the retina clinic of the Polytechnic University of Marche. The patient has received two consecutive monthly intravitreal injections of 1.25 mg bevacizumab with no benefit. At base line, the anterior segment had no anomalies in both eyes (BE). The best-corrected visual acuity (BCVA) was 20/50 and 20/20 in his LE, and right eye (RE), respectively. The intraocular pressure was within the normal limits in BE. The posterior pole examination showed a yellow-whitish area in the temporal side of the optic nerve head, with a grayish choroidal lesion, surrounded by fresh blood on its temporal edge. On the basis of the scarce response to bevacizumab, the patient underwent three consecutive monthly intravitreal injections of 0.5 mg ranibizumab. Unfortunately, no improvement was observed: the patient still complained metamorphopsia and the BCVA was again 20/50 in his LE. Fundus examination of the LE still showed an active CNV surrounded by fresh blood on its temporal edge involving the foveal area [Fig. 1]. Spectral domain optical coherence tomography (SD-OCT) in the LE showed persistent serous
Fig. 1 At presentation, a 45-year-old man had visual distortion with the best-corrected visual acuity (BCVA) of 20/50 despite of previous treatments with ranibizumab and bevacizumab. Color
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Int Ophthalmol (2015) 35:441–444
subretinal fluid [Fig. 2a]. Since no benefit was observed after both the treatment with bevacizumab and ranibizumab, aflibercept was considered as a rescue therapy. The patient underwent three consecutive monthly intravitreal injections of aflibercept (2.0 mg). One month after the third injection of aflibercept, SD-OCT showed no fluid under the retina as well as no blood [Fig. 2b], BCVA improved to 20/32 and the patient reported an evident reduction of metamorphopsia. One month after the third injection of aflibercept, SD-OCT showed no fluid under the retina as well as no blood [Fig. 2b], BCVA improved to 20/32 and the patient reported an evident decrease of metamorphopsia. At last follow-up, 10 months after the initiation of treatment with aflibercept, SD-OCT remained stable, as well as BCVA. No serious or minor adverse events were reported up to date.
Discussion CNV occurs within 10 years in 31–47 % of patients affected by CO [3, 4]. The treatment of CNV secondary to CO still remains controversial. When untreated, osteoma-associated CNV can result in a progressive and permanent visual impairment [4]. Several therapies have been proposed, such as laser photocoagulation, transpupillary thermal therapy, photodynamic therapy (PDT), and surgical excision,
and red-free photographs showed peripapillary choroidal osteoma complicated with hemorrhagic CNV involving the central macula
Int Ophthalmol (2015) 35:441–444
443
Fig. 2 a At presentation, spectral domain optical coherence tomography (SD-OCT) showed the presence of persistent subfoveal fluid and hyper-reflective material overlying the retinal pigmented epithelium. b One month after three consecutive intravitreal injections of aflibercept, SD-OCT
images showed a complete resolution of subfoveal fluid and decrease of the hyper-reflective material overlying the RPE. At final follow-up of 10 months, the lesion remained stable with fluid-free macula on SD-OCT and BCVA was 20/32 with a reduction of metamorphopsia
but none of them has proven effective in controlling CNV activity, as well as in improving visual acuity. Moreover, when CNV is located beneath the fovea, PDT should be avoided since decalcification of CO could result in a worsening of visual acuity: impairment of both retinal pigment epithelium and choroidal perfusion can lead to a further impairment of visual function [15]. More recently, anti-VEGF therapy has shown promising results in CO-related CNV. Several case series have described encouraging results with the use of ranibizumab or bevacizumab for CO-related CNV with an improvement of both retinal structure and visual acuity [5–10, 15]. Therefore, these data suggest that monotherapies with traditional intravitreal antiangiogenic agents might be considered an effective therapeutic option for subfoveal CO-associated CNV. On the other hand, an unpredictable number of injections are necessary for the control of CNV
activity, leading to possible tachyphylaxis, which is the reduction of therapeutic response to anti-VEGF agents. Recently, Khan et al. reported the presence of persistent subretinal fluid in 1 of 4 patients (25 %) after anti-VEGF therapy [15]. Aflibercept is a humanized fusion protein, approved in November 2011 by the Food and Drug Administration for the treatment of neovascular age-related macular degeneration [11]. Differently than ranibizumab and bevacizumab, which bind selectively VEGF-A only, aflibercept targets VEGF-B, and placental growth factor (PGF) as well. These properties lead to a superior affinity for VEGF, when compared to ranibizumab and bevacizumab. Moreover, the biologic qualities of aflibercept make this molecule potentially more efficient in the long-term control of neovascular activity, allowing less frequent re-injections, as supported by clinical trials. Recently, most case series have indicated that 2.0 mg aflibercept leads to a better anatomic
123
444
improvement in patients with persistent subretinal fluid due to macular degeneration, non-responder to traditional anti-VEGF agents [12–14]. In our case, the patient presented subretinal hemorrhage and persistent subretinal fluid despite previous treatment with intravitreal injection of bevacizumab and ranibizumab for CO-related CNV. After switching to 2.0 mg of aflibercept, there was an anatomical improvement, as well as a visual gain. The better binding affinity to VEGF-A and VEGF-B, as well as PGF, may explain the good outcome in our patient. On the other hand, we cannot rule out that tachyphylaxis may have contributed to the insufficient response to previous therapies. In conclusion, our case suggests that intravitreal aflibercept can be a promising option for CNV secondary to CO, non-responder to traditional antiVEGF agents. However, further large and long-term prospective randomized studies are necessary in order to validate the data reported in the present manuscript. Conflict of interest The authors have no conflicts of interest to declare.
Int Ophthalmol (2015) 35:441–444
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References 1. Gass JD, Guerry RK, Jack RL, Harris G (1978) Choroidal osteoma. Arch Ophthalmol 96:428–435 2. Aylward GW, Chang TS, Pautler SE, Gass JD (1998) A long-term follow-up of choroidal osteoma. Arch Ophthalmol 116:1337–1341 3. Shields CL, Sun H, Demirci H, Shields JA (2005) Factors predictive of tumor growth, tumor decalcification, choroidal neovascularization, and visual outcome in 74 eyes with choroidal osteoma. Arch Ophthalmol 123(12):1658–1666 4. Shields CL, Perez B, Materin MA, Mehta S, Shields JA (2007) Optical coherence tomography of choroidal osteoma in 22 cases: evidence for photoreceptor atrophy over the decalcified portion of the tumor. Ophthalmology 114(12):53–58 5. Ahmadieh H, Vafi N (2007) Dramatic response of choroidal neovascularization associated with choroidal osteoma to the
123
14.
15.
intravitreal injection of bevacizumab (Avastin). Graefes Arch Clin Exp Ophthalmol 245:1731–1733 Song WK, Koh HJ, Kwon OW, Byeon SH, Lee SC (2009) Intravitreal bevacizumab for choroidal neovascularization secondary to choroidal osteoma. Acta Ophthalmol 87:100–101. doi:10.1111/j.1600-0420.2007.01136.x Pandey N, Guruprasad A (2010) Choroidal osteoma with choroidal neovascular membrane: successful treatment with intravitreal bevacizumab. Clin Ophthalmol 4:1081–1084. doi:10.2147/OPTH.S13730 Song MH, Roh YJ (2009) Intravitreal ranibizumab in a patient with choroidal neovascularization secondary to choroidal osteoma. Eye (Lond) 23:1745–1746. doi:10.1038/ eye.2008.313 Carle MV, Chu TG, Liao D, Boyer DS (2014) Successful use of anti-VEGF treatment for subretinal hemorrhage and fluid in a young patient with choroidal osteoma. Ophthalmic Surg Lasers Imaging Retina 45(2):169–171. doi:10.3928/ 23258160-20140306-12 Mansour AM, Arevalo F, Al Kahtani E et al (2014) Role of intravitreal antivascular endothelial growth factor injections for choroidal neovascularization due to choroidal osteoma. J Ophthalmol 2014:210458. doi:10.1155/2014/210458 Heier JS, Brown DM, Chong V, Korobelnik JF et al (2012) Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 119(112):2537–2548. doi:10.1016/j.ophtha.2012.09.006 Bakall B, Folk JC, Boldt HC et al (2013) Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. Am J Ophthalmol 156(1):15–22. doi:10.1016/j.ajo.2013.02.017 Cho H, Shah CP, Weber M, Heier JS (2013) Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab. Br J Ophthalmol 97(8):1032–1035. doi:10. 1136/bjophthalmol-2013-303344 Kumar N, Marsiglia M, Mrejen S et al (2013) Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration. Retina 33(8):1605–1612. doi:10. 1097/IAE.0b013e31828e8551 Khan MA, DeCroos FC, Storey PP, Shields JA, Garg SJ, Shields CL (2014) Outcomes of anti-vascular endothelial growth factor therapy in the management of choroidal neovascularization associated with choroidal osteoma. Retina 34(9):1750–1756. doi:10.1097/IAE.0000000000000187
CASE REPORT
Rescue therapy with intravitreal aflibercept for choroidal neovascularization secondary to choroidal osteoma nonresponder to intravitreal bevacizumab and ranibizumab Andrea Saitta • Michele Nicolai • Piergiorgio Neri Michele Reibaldi • Alfonso Giovannini • Cesare Mariotti
•
Received: 10 January 2015 / Accepted: 7 March 2015 / Published online: 12 March 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract To investigate the effect of aflibercept in a rare case of choroidal neovascularization (CNV) secondary to choroidal osteoma (CO) and refractory to ranibizumab and bevacizumab. A 45-year-old male with CO-related CNV in his left eye received prior two intravitreal 1.25 mg bevacizumab injections and three intravitreal 0.5 mg ranibizumab injections without visual and anatomic improvement. Best-corrected visual acuity assessment, ophthalmic examination, fundus photography, and optical coherence tomography (OCT) were performed. Switching to intravitreal injection of 2.0 mg aflibercept was performed. After three loading doses of intravitreal aflibercept, visual acuity of the left eye improved from 20/50 to 20/32. Resolution of the persistent subfoveal fluid and reduction of retinal hemorrhage were confirmed according to ophthalmoscopy and OCT findings. No serious adverse events were observed. The treatment effect persisted during a 10-month follow-up period. In choroidal osteoma, switching to intravitreal aflibercept injection may be an effective therapeutic option
A. Saitta (&) M. Nicolai P. Neri A. Giovannini C. Mariotti Ophthalmology Department, Polytechnic University of Marche, Via Conca 71, 60020 Ancona, Italy e-mail: [email protected] M. Reibaldi Ophthalmology Department, University of Catania, Catania, Italy
for treatment of CNV refractory to ranibizumab and bevacizumab. Keywords Aflibercept Choroidal osteoma Switching Non-responder Anti-VEGF therapy
Introduction Choroidal osteoma (CO) is a rare, benign, choroidal tumor, which is composed by mature bone cells, involving mostly young healthy females in the second decade of life [1, 2]. CO is unilateral in approximately 75 % of cases and tends to be located in the juxtapapillary or peripapillary area, often with extension into the macula [3]. Choroidal neovascularization (CNV) is the most frequent complication of CO, leading to severe visual impairment [4]. Intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents, such as ranibizumab (Lucentis; Genentech, Inc, South San Francisco, CA, USA) and bevacizumab (Avastin; Genentech, Inc), can be an effective therapeutic option for CO-associated CNV, particularly when subfoveal [5–10]. Recently, a new anti-VEGF agent, aflibercept (Eylea; Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA), has shown promising efficacy for those patients non-responder to ranibizumab and bevacizumab in CNV associated with age-related macular degeneration (AMD) [11– 14]. We report a case of CO-related CNV resistant to
123
442
other anti-VEGF agents which was successfully treated with aflibercept intravitreal injection.
Case report A 45-year-old man with CNV secondary to CO in his left eye (LE) was referred to the retina clinic of the Polytechnic University of Marche. The patient has received two consecutive monthly intravitreal injections of 1.25 mg bevacizumab with no benefit. At base line, the anterior segment had no anomalies in both eyes (BE). The best-corrected visual acuity (BCVA) was 20/50 and 20/20 in his LE, and right eye (RE), respectively. The intraocular pressure was within the normal limits in BE. The posterior pole examination showed a yellow-whitish area in the temporal side of the optic nerve head, with a grayish choroidal lesion, surrounded by fresh blood on its temporal edge. On the basis of the scarce response to bevacizumab, the patient underwent three consecutive monthly intravitreal injections of 0.5 mg ranibizumab. Unfortunately, no improvement was observed: the patient still complained metamorphopsia and the BCVA was again 20/50 in his LE. Fundus examination of the LE still showed an active CNV surrounded by fresh blood on its temporal edge involving the foveal area [Fig. 1]. Spectral domain optical coherence tomography (SD-OCT) in the LE showed persistent serous
Fig. 1 At presentation, a 45-year-old man had visual distortion with the best-corrected visual acuity (BCVA) of 20/50 despite of previous treatments with ranibizumab and bevacizumab. Color
123
Int Ophthalmol (2015) 35:441–444
subretinal fluid [Fig. 2a]. Since no benefit was observed after both the treatment with bevacizumab and ranibizumab, aflibercept was considered as a rescue therapy. The patient underwent three consecutive monthly intravitreal injections of aflibercept (2.0 mg). One month after the third injection of aflibercept, SD-OCT showed no fluid under the retina as well as no blood [Fig. 2b], BCVA improved to 20/32 and the patient reported an evident reduction of metamorphopsia. One month after the third injection of aflibercept, SD-OCT showed no fluid under the retina as well as no blood [Fig. 2b], BCVA improved to 20/32 and the patient reported an evident decrease of metamorphopsia. At last follow-up, 10 months after the initiation of treatment with aflibercept, SD-OCT remained stable, as well as BCVA. No serious or minor adverse events were reported up to date.
Discussion CNV occurs within 10 years in 31–47 % of patients affected by CO [3, 4]. The treatment of CNV secondary to CO still remains controversial. When untreated, osteoma-associated CNV can result in a progressive and permanent visual impairment [4]. Several therapies have been proposed, such as laser photocoagulation, transpupillary thermal therapy, photodynamic therapy (PDT), and surgical excision,
and red-free photographs showed peripapillary choroidal osteoma complicated with hemorrhagic CNV involving the central macula
Int Ophthalmol (2015) 35:441–444
443
Fig. 2 a At presentation, spectral domain optical coherence tomography (SD-OCT) showed the presence of persistent subfoveal fluid and hyper-reflective material overlying the retinal pigmented epithelium. b One month after three consecutive intravitreal injections of aflibercept, SD-OCT
images showed a complete resolution of subfoveal fluid and decrease of the hyper-reflective material overlying the RPE. At final follow-up of 10 months, the lesion remained stable with fluid-free macula on SD-OCT and BCVA was 20/32 with a reduction of metamorphopsia
but none of them has proven effective in controlling CNV activity, as well as in improving visual acuity. Moreover, when CNV is located beneath the fovea, PDT should be avoided since decalcification of CO could result in a worsening of visual acuity: impairment of both retinal pigment epithelium and choroidal perfusion can lead to a further impairment of visual function [15]. More recently, anti-VEGF therapy has shown promising results in CO-related CNV. Several case series have described encouraging results with the use of ranibizumab or bevacizumab for CO-related CNV with an improvement of both retinal structure and visual acuity [5–10, 15]. Therefore, these data suggest that monotherapies with traditional intravitreal antiangiogenic agents might be considered an effective therapeutic option for subfoveal CO-associated CNV. On the other hand, an unpredictable number of injections are necessary for the control of CNV
activity, leading to possible tachyphylaxis, which is the reduction of therapeutic response to anti-VEGF agents. Recently, Khan et al. reported the presence of persistent subretinal fluid in 1 of 4 patients (25 %) after anti-VEGF therapy [15]. Aflibercept is a humanized fusion protein, approved in November 2011 by the Food and Drug Administration for the treatment of neovascular age-related macular degeneration [11]. Differently than ranibizumab and bevacizumab, which bind selectively VEGF-A only, aflibercept targets VEGF-B, and placental growth factor (PGF) as well. These properties lead to a superior affinity for VEGF, when compared to ranibizumab and bevacizumab. Moreover, the biologic qualities of aflibercept make this molecule potentially more efficient in the long-term control of neovascular activity, allowing less frequent re-injections, as supported by clinical trials. Recently, most case series have indicated that 2.0 mg aflibercept leads to a better anatomic
123
444
improvement in patients with persistent subretinal fluid due to macular degeneration, non-responder to traditional anti-VEGF agents [12–14]. In our case, the patient presented subretinal hemorrhage and persistent subretinal fluid despite previous treatment with intravitreal injection of bevacizumab and ranibizumab for CO-related CNV. After switching to 2.0 mg of aflibercept, there was an anatomical improvement, as well as a visual gain. The better binding affinity to VEGF-A and VEGF-B, as well as PGF, may explain the good outcome in our patient. On the other hand, we cannot rule out that tachyphylaxis may have contributed to the insufficient response to previous therapies. In conclusion, our case suggests that intravitreal aflibercept can be a promising option for CNV secondary to CO, non-responder to traditional antiVEGF agents. However, further large and long-term prospective randomized studies are necessary in order to validate the data reported in the present manuscript. Conflict of interest The authors have no conflicts of interest to declare.
Int Ophthalmol (2015) 35:441–444
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8.
9.
10.
11.
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References 1. Gass JD, Guerry RK, Jack RL, Harris G (1978) Choroidal osteoma. Arch Ophthalmol 96:428–435 2. Aylward GW, Chang TS, Pautler SE, Gass JD (1998) A long-term follow-up of choroidal osteoma. Arch Ophthalmol 116:1337–1341 3. Shields CL, Sun H, Demirci H, Shields JA (2005) Factors predictive of tumor growth, tumor decalcification, choroidal neovascularization, and visual outcome in 74 eyes with choroidal osteoma. Arch Ophthalmol 123(12):1658–1666 4. Shields CL, Perez B, Materin MA, Mehta S, Shields JA (2007) Optical coherence tomography of choroidal osteoma in 22 cases: evidence for photoreceptor atrophy over the decalcified portion of the tumor. Ophthalmology 114(12):53–58 5. Ahmadieh H, Vafi N (2007) Dramatic response of choroidal neovascularization associated with choroidal osteoma to the
123
14.
15.
intravitreal injection of bevacizumab (Avastin). Graefes Arch Clin Exp Ophthalmol 245:1731–1733 Song WK, Koh HJ, Kwon OW, Byeon SH, Lee SC (2009) Intravitreal bevacizumab for choroidal neovascularization secondary to choroidal osteoma. Acta Ophthalmol 87:100–101. doi:10.1111/j.1600-0420.2007.01136.x Pandey N, Guruprasad A (2010) Choroidal osteoma with choroidal neovascular membrane: successful treatment with intravitreal bevacizumab. Clin Ophthalmol 4:1081–1084. doi:10.2147/OPTH.S13730 Song MH, Roh YJ (2009) Intravitreal ranibizumab in a patient with choroidal neovascularization secondary to choroidal osteoma. Eye (Lond) 23:1745–1746. doi:10.1038/ eye.2008.313 Carle MV, Chu TG, Liao D, Boyer DS (2014) Successful use of anti-VEGF treatment for subretinal hemorrhage and fluid in a young patient with choroidal osteoma. Ophthalmic Surg Lasers Imaging Retina 45(2):169–171. doi:10.3928/ 23258160-20140306-12 Mansour AM, Arevalo F, Al Kahtani E et al (2014) Role of intravitreal antivascular endothelial growth factor injections for choroidal neovascularization due to choroidal osteoma. J Ophthalmol 2014:210458. doi:10.1155/2014/210458 Heier JS, Brown DM, Chong V, Korobelnik JF et al (2012) Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 119(112):2537–2548. doi:10.1016/j.ophtha.2012.09.006 Bakall B, Folk JC, Boldt HC et al (2013) Aflibercept therapy for exudative age-related macular degeneration resistant to bevacizumab and ranibizumab. Am J Ophthalmol 156(1):15–22. doi:10.1016/j.ajo.2013.02.017 Cho H, Shah CP, Weber M, Heier JS (2013) Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab. Br J Ophthalmol 97(8):1032–1035. doi:10. 1136/bjophthalmol-2013-303344 Kumar N, Marsiglia M, Mrejen S et al (2013) Visual and anatomical outcomes of intravitreal aflibercept in eyes with persistent subfoveal fluid despite previous treatments with ranibizumab in patients with neovascular age-related macular degeneration. Retina 33(8):1605–1612. doi:10. 1097/IAE.0b013e31828e8551 Khan MA, DeCroos FC, Storey PP, Shields JA, Garg SJ, Shields CL (2014) Outcomes of anti-vascular endothelial growth factor therapy in the management of choroidal neovascularization associated with choroidal osteoma. Retina 34(9):1750–1756. doi:10.1097/IAE.0000000000000187
