Purpose
To compare the efficacy of combined therapy with intravitreal triamcinolone (IVTA) and photodynamic therapy (PDT; IVTA plus PDT) with intravitreal bevacizumab (IVB) and PDT (IVB plus PDT) for patients with retinal angiomatous proliferation (RAP).
Design
Retrospective, observational case series.
Methods
We retrospectively reviewed 25 treatment-naïve eyes of 22 Japanese patients (11 men, 11 women) with retinal angiomatous proliferation. Twelve eyes of 11 patients were treated with combined therapy of IVTA plus PDT from September 1, 2004, through July 31, 2006. Thirteen eyes of 11 patients were treated with combined therapy of IVB plus PDT from February 1, 2007, through January 31, 2008.
Results
In 12 eyes treated with IVTA plus PDT, the mean best-corrected visual acuity (BCVA) levels at baseline and 12 months were 0.29 and 0.13, respectively. A significant ( P < .05) decline in the mean BCVA from baseline was observed at 12 months. In 13 eyes treated with IVB plus PDT, the mean BCVA levels at baseline and 12 months were 0.25 and 0.37. A significant ( P < .05) improvement in the mean BCVA from baseline was observed. At 12 months, the difference in BCVA between the 2 groups was significant ( P < .05). The mean numbers of treatments at 12 months in the IVTA plus PDT group and the IVB plus PDT group were 2.7 and 1.6, respectively. The difference between the 2 treatments reached significance ( P < .05). No complications developed.
Conclusions
Compared with IVTA plus PDT, IVB plus PDT was significantly more effective in maintaining and improving visual acuity and in reducing the number of treatment for patients with retinal angiomatous proliferation.
Retinal angiomatous proliferation (RAP) has been described as a variant of exudative age-related macular degeneration (AMD). The term RAP was first coined by Yannuzzi and associates in 2001. RAP is differentiated into 3 stages based on clinical and angiographic observations: stage 1, proliferation of intraretinal capillaries originating from the deep retinal complex (intraretinal neovascularization); stage 2, growth of the retinal vessels into the subretinal space (subretinal neovascularization); and stage 3, clinically or angiographically observed choroidal neovascularization (CNV). RAP sometimes is referred to as type 3 neovascularization to distinguish it from the type 1 and 2 CNV anatomic classifications described by Freund and associates.
RAP represents 15% of all neovascular AMD in white patients and 4.5% of all neovascular AMD in Japanese patients. The natural course of RAP differs from typical exudative AMD and has poor visual outcomes. Furthermore, various treatments for RAP such as conventional laser photocoagulation, transpupillary thermotherapy, surgical ablation, and monotherapy of photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis Pharma AG, Basel, Switzerland) have not been efficacious.
CNV complexes are comprised of inflammatory cells and vascular endothelial growth factor (VEGF). Corticosteroids such as triamcinolone acetonide (TA) have antiangiogenic, antiinflammatory, and anti-VEGF effects. Recent studies have reported that combined therapy of intravitreal TA (IVTA) and PDT for RAP effectively resolves angiographic leakage and maintains or improves visual acuity (VA).
Anti-VEGF therapy prevents formation of CNV and decreases leakage from existing CNV in animal models. VEGF monoclonal antibodies and aptamers such as ranibizumab (Lucentis; Genentech, Inc, South San Francisco, California, USA), bevacizumab (Avastin; Genentech), and pegaptanib (Macugen; EyeTech Pharmaceuticals, Lexington, Massachusetts, USA) reduce vascular leakage and improve visual outcomes in patients with CNV secondary to AMD. Moreover, combined therapy of intravitreal bevacizumab (IVB) injections and PDT administered to treat CNV reduced the retreatment rates in patients with AMD. We reported recently that combined therapy of IVB and PDT was effective for treating RAP after 6 months of follow-up. The purpose of the current study was to clarify the efficiency of combined therapy of IVB plus PDT compared with combined therapy of IVTA plus PDT for treating patients with RAP over 12 months.
Methods
We retrospectively reviewed 25 eyes of 22 Japanese patients (11 men, 11 women; age range, 63 to 90 years; mean ± standard deviation, 78.3 ± 8.8 years) with RAP. Twelve eyes of 11 patients (3 men, 8 women; age range, 63 to 90 years; mean age, 78.3 years) were treated with combined therapy of IVTA plus PDT from September 1, 2004, through July 31, 2006. Thirteen eyes of 11 patients (8 men, 3 women; age range, 63 to 89 years; mean age, 78.3 years) were treated with combined therapy of IVB and PDT from February 1, 2007, through January 31, 2008. The 6-month results for 8 of the 13 eyes treated with IVB plus PDT were reported previously. The patients were followed up for at least 12 months at Fukushima Medical University Hospital or Kagawa University Hospital. No patient had undergone a previous treatment. The treatment was approved by the Institutional Review Boards/Ethics Committees at Fukushima Medical University and Kagawa University. After the potential risks and benefits were explained in detail, all patients provided written informed consent. The exclusion criteria were previous treatment for RAP such as laser photocoagulation, submacular surgery, transpupillary thermotherapy, and PDT; glaucoma; tears in the retinal pigment epithelium; and maculopathies such as diabetic maculopathy, retinal vascular occlusion, or idiopathic juxtafoveal retinal telangiectasis.
We recorded the best-corrected visual acuity (BCVA) measured with a Japanese standard decimal VA chart and calculated the mean BCVA using the logarithm of the minimal angle of resolution (logMAR) scale. All patients underwent a standardized examination including slit-lamp biomicroscopy with a contact lens, fundus color photography, fluorescein angiography (FA), and indocyanine green angiography (ICGA) with a fundus camera (TRC-50 FA/IA/IMAGEnet H1024 system; Topcon, Tokyo, Japan), with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2; Heidelberg Engineering, Heidelberg, Germany), or both. All examinations were performed using time-domain optical coherence tomography (OCT; OCT 3000; Carl Zeiss, Meditec, Dublin, California, USA; or OCT-Ophthalmoscope; Nidek-OTI, Gamagori, Japan) in eyes treated with IVTA plus PDT and spectral-domain OCT (3D-OCT; Topcon; or Cirrus OCT, Carl Zeiss) in eyes treated with IVB plus PDT. All patients were examined using the same OCT machine during the follow-up. FA was performed to determine the lesion type, the location, and the activity of the RAP lesions. ICGA was performed to diagnose RAP and to identify retinal–retinal anastomosis. The central retinal thickness, defined as the distance from the retinal pigment epithelium to the inner limiting membrane, was measured at baseline and at 3, 6, 9, and 12 months after treatment using internal caliper software.
All patients had documented visual loss before treatment. IVTA (4 mg/0.1 mL) or IVB (1.25 mg/0.05 mL) was injected 3.5 to 4.0 mm posterior to the corneal limbus into the vitreous cavity using a 27-gauge needle after topical anesthesia was applied. In the patients treated with IVTA plus PDT, PDT was performed 7 days after IVTA was injected. In the patients treated with IVB plus PDT, PDT was administered 1 or 2 days after IVB was injected. PDT with verteporfin was administered according to the protocol of the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy study. A 689-nm laser system (Carl Zeiss Meditec) was used and 50 J/cm 2 energy was delivered with an 83-second exposure time. The greatest linear dimension (GLD) was measured based on FA findings. The laser spot size was determined by FA (FA-guided PDT) in 20 eyes and by ICGA (ICGA-guided PDT) in 5 eyes. FA-guided PDT was performed for the entire lesion seen on FA. ICGA-guided PDT was chosen if the lesion comprised a larger subretinal hemorrhage at least 1 disc diameter in size.
All patients were examined 3, 6, 9, and 12 months after the initial PDT was administered. Statistical analysis was performed using the Student t test to compare the VA and the central retinal thickness 3, 6, 9, and 12 months from baseline.
Results
Tables 1 and 2 show the characteristics and clinical data of the 22 patients (25 eyes) at baseline and after treatment. All patients were Japanese and were observed for 12 months. There was no difference in the mean age between the 2 groups. In the 12 eyes treated with IVTA plus PDT, 7 eyes had stage 2 RAP without a retinal pigment epithelial detachment (PED) and 5 eyes had stage 2 RAP with a PED. In the 13 eyes treated with IVB plus PDT, 5 eyes had stage 2 RAP without a PED, 6 eyes had stage 2 RAP with a PED, and 2 eyes had stage 3 RAP. The mean GLD of the entire lesion was 2670 μm. There was no significant difference in the baseline patient characteristics between the 2 treatment groups.
| Case No. | Age (yrs) | Gender | Eye | RAP Stage | Lens Status | Baseline | 12 Months after Treatment | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| VA | Central Retinal Thickness (μm) | RRA | GLD (μm) | IOP (mmHg) | VA | Central Retinal Thickness (μm) | RRA | GLD (μm) | IOP (mmHg) | No. Treatments | ||||||
| 1 | 74 | F | Right | 2+PED | Phakic eye | 0.8 | 279 | Yes | 1590 | 13 | 0.8 | 34 | No | 0 | 12 | 1 |
| 2 | 85 | F | Right | 2 | Pseudophakia | 0.2 | 385 | Yes | 1100 | 13 | 0.1 | 115 | Yes | 0 | 11 | 2 |
| 3 | 86 | M | Right | 2 | Phakic eye | 0.4 | 293 | Yes | 2570 | 10 | 0.1 | 550 | Yes | 2197 | 10 | 4 |
| 4 | 86 | M | Left | 2+PED | Phakic eye | 0.3 | 350 | Yes | 1080 | 11 | 0.2 | 289 | Yes | 957 | 11 | 4 |
| 5 | 74 | F | Left | 2 | Pseudophakia | 0.8 | 542 | Yes | 3600 | 13 | 0.5 | 232 | No | 0 | 12 | 3 |
| 6 | 63 | M | Right | 2+PED | Phakic eye | 0.8 | 267 | Yes | 5610 | 17 | 0.06 | 481 | Yes | 4784 | 18 | 3 |
| 7 | 84 | F | Right | 2+PED | Phakic eye | 0.6 | 355 | Yes | 2690 | 10 | 0.08 | 407 | Yes | 3296 | 9 | 5 |
| 8 | 90 | F | Right | 2 | Pseudophakia | 0.3 | 314 | No | 4516 | 13 | 0.03 | 83 | — | 0 | 16 | 1 |
| 9 | 70 | F | Left | 2 | Pseudophakia | 0.09 | 367 | Yes | 2450 | 16 | 0.2 | 324 | Yes | 0 | 19 | 2 |
| 10 | 69 | F | Right | 2 | Phakic eye | 0.15 | 625 | Yes | 3334 | 14 | 0.1 | 135 | Yes | 0 | 10 | 3 |
| 11 | 68 | M | Right | 2 | Pseudophakia | 0.1 | 521 | Yes | 3430 | 20 | 0.3 | 237 | Yes | 0 | 16 | 2 |
| 12 | 90 | F | Right | 2+PED | Pseudophakia | 0.1 | 575 | Yes | 2648 | 14 | 0.05 | 423 | Yes | 0 | 15 | 2 |
| Mean | 78 | — | — | — | — | 0.29 | 406 | — | 2885 | 13.7 | 0.13 | 276 | — | 936 | 13.3 | 2.7 |
| SD | 9.5 | — | — | — | — | — | 125 | — | 1335 | 2.9 | — | 166 | — | 1623 | 3.4 | 1.2 |
| Case No. | Age (yrs) | Gender | Eye | RAP Stage | Lens Status | Baseline | 12 Months after Treatment | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| VA | Central Retinal Thickness (μm) | RRA | GLD (μm) | IOP (mmHg) | VA | Central Retinal Thickness (μm) | RRA | GLD (μm) | IOP (mmHg) | No. Treatments | ||||||
| 13 | 64 | F | Right | 2 | Phakic eye | 1.0 | 234 | No | 602 | 16 | 1.0 | 117 | — | 0 | 12 | 2 |
| 14 | 63 | M | Right | 2+PED | Phakic eye | 0.07 | 601 | Yes | 4331 | 12 | 0.2 | 126 | No | 0 | 10 | 2 |
| 15 | 81 | M | Right | 2 | Phakic eye | 0.4 | 393 | No | 1900 | 15 | 1.0 | 124 | — | 0 | 13 | 1 |
| 16 | 78 | M | Left | 2 | Phakic eye | 0.6 | 406 | No | 1998 | 11 | 1.2 | 125 | — | 0 | 11 | 1 |
| 17 | 89 | M | Left | 2+PED | Pseudophakia | 0.3 | 379 | Yes | 3531 | 16 | 0.6 | 182 | No | 0 | 13 | 1 |
| 18 | 87 | F | Right | 3 | Pseudophakia | 0.06 | 394 | Yes | 2368 | 10 | 0.07 | 140 | Yes | 0 | 10 | 1 |
| 19 | 87 | F | Left | 2+PED | Pseudophakia | 0.7 | 396 | Yes | 5532 | 10 | 0.7 | 112 | Yes | 0 | 10 | 2 |
| 20 | 78 | M | Left | 2 | Phakic eye | 0.9 | 430 | Yes | 975 | 15 | 0.8 | 127 | No | 0 | 14 | 2 |
| 21 | 83 | F | Right | 2 | Phakic eye | 0.05 | 514 | Yes | 3489 | 19 | 0.05 | 88 | No | 0 | 14 | 2 |
| 22 | 83 | F | Left | 2+PED | Pseudophakia | 0.3 | 479 | Yes | 4568 | 17 | 0.6 | 44 | No | 0 | 16 | 3 |
| 23 | 72 | M | Right | 2+PED | Phakic eye | 0.3 | 360 | Yes | 3300 | 16 | 0.2 | 74 | No | 0 | 13 | 2 |
| 24 | 74 | M | Right | 3 | Phakic eye | 0.06 | 950 | Yes | 4494 | 15 | 0.09 | 426 | No | 0 | 11 | 1 |
| 25 | 79 | M | Left | 2+PED | Pseudophakia | 0.3 | 389 | Yes | 3321 | 11 | 0.9 | 66 | No | 0 | 10 | 1 |
| Mean | 78 | — | — | — | — | 0.25 | 456 | — | 3108 | 14.1 | 0.37 | 135 | — | 0 | 12.1 | 1.6 |
| SD | 8.2 | — | — | — | — | — | 171 | — | 1469 | 2.9 | — | 94 | — | — | 1.9 | 0.7 |
In the 12 eyes treated with IVTA plus PDT, the mean BCVA levels at baseline and 3, 6, 9, and 12 months after treatment were 0.29, 0.25, 0.27, 0.22, and 0.13, respectively ( Figure 1 ), indicating a significant ( P < .05, paired t test) decline in the mean BCVA from baseline at 12 months. The mean changes in the BCVA at 6 and 12 months from baseline were a decline of 0.19 and 3.28 lines, respectively. One of the 12 eyes (8.3%) had an increase in the BCVA of 3 lines or more, 10 eyes (83.4%) had stable VA, and 1 eye (8.3%) had a decrease in the BCVA of 3 lines or more 6 months from baseline. At 12 months, 2 (16.7%) of 12 eyes had an increase in the BCVA of 3 lines or more, 7 eyes (58.3%) had stable VA, and 3 eyes (25%) had a decrease in the BCVA of 3 lines or more from baseline ( Figure 2 ). The central retinal thickness significantly ( P < .05, paired t test) decreased from baseline from 406 ± 125 μm (mean ± standard deviation) to 287 ± 124 μm at 3 months, 274 ± 174 μm at 6 months, 261 ± 208 μm at 9 months, and 276 ± 166 μm at 12 months. At baseline, cystoid macular edema (CME) was observed in 11 of the 12 eyes; there was a serous retinal detachment (SRD) in 7 of the 12 eyes, and a PED in 5 of the 12 eyes. The CME resolved in 5 (45.5%) eyes a mean of 5.4 weeks after baseline and decreased in 6 eyes. The SRD resolved completely in 5 (71.4%) eyes a mean of 3.1 weeks after baseline and decreased in 2 eyes. The PED resolved completely in 2 (40%) eyes a mean of 6.5 weeks after baseline and remained in 3 eyes. The mean GLD of the entire lesion was 2885 μm at baseline and 936 μm at 12 months ( P = .06 compared with baseline). Six eyes were phakic and 6 eyes were pseudophakia. The mean intraocular pressure (IOP) was 13.7 mm Hg at baseline and 13.3 mm Hg at 12 months. Figures 3 and 4 show ocular images obtained from a patient treated with IVTA plus PDT.
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