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Intravitreal Bevacizumab for Idiopathic Choroidal Neovascularization After Previous Injection With Posterior Subtenon Triamcinolone
Intravitreal Bevacizumab for Idiopathic Choroidal Neovascularization After Previous Injection With Posterior Subtenon Triamcinolone Fumi Gomi, MD, Kentaro Nishida, MD, Yusuke Oshima, MD, Hirokazu Sakaguchi, MD, Miki Sawa, MD, Motokazu Tsujikawa, MD, and Yasuo Tano, MD PURPOSE: To assess short-term efficacy and safety of intravitreal bevacizumab injections for idiopathic choroidal neovascularization (CNV) refractory to posterior subtenon triamcinolone injections. DESIGN: Noncomparative, interventional case series. METHODS: Intravitreal bevacizumab was injected into 10 eyes with idiopathic CNV in which posterior subtenon triamcinolone injections were not efficacious for more than three months. The main outcome measures were changes in best-corrected visual acuity (BCVA), central retinal thickness (CRT), and fluorescein angiography findings before and after bevacizumab injection. RESULTS: After treatment, the BCVA improvement at one month (P ⴝ .029) continued to three months (P ⴝ .003). CRT decreased significantly (P < .001). Leakage from idiopathic CNV three months after treatment stopped in seven eyes, decreased in two, and continued in one. In one patient, conjunctival swelling developed after the injection but resolved and did not recur after another injection. No other complications developed. CONCLUSIONS: Intravitreal bevacizumab improves BCVA in eyes with idiopathic CNV refractory to triamcinolone. (Am J Ophthalmol 2007;143:507–509. © 2007 by Elsevier Inc. All rights reserved.)
I
DIOPATHIC CHOROIDAL NEOVASCULARIZATION (CNV) IN
younger patients is inflammatory in nature and sometimes responsive to systemic or focal steroids.1 When CNV is refractory to steroids or other treatments, photodynamic therapy may be effective for idiopathic CNV.2 However, severe damage to the retinal pigment epithelium has been reported after photodynamic therapy in young women.3 Recently, bevacizumab (Avastin®, Genentech, South San Francisco, California, USA), a recombinant humanized monoclonal antibody against all vascular endothelial growth factor (VEGF) isoforms developed originally to treat metastatic carcinoma of the colon and rectum, was Supplemental Material available at AJO.com. Accepted for publication Oct 26, 2006. From the Department of Ophthalmology, Osaka University Medical School, Osaka, Japan. Inquiries to Fumi Gomi, MD, Department of Ophthalmology, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; e-mail: [email protected] 0002-9394/07/$32.00
©
2007 BY
efficacious against CNV that was the result of age-related macular degeneration4 – 6 and pathological myopia.7 We evaluated the efficacy and safety of intravitreal injections of bevacizumab for idiopathic CNV in patients whose illness had failed to respond to a previous posterior subtenon injection of triamcinolone. Ten eyes of 10 patients with idiopathic CNV who sought care at the Osaka University Hospital were enrolled onto this prospective interventional case study, which was approved by the Institutional Review Board. Informed consent was obtained from all patients or their parents. The inclusion criteria were age 50 years or younger, a refractive error of ⫺6.0 diopters or less, and subfoveal or juxtafoveal idiopathic CNV which was not stabilized by more than one administration of posterior subtenon triamcinolone (20 mg) injection during at least three months’ follow-up. Best-corrected visual acuity (BCVA), as assessed by Landolt C charts, and central retinal thickness (CRT), as assessed by optical coherence tomography, was measured before and one and three months after treatment with one injection of 1 mg intravitreal bevacizumab. The BCVA was converted to the logarithm of minimal angle of resolution (logMAR) to facilitate visual comparison and statistical analysis. Fluorescein angiography was performed before and three months after therapy. The patient profiles and the main outcomes are listed in the Table. Previous triamcinolone injections improved the BCVA three months after injection in one eye with ⱖ0.2 logMAR vision but were ineffective in nine eyes. CNV recurred in the one eye in which the BCVA improved, and the vision worsened four months later. Before the bevacizumab injection, the mean BCVA was 0.46 (approximate Snellen equivalent, 20/43) and the mean CRT was 270 m. One month after treatment, the mean BCVA improved to 0.58 (20/35) (P ⫽ .029). The mean BCVA at three months improved to 0.69 (20/29) (P ⫽ .003), and five of 10 eyes had improved vision (0.2 logMAR vision or better). The mean CRT decreased to 211 m (P ⬍ .001) (see Supplementary Figure at AJO.com). Fluorescein angiography three months after injection showed no leakage in seven eyes (Figure), decreased leakage in two eyes, and no change in one eye. A second bevacizumab injection was administered to eyes with residual leakage. The follow-up period ranged from five to 12 months (mean 6.8 months), and six eyes received only one injection during that period. Conjunctival swelling at the bevacizumab injection site lasting a few days developed in one eye. A second injection administered to this eye did not show remarkable changes, so whether the swelling was associated with the bevacizumab injection remains unclear. Because bevacizumab is a full-length VEGF antibody, it is too large to penetrate the normal retina. However, recent studies reported the efficacy of intravitreal bevacizumab for various CNV types.5–7 Although eyes with idiopathic CNV have a healthier retina than aged or myopic eyes, our results showed the efficacy of intravitreal
ELSEVIER INC. ALL
RIGHTS RESERVED.
507
TABLE. Patient Characteristics and Clinical Data Before and After Intravitreal Injection of Bevacizumab for Idiopathic CNV Central Retinal Thickness BCVA (m) Time From Refractive Last TA 1 Month 3 Months 3 Months Age Error Location of Injection Before 3 Months Before After After Before After Patient (years) Gender (diopters) CNV (months) TA After TA Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab
1 2 3 4 5 6 7 8 9 10
36 36 27 38 22 35 16 23 39 41
F M F M F F M F M M
⫺5.0 ⫺4.75 ⫺1.75 ⫺1.25 ⫺4.5 ⫺3.25 ⫺4.5 ⫺4.5 ⫺2.5 ⫺3.5
Subfovea Subfovea Subfovea Subfovea Subfovea Subfovea Juxtafovea Subfovea Subfovea Juxtafovea
7 8 5 5 4 7 10 4 4 3
0.3 0.2 0.8 0.5 0.4 0.3 0.2 0.8 0.5 0.8
0.2 0.3 0.6 0.5 0.5 0.9 0.15 0.7 0.4 0.7
0.2 0.3 0.6 0.6 0.5 0.7 0.3 0.7 0.4 0.7
0.2 0.7 0.8 0.6 0.5 0.9 0.5 0.9 0.5 0.7
0.2 0.7 0.9 1.2 0.5 1.2 0.6 1.2 0.7 0.7
183 246 359 262 279 287 238 230 293 326
180 156 302 162 221 224 167 186 199 316
Leakage on FA at 3 Months
Decreased No Decreased No No No No No No Unchanged
BCVA ⫽ best-corrected visual acuity; CNV ⫽ choroidal neovascularization; F⫽ female; M⫽ male; FA ⫽ fluorescein angiography; TA ⫽ triamcinolone acetonide.
FIGURE. Fluorescein angiography of idiopathic choroidal neovascularization (CNV) treated by intravitreal injection of bevacizumab after subtenon triamcinolone. (Top left) Leakage from small idiopathic CNV in patient 2 was seen at baseline. (Top center) Despite subtenon triamcinolone injection, CNV enlarged, and leakage increased until bevacizumab injection. (Top right) Three months after bevacizumab injection, the lesion shrank and leakage stopped. Severe leakage from idiopathic CNV in patient 8 (Bottom left) was not stopped by triamcinolone at three months after treatment (Bottom middle). (Bottom right) Three months after intravitreal bevacizumab injection, eccentric fibrotic scar after contraction of original subfoveal CNV is seen.
bevacizumab after failed triamcinolone treatment. Acute serious adverse events were not observed; therefore, bevacizumab may be beneficial to treat idiopathic CNV for early regression, although the efficacy should be compared with other anti-VEGF drugs. 508
AMERICAN JOURNAL
Although the sample size in the current study was small and the follow-up was short, fewer eyes required retreatments within three months than in eyes with age-related macular degeneration,6 and we could not determine the need for periodic injections for all cases of idiopathic CNV, which is OF
OPHTHALMOLOGY
MARCH 2007
self-limited in nature. Further studies should be undertaken to determine the long-term efficacy and safety and the ideal dose, number, and frequency of injections.
4.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FInancial conflict of interest. Involved in design of study (F.G., Y.O., H.S.), conduct of study (F.G., M.S., M.T.), data analysis (F.G., N.K.), and critical revision of the article (F.G., Y.O., Y.T.).
5. REFERENCES
1. Flaxel CJ, Owens SL, Mulholland B, et al. The use of corticosteroids for choroidal neovascularization in young patients. Eye 1998;12:266 –272. 2. Chan WM, Lam DSC, Wong TH, et al. Photodynamic therapy with verteporfin for subfoveal idiopathic choroidal neovascularization: one-year results from a prospective case series. Ophthalmology 2003;110:2395–2402. 3. Postelmans L, Pasteels B, Coquelet P, et al. Severe pigment epithelial alterations in the treatment area following pho-
VOL. 143, NO. 3
6.
7.
todynamic therapy for classic choroidal neovascularization in young females. Am J Ophthalmol 2004;138:803– 808. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331– 335. Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26:383– 390. Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26:495– 511. Sakaguchi H, Ikuno Y, Gomi F, et al. Intravitreal injection of bevacizumab for choroidal neovascularization associated with pathological myopia. Br J Ophthalmol 2007;91:161–165.
BRIEF REPORTS
509
FIGURE. The optical coherence tomography (OCT) scans before and after bevacizumab injection for idiopathic CNV. (Top left) The macular edema at the choroidal neovascularization (CNV) from patient 2 was apparent before bevacizumab injection. (Top right) The resolution of the edema and the contracted CNV was seen three months after injection. The macular edema observed before bevacizumab injection from patient 9 (Bottom left) reduced apparently three months after one injection (Bottom right).
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OPHTHALMOLOGY
MARCH 2007
I
DIOPATHIC CHOROIDAL NEOVASCULARIZATION (CNV) IN
younger patients is inflammatory in nature and sometimes responsive to systemic or focal steroids.1 When CNV is refractory to steroids or other treatments, photodynamic therapy may be effective for idiopathic CNV.2 However, severe damage to the retinal pigment epithelium has been reported after photodynamic therapy in young women.3 Recently, bevacizumab (Avastin®, Genentech, South San Francisco, California, USA), a recombinant humanized monoclonal antibody against all vascular endothelial growth factor (VEGF) isoforms developed originally to treat metastatic carcinoma of the colon and rectum, was Supplemental Material available at AJO.com. Accepted for publication Oct 26, 2006. From the Department of Ophthalmology, Osaka University Medical School, Osaka, Japan. Inquiries to Fumi Gomi, MD, Department of Ophthalmology, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan; e-mail: [email protected] 0002-9394/07/$32.00
©
2007 BY
efficacious against CNV that was the result of age-related macular degeneration4 – 6 and pathological myopia.7 We evaluated the efficacy and safety of intravitreal injections of bevacizumab for idiopathic CNV in patients whose illness had failed to respond to a previous posterior subtenon injection of triamcinolone. Ten eyes of 10 patients with idiopathic CNV who sought care at the Osaka University Hospital were enrolled onto this prospective interventional case study, which was approved by the Institutional Review Board. Informed consent was obtained from all patients or their parents. The inclusion criteria were age 50 years or younger, a refractive error of ⫺6.0 diopters or less, and subfoveal or juxtafoveal idiopathic CNV which was not stabilized by more than one administration of posterior subtenon triamcinolone (20 mg) injection during at least three months’ follow-up. Best-corrected visual acuity (BCVA), as assessed by Landolt C charts, and central retinal thickness (CRT), as assessed by optical coherence tomography, was measured before and one and three months after treatment with one injection of 1 mg intravitreal bevacizumab. The BCVA was converted to the logarithm of minimal angle of resolution (logMAR) to facilitate visual comparison and statistical analysis. Fluorescein angiography was performed before and three months after therapy. The patient profiles and the main outcomes are listed in the Table. Previous triamcinolone injections improved the BCVA three months after injection in one eye with ⱖ0.2 logMAR vision but were ineffective in nine eyes. CNV recurred in the one eye in which the BCVA improved, and the vision worsened four months later. Before the bevacizumab injection, the mean BCVA was 0.46 (approximate Snellen equivalent, 20/43) and the mean CRT was 270 m. One month after treatment, the mean BCVA improved to 0.58 (20/35) (P ⫽ .029). The mean BCVA at three months improved to 0.69 (20/29) (P ⫽ .003), and five of 10 eyes had improved vision (0.2 logMAR vision or better). The mean CRT decreased to 211 m (P ⬍ .001) (see Supplementary Figure at AJO.com). Fluorescein angiography three months after injection showed no leakage in seven eyes (Figure), decreased leakage in two eyes, and no change in one eye. A second bevacizumab injection was administered to eyes with residual leakage. The follow-up period ranged from five to 12 months (mean 6.8 months), and six eyes received only one injection during that period. Conjunctival swelling at the bevacizumab injection site lasting a few days developed in one eye. A second injection administered to this eye did not show remarkable changes, so whether the swelling was associated with the bevacizumab injection remains unclear. Because bevacizumab is a full-length VEGF antibody, it is too large to penetrate the normal retina. However, recent studies reported the efficacy of intravitreal bevacizumab for various CNV types.5–7 Although eyes with idiopathic CNV have a healthier retina than aged or myopic eyes, our results showed the efficacy of intravitreal
ELSEVIER INC. ALL
RIGHTS RESERVED.
507
TABLE. Patient Characteristics and Clinical Data Before and After Intravitreal Injection of Bevacizumab for Idiopathic CNV Central Retinal Thickness BCVA (m) Time From Refractive Last TA 1 Month 3 Months 3 Months Age Error Location of Injection Before 3 Months Before After After Before After Patient (years) Gender (diopters) CNV (months) TA After TA Bevacizumab Bevacizumab Bevacizumab Bevacizumab Bevacizumab
1 2 3 4 5 6 7 8 9 10
36 36 27 38 22 35 16 23 39 41
F M F M F F M F M M
⫺5.0 ⫺4.75 ⫺1.75 ⫺1.25 ⫺4.5 ⫺3.25 ⫺4.5 ⫺4.5 ⫺2.5 ⫺3.5
Subfovea Subfovea Subfovea Subfovea Subfovea Subfovea Juxtafovea Subfovea Subfovea Juxtafovea
7 8 5 5 4 7 10 4 4 3
0.3 0.2 0.8 0.5 0.4 0.3 0.2 0.8 0.5 0.8
0.2 0.3 0.6 0.5 0.5 0.9 0.15 0.7 0.4 0.7
0.2 0.3 0.6 0.6 0.5 0.7 0.3 0.7 0.4 0.7
0.2 0.7 0.8 0.6 0.5 0.9 0.5 0.9 0.5 0.7
0.2 0.7 0.9 1.2 0.5 1.2 0.6 1.2 0.7 0.7
183 246 359 262 279 287 238 230 293 326
180 156 302 162 221 224 167 186 199 316
Leakage on FA at 3 Months
Decreased No Decreased No No No No No No Unchanged
BCVA ⫽ best-corrected visual acuity; CNV ⫽ choroidal neovascularization; F⫽ female; M⫽ male; FA ⫽ fluorescein angiography; TA ⫽ triamcinolone acetonide.
FIGURE. Fluorescein angiography of idiopathic choroidal neovascularization (CNV) treated by intravitreal injection of bevacizumab after subtenon triamcinolone. (Top left) Leakage from small idiopathic CNV in patient 2 was seen at baseline. (Top center) Despite subtenon triamcinolone injection, CNV enlarged, and leakage increased until bevacizumab injection. (Top right) Three months after bevacizumab injection, the lesion shrank and leakage stopped. Severe leakage from idiopathic CNV in patient 8 (Bottom left) was not stopped by triamcinolone at three months after treatment (Bottom middle). (Bottom right) Three months after intravitreal bevacizumab injection, eccentric fibrotic scar after contraction of original subfoveal CNV is seen.
bevacizumab after failed triamcinolone treatment. Acute serious adverse events were not observed; therefore, bevacizumab may be beneficial to treat idiopathic CNV for early regression, although the efficacy should be compared with other anti-VEGF drugs. 508
AMERICAN JOURNAL
Although the sample size in the current study was small and the follow-up was short, fewer eyes required retreatments within three months than in eyes with age-related macular degeneration,6 and we could not determine the need for periodic injections for all cases of idiopathic CNV, which is OF
OPHTHALMOLOGY
MARCH 2007
self-limited in nature. Further studies should be undertaken to determine the long-term efficacy and safety and the ideal dose, number, and frequency of injections.
4.
THE AUTHORS INDICATE NO FINANCIAL SUPPORT OR FInancial conflict of interest. Involved in design of study (F.G., Y.O., H.S.), conduct of study (F.G., M.S., M.T.), data analysis (F.G., N.K.), and critical revision of the article (F.G., Y.O., Y.T.).
5. REFERENCES
1. Flaxel CJ, Owens SL, Mulholland B, et al. The use of corticosteroids for choroidal neovascularization in young patients. Eye 1998;12:266 –272. 2. Chan WM, Lam DSC, Wong TH, et al. Photodynamic therapy with verteporfin for subfoveal idiopathic choroidal neovascularization: one-year results from a prospective case series. Ophthalmology 2003;110:2395–2402. 3. Postelmans L, Pasteels B, Coquelet P, et al. Severe pigment epithelial alterations in the treatment area following pho-
VOL. 143, NO. 3
6.
7.
todynamic therapy for classic choroidal neovascularization in young females. Am J Ophthalmol 2004;138:803– 808. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005;36:331– 335. Spaide RF, Laud K, Fine HF, et al. Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006;26:383– 390. Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006;26:495– 511. Sakaguchi H, Ikuno Y, Gomi F, et al. Intravitreal injection of bevacizumab for choroidal neovascularization associated with pathological myopia. Br J Ophthalmol 2007;91:161–165.
BRIEF REPORTS
509
FIGURE. The optical coherence tomography (OCT) scans before and after bevacizumab injection for idiopathic CNV. (Top left) The macular edema at the choroidal neovascularization (CNV) from patient 2 was apparent before bevacizumab injection. (Top right) The resolution of the edema and the contracted CNV was seen three months after injection. The macular edema observed before bevacizumab injection from patient 9 (Bottom left) reduced apparently three months after one injection (Bottom right).
509.e1
AMERICAN JOURNAL
OF
OPHTHALMOLOGY
MARCH 2007