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Comparison of Early Retreatment with the Standard Regimen in Verteporfin Therapy of Neovascular Age-Related Macular Degeneration
Comparison of Early Retreatment with the Standard Regimen in Verteporfin Therapy of Neovascular Age-Related Macular Degeneration Stephan Michels, MD,1 Joachim Wachtlin, MD,2 Maria A. Gamulescu, MD,3 Heinrich Heimann, MD,4 Christian Prünte, MD,5 Werner Inhoffen, PhD,6 Ilse Krebs, MD,7 Ursula Schmidt-Erfurth, MD1 Purpose: To compare the efficacy and safety of early retreatment with verteporfin therapy with that of approved standard verteporfin therapy in neovascular age-related macular degeneration. Design: Prospective, randomized, multicenter clinical trial. Participants: Two hundred three patients with predominantly classic choroidal neovascularization secondary to age-related macular degeneration. Methods: Throughout the first 6 months of follow-up, patients received retreatment with verteporfin therapy either every 2 months (group A) or 3 months (group B). From 6 to 12 months, both groups received retreatment at 3-month intervals. Main Outcome Measures: The primary outcome of the study was best-corrected mean visual acuity as measured using the Early Treatment Diabetic Retinopathy Study protocol. The secondary outcomes were percentage of patients losing at least 3 lines of vision, percentage of patients gaining at least 1 line of vision, and lesion size based on the greatest linear dimension (GLD) documented by fluorescein angiography, impact of initial lesion size, and retreatment rate as well as safety. Results: Visual acuity was similar in both groups at baseline with a mean visual acuity of 20/100⫺1. During the 12 months of follow-up, mean visual acuity was better in the early retreatment group at all intervals; however, no statistically significant benefit was seen in the overall population at any time (P⬎0.1). At month 12, mean visual acuity was 20/160⫹1 in group A and 20/160⫺1 in group B. There was a trend for better outcomes in the early retreatment group with regard to loss of less than 3 lines of vision at 12 months (61% vs. 51.7%). No statistically significant difference was seen with regard to lesion size for either group throughout follow-up with a final GLD of the lesion of 2790 m (group A) and 2996 m (group B). However, subgroup analysis indicated a statistically relevant benefit (Pⱕ0.004) for patients with small lesions (GLD⬍2000 m) at baseline receiving early retreatment. Conclusions: Early retreatment in 2-month intervals did not show a significant overall benefit at 1 year of follow-up compared with the standard regimen. However, smaller lesions seemed to benefit from early retreatment with verteporfin therapy in contrast to larger lesions. Ophthalmology 2005;112:2070 –2075 © 2005 by the American Academy of Ophthalmology.
Exudative age-related macular degeneration (AMD) is one of the leading causes of legal blindness in industrialized countries.1,2 Photodynamic therapy (PDT) using verteporfin (Visudyne, Novartis Pharma AG, Basel, Switzerland) has Originally received: January 31, 2005. Accepted: June 24, 2005. Manuscript no. 2005-98. 1 Klinik für Augenheilkunde und Optometrie, Medizinische Universität Wien, Vienna, Austria. 2 Augenklinik der Charité–Universitätsmedizin Berlin, Berlin, Germany. 3 Klinikum der Universität Regensburg, Klinik und Poliklinik für Augenheilkunde, Regensburg, Germany. 4 St. Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom. 5 Universitäts-Augenklinik Basel, Basel, Switzerland. 6 Universitäts-Augenklinik Tübingen, Tübingen, Germany. 7 Augenklinik Rudolfstiftung, Vienna, Austria.
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© 2005 by the American Academy of Ophthalmology Published by Elsevier Inc.
been shown to be an effective, relatively selective, and safe treatment of neovascular AMD in large multicenter, randomized, placebo-controlled trials.3–5 Predominantly classic lesions as defined by fluorescein angiography, which are the
Supported by the German Research Foundation (Bonn, Germany) Priority Program (grant no.: DFG Schm 835-2). Medication (verteporfin) was provided in part by Novartis Pharma AG, Basel, Switzerland. Dr Schmidt-Erfurth is an owner of the patent on the use of green porphyrins in neovasculature of the eye under the guidelines of the Wellman Laboratories of Photomedicine, Harvard Medical School, Boston, Massachusetts. The remaining authors do not have any conflict of interest in the material presented in the article. Correspondence to Ursula Schmidt-Erfurth, MD, Klinik für Augenheilkunde und Optometrie, Medizinische Universität Wien, Währinger Gürtel 18-20, 1090 Wien, Austria. ISSN 0161-6420/05/$–see front matter doi:10.1016/j.ophtha.2005.06.034
Michels et al 䡠 Early Retreatment in Verteporfin Therapy most aggressive subtype, appear to benefit most from treatment with PDT.6 In the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) study, a significant visual benefit after PDT compared with placebo was sustained over 24 months. However, despite a significant treatment benefit, patients still lost an average of 2.2 lines of vision at 12 months and of 2.7 lines at 24 months.4 In patients treated with repeated PDT every 3 months over the course of 2 years, 75% and 82% of visual loss occurred within the first 6 and 12 months, respectively. Despite repeated PDT with verteporfin 6 months after initial treatment, no significant change in visual acuity was seen during continued follow-up, and only 18.8% of patients had complete absence of leakage from classic choroidal neovascularization (CNV) at the 12-month follow-up.6 Earlier retreatment with PDT offers the potential to inhibit progressive CNV growth and to provide better visual outcomes. Several studies have indicated that primary CNV closure after PDT is transient and that CNV recanalization and progressive growth occurs as early as 4 to 6 weeks after PDT.7,8 Early retreatment with PDT, however, also may have adverse effects limiting visual recovery. For example, despite the relative selectivity of PDT, transient choriocapillaris closure occurs 1 week after PDT.9,10 Immunohistochemistry performed 1 week after verteporfin therapy exhibited an enhanced angiogenic response to verteporfin therapy.11 Repeating PDT as late as 2 months after initial treatment may offer the choriocapillaris time to reperfuse and may still limit CNV recanalization and regrowth after PDT-induced occlusion more effectively than the extended intervals of 3 months recommended by the standard regimen. This study was designed to compare earlier retreatment every 8 weeks within the sensitive first 6 months after initiation of verteporfin treatment with standard therapy. In comparison, the Verteporfin Early Retreatment Study was designed after the presented study to evaluate retreatment every 6 weeks and larger, predominantly classic CNV, up to 5400 m in greatest linear dimension (GLD). The primary outcome of the presented study was mean visual acuity. The secondary outcomes were percentage of patients losing at least 3 lines of vision, the percentage of patients gaining at least 1 line of vision, CNV growth, and retreatment rate as well as safety.
Patients and Methods The study was a randomized, controlled, multicenter, phase IIIb study. Fourteen clinical centers (see “Appendix”) participated throughout Europe. The study design was reviewed and approved by an independent study advisory group as well as by the institutional review boards of each participating clinical center. The study was approved and supported by the German Research Council Priority Program (Deutsche Forschungsgemeinschaft DFG Schm 835-2). The protocol adhered to the Helsinki Declaration.
Patient Selection Two hundred three patients with subfoveal, predominantly classic choroidal neovascularization (CNV) secondary to AMD were en-
rolled in the study between August 2000 and May 2002. Before enrollment of each patient into the study, a central angiographic reading center (University Eye Hospital, Luebeck, Germany) assessed fluorescein angiograms and fundus photographs to confirm that all eligibility criteria were met. Inclusion criteria included: CNV secondary to AMD; CNV under the geometric center of the foveal avascular zone; evidence of at least 50% classic CNV as defined by fluorescein angiography; greatest linear dimension ⬍4400 m (6 disc areas); best-corrected visual acuity from 20/40 to 20/200; age 50 years or older; willing and able to provide written informed consent. Exclusion criteria included: any significant ocular disease that could compromise vision in the study eye; concurrent use of any investigational drug; active hepatitis or other clinically significant liver disease; porphyria or porphyrin sensitivity; intraocular surgery within 1 month before study enrollment; previous laser or verteporfin therapy in the study eye; uncontrolled hypertension (⬎140/90 mmHg).
Evaluation At every visit, best-corrected visual acuity was assessed at 2 m distance using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity protocol. In addition, a complete ophthalmologic examination, fundus photographs, and fluorescein angiography were performed. Fundus photography included digital color photos taken at a 30° field. Fluorescein angiography was performed using intravenous application of 5 ml of a 10% sodium fluorescein solution and the regimen used by the TAP study protocol.4 The Heidelberg Retina Angiograph (Heidelberg Instruments, Dossenheim, Germany) and the Zeiss FF 450 System (Carl Zeiss, Oberkochen, Germany) were approved to be used in the study. Patients were seen for follow-up visits according to their treatment group within 1 week before the first treatment and every 2 months (group A) or 3 months (group B) for the first 6 months. Thereafter, all patients were seen at 3-month intervals up to month 12.
Treatment Protocol All patients defined as eligible by the central reading center were randomized (1:1) to either the 2-month (group A) or the 3-month (group B) treatment group. Patients in the 2-month treatment group (group A) received verteporfin therapy at 2-month intervals during the first 6 months and retreatment beyond month 6 at 3-month intervals. Patients randomized to the 3-month treatment group (group B) were treated with verteporfin therapy according to the TAP criteria with retreatment at 3-month intervals. Patients in both treatment arms received retreatment only if leakage was present angiographically. Verteporfin treatment was given to all study patients according to the TAP study.4 Briefly, verteporfin was infused at a dose of 6 mg/m2 of body surface area for 10 minutes. Five minutes after the end of the infusion, a nonthermal laser light (689 nm) of 50 J/cm2 irradiating at an intensity of 600 mW/cm2 was applied for 83 seconds. Before treatment, the GLD of the lesion was determined by the treating investigator at each study center using the Heidelberg Eye Explorer or the Zeiss Visupac software. A 500-m circular security margin was added to the GLD of the lesion to obtain the adequate coverage of the entire lesion during photosensitization.
Statistical Analysis The primary efficacy analysis was based on an intent-to-treat analysis. Patients were analyzed within the group to which they were randomized. All 203 randomized patients were included in
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Ophthalmology Volume 112, Number 12, December 2005 was less frequent in the early retreatment than in the standard treatment group (20% vs. 31.6% retreatment rate; P ⫽ 0.073).
Vision Outcomes
Figure 1. Graph showing mean visual acuity of early versus standard verteporfin therapy. P values refer to change from baseline. SEM ⫽ standard error of mean.
the statistical analysis. Mean visual acuity and lesion size were evaluated using a paired t test for change from baseline. The Pearson chi-square test was used to compare proportions of patients losing at least 15 or 30 letters and gaining at least 5 letters. Analysis of variance was used for between-treatment difference evaluation and for subgroup analysis based on baseline GLD. Statistical significance was defined as P⬍0.05.
Results Baseline Characteristics Of the 203 patients included in this study, 103 were randomized to receive the standard treatment and 100 to early treatment. All 203 patients were included into the intent-to-treat population. The mean age was 75.1 years in the standard treatment and 72.7 years in the early treatment group. Visual acuity was balanced at baseline. Mean visual acuity in the standard treatment group was 48.9 letters versus 49.3 letters (approximately 20/100⫺1) in the early treatment group. Nine patients evaluated at the angiographic reading center did not meet the inclusion criteria; 7 patients had a baseline visual acuity of ⬍34 letters (⬍20/200) and 2 patients had baseline lesion sizes of ⬎6 macular photocoagulation study disc areas (GLD ⬎ 4400 m).
Follow-up and Number of Retreatments In both treatment groups, at least 90% of patients completed the 12-month follow-up. The mean number of retreatments over the first year was 3.81 treatments (maximum possible treatments, 5) in group A compared with 3.25 treatments (maximum possible treatments, 4) in group B. At the month 12 follow-up visit, retreatment
In both groups, mean visual acuity decreased by approximately 1 line at 6 months. Patients in the early treatment group (group A) had a mean loss of 4.3 to 44.7 letters (approximately 20/125) compared with a loss of 6.1 to 42.6 letters (approximately 20/125⫺2) in the standard treatment group (group B) at month 6 (Fig 1). The between-treatment group difference was 1.9 letters (P ⫽ 0.427) in favor of the early retreatment. At 6 months, 26.9% of patients in group A and 29.7 % of patients in group B had lost at least 15 letters (3 lines; Table 1). Improvement of vision of at least 5 letters (1 line) at 6 months was seen in 39.8% of patients in group A and in 23.8% of patients in group B (Table 1). At month 9, patients in the standard treatment group lost 3.9 letters more compared with those in the early retreatment group (P ⫽ 0.161). Mean visual acuity was 39.8 letters (approximately 20/160) versus 43.7 letters (approximately 20/125⫺1) in the standard and early treatment groups, respectively. However, at month 12 the between-treatment difference in favor of the early treatment group decreased to 1.5 letters (P ⫽ 0.589). Mean visual acuity was 39.1 letters (approximately 20/160⫺1) in the standard treatment group and 40.8 letters (approximately 20/160⫹1) in the early retreatment group. In the standard treatment group, 48.3% of patients lost at least 15 letters (3 lines) compared with 39.0% in the early retreatment group. A gain in vision of at least 1 line was seen in 27% of the standard treatment group and 24.7% in the early treatment group. Despite an overall favorable trend for the early retreatment group, none of the visual acuity data within the 1-year follow-up showed a statistically significant benefit for either group. Further analysis combining the early and standard treatment regimen indicated a change in visual acuity from baseline to be associated with change in GLD from baseline (Fig 2). Patients with a loss of more than 15 letters (3 lines) showed a mean increase in GLD of at least 1002 m at 6 and 12 months of follow-up. Patients gaining at least 5 letters at 6 and 12 months of follow-up had, in comparison, a mean increase in GLD of less than 261 m.
Fluorescein Angiography Outcomes This study used an angiographic eligibility review at study entry, and all patients included in the study had a predominantly classic CNV resulting from AMD. The mean GLD of the lesion, 2104 m in the early treatment group (group A) and 2179 m in the standard treatment group (group B), was comparable between the 2 treatment groups at baseline. Progressive lesion growth was seen in both groups. At 6 months, mean lesion diameters increased to 2842 m in the standard treatment and to 2512 m in the early treatment group. Lesion growth was generally slower between 6and 12-month follow-up. The GLD increased to 2871 m and 2546 m at 9 months and to 2996 m and 2790 m at 12 months in the standard treatment and early treatment groups, respectively (Fig 3). The between-treatment group differences were not statis-
Table 1. Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Outcomes 6 Months
Mean change Loss ⱖ15 letters Gain ⱖ5 letters
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12 Months
Early Retreatment
Standard
P Value
Early Retreatment
Standard
P Value
⫺4.3 26.9% 39.8%
⫺6.1 29.7% 23.8%
0.427 0.663 0.016
⫺8.5 39% 24.7%
⫺9.9 48.3% 27%
0.589 0.226 0.737
Michels et al 䡠 Early Retreatment in Verteporfin Therapy
Figure 2. Graph showing the increase in greatest linear diameter (GLD) from baseline compared with change in visual acuity at 6 and 12 months. The figure indicates an association of lesion growth and loss in visual acuity.
tically significant at any point (Pⱖ0.059). However, there was a trend toward less intensive lesion growth in group A.
Subgroup Analysis Visual acuity scores were analyzed for 2 subgroups: patients with a baseline GLD ⱕ2000 m and patients with a baseline GLD ⬎2000 m. The mean visual acuity letter scores at follow-up are shown in Figure 4. In the subgroup of patients with small lesions (ⱕ2000 m), patients who received early retreatment had a more favorable outcome than those who received standard treatment at all follow-up visits. However, only at 9 months of follow-up was
Figure 4. Graph showing the subgroup analysis for mean visual acuity. GLD ⫽ greatest linear dimension; SEM ⫽ standard error of mean.
the difference in mean visual acuity of 7.7 letters between these 2 treatment groups statistically significant (P ⫽ 0.046). Accordingly, patients with large lesions (⬎2000 m) at baseline receiving early retreatment had the least favorable visual outcome, as shown in Figure 4. These patients lost a mean of 14 letters during the next 12 months compared with patients with large lesions at baseline in the standard treatment group who lost a mean of 11 letters. Patients in the early retreatment group with small lesions (ⱕ2000 m) at baseline had significantly better mean visual acuity outcomes than patients with larger lesions (⬎2000 m) at month 6 (P ⫽ 0.002), 9 (P ⫽ 0.004), and 12 (P ⫽ 0.002). Within the standard treatment group (group B), a difference in mean visual acuity between initially small lesions (ⱕ2000 m) and large lesions (⬎2000 m) also was seen; however, the difference did not become statistically significant at any follow-up visit (Pⱖ0.282; Fig 4). Figures 5 and 6 demonstrate the impact of baseline lesion size on change in visual acuity from baseline at 6 and 12 months of follow-up for patients with early treatment and standard treatment. Very small lesions (ⱕ1000 m) had overall the best vision outcome in both treatment groups, losing a mean of 1.4 letters in the early treatment group and 1 letter in the standard treatment group at month 12. Figure 5 indicates more vision loss with increasing lesion size at baseline for patients receiving early treatment. Very small lesions in the standard treatment group also benefitted most; however, with increasing baseline lesion size, progressive vision loss is not seen as clearly as in the early treatment group.
Safety
Figure 3. Graph showing the mean greatest linear dimension (GLD) of choroidal neovascularization (CNV). All changes in GLD were statistically significant from baseline (Pⱕ0.002). SEM ⫽ standard error of mean.
Severe loss of vision of at least 30 letters (6 lines) was seen less frequently in the early treatment group (group A). At 12 months of follow-up, there was severe vision loss in 21.3% of patients in the standard group and 10.4% of patients in the early retreatment group (P ⫽ 0.056). Within the first 12 months of follow-up, there were no severe ocular or systemic side effects related to early retreatment. None of the patients showed retinal ischemia, nor
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Figure 5. Graph showing the baseline greatest linear dimension (GLD) compared with mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity at 6 and 12 months of follow-up in the early retreatment group.
were there any reports of early, severe vision decrease defined as vision loss of at least 20 letters (4 lines) within 7 days of verteporfin therapy. The risk of subretinal hemorrhage and intravitreal hemorrhage was not increased in either group.
that most significant mean visual outcome differences were dependent on initial lesion size for minimally classic and occult-only lesions.12 A recent prospective study on verteporfin therapy supported this hypothesis also for predominantly classic CNV in AMD, and a smaller initial lesion size also was discussed as a base for improved outcomes in a verteporfin trial in Japanese patients.13,14 However, an impact of lesion size was not shown for predominantly classic CNV in the TAP study. Our study presents a group of 203 individuals exclusively with predominantly classic features. For this well-defined group, lesion size plays an important role. Interestingly, small lesions with typically better initial visual acuity responded better to verteporfin therapy, despite their higher potential for progressive growth and severe vision loss. This difference from the TAP study could be explained by the smaller mean lesion size at baseline in the presented study. However, the most important prognostic factor may be the associated treatment spot size used in verteporfin therapy, and not baseline lesion size. Verteporfin therapy, using standard parameters, induces transient choriocapillaris closure, resulting in an angiogenic response.9 –11 The treatment of small lesions with PDT needs a small treatment spot exposing a limited area of adjacent choriocapillaris to damage. The beneficial effect of verteporfin therapy-induced CNV closure of small lesions may outweigh the limited angiogenic stimulus using a small treatment spot. This may explain why there was a benefit in mean visual acuity for small lesions (ⱕ2000 m) retreated early versus small lesions (ⱕ2000 m) treated with standard therapy (Fig 4). Adding a 1000-m security margin to the GLD— especially in the verteporfin
Discussion The 12-month follow-up of a comparison trial between early verteporfin retreatment and standard verteporfin treatment did not show a statistically significant benefit in primary or secondary outcomes for either treatment protocol (Pⱖ0.161). However, at all follow-up visits, the early retreatment group lost less mean vision, fewer patients lost at least 3 lines of visual acuity, more patients gained at least 1 line of vision, and CNV growth was less progressive (Figs 1, 3, 4; Table 1). This study presents the largest treated study population with the uniform feature of a predominantly classic lesion and a prospective study protocol for verteporfin therapy. This subtype was seen in the TAP study group as a subgroup in 160 patients treated with verteporfin therapy and thus allows some comparison. The mean change in visual acuity over 12 months in the presented study was a loss of 1.7 and 2 lines, which is consistent with the 2.2-line difference observed in the TAP study group. The TAP and the Verteporfin in Photodynamic Therapy studies indicated that lesion size is the most important prognostic factor in verteporfin therapy. This conclusion was reached using a multiple linear regression model of TAP and Verteporfin in Photodynamic Therapy subgroup data. One study reported
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Figure 6. Graph showing the baseline greatest linear dimension (GLD) compared with mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity at 6 and 12 months of follow-up in the standard retreatment group.
Michels et al 䡠 Early Retreatment in Verteporfin Therapy treatment of large CNV—leads to a much larger area of physiological choriocapillaris affected. Hypoperfusion of a larger area of choriocapillaris possibly evokes a stronger angiogenic stimulus and consequently a more progressive regrowth of CNV with increased leakage. This may play an even more important role in early retreatment of large versus small CNV and in an early versus a standard retreatment regimen. The results of this study correlate with other studies with shortened retreatment intervals.7,15 They all showed no significant benefit for the overall group of patients using early retreatment. However, early retreatment was not associated with any additional side effects or safety compromise. Patients retreated earlier had a lower risk of severe vision loss, and the rate of hemorrhages was not increased. The standard regimen as identified by the TAP study seems to be a useful recommendation, and treatment protocols should not be modified arbitrarily. However, the recommendation of a treatment spot larger than the lesion size exposing more physiologic choroid to photodynamic effects should be discussed again. Biological tissue effects can explain why baseline lesion size associated with treatment spot size seems to be a prognostic factor and why more frequent occlusive effects may not provide any overall advantage in verteporfin therapy.
References 1. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 1992;99:933– 43. 2. Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 1995;102:205–10. 3. Verteporfin in Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—Verteporfin in Photodynamic Therapy report 2. Am J Ophthalmol 2001;131:541– 60. 4. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-TAP report 2. Arch Ophthalmol 2001; 119:198 –207. 5. Visudyne in Minimally Classic Choroidal Neovascularization Study Group. Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial. Arch Ophthalmol 2005;123:448 –57. 6. Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report 1. Arch Ophthalmol 1999; 117:1329 – 45. 7. Schmidt-Erfurth U, Miller JW, Sickenberg M, et al. Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: results of retreatments in a phase 1 and 2 study. Arch Ophthalmol 1999;117:1177– 87.
8. Schmidt-Erfurth U, Michels S, Barbazetto I, Laqua H. Photodynamic effects on choroidal neovascularization and physiological choroid. Invest Ophthalmol Vis Sci 2002;43:830 – 41. 9. Michels S, Schmidt-Erfurth U. Sequence of early vascular events after photodynamic therapy. Invest Ophthalmol Vis Sci 2003;44:2147–54. 10. Schlotzer-Schrehardt U, Viestenz A, Naumann GO, et al. Dose-related structural effects of photodynamic therapy on choroidal and retinal structures of human eyes. Graefes Arch Clin Exp Ophthalmol 2002;240:748 –57. 11. Schmidt-Erfurth U, Schlotzer-Schrehard U, Cursiefen C, et al. Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 2003;44:4473– 80. 12. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Group, Verteporfin in Photodynamic Therapy Study Group. Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1. Am J Ophthalmol 2003;136:407–18. 13. Arias L, Pujol O, Berniell J, et al. Impact of lesion size on photodynamic therapy with verteporfin of predominantly classic lesions in age related macular degeneration. Br J Ophthalmol 2005;89:312–5. 14. Japanese Age-Related Macular Degeneration Trial (JAT) Study Group. Japanese Age-Related Macular Degeneration Trial: 1-year results of photodynamic therapy with verteporfin in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Am J Ophthalmol 2003;136:1049 – 61. 15. Eter N, Vogel A, Inhetvin-Hutter C, Spitznas M. Interval reduction of photodynamic therapy (PDT) in age-related macular degeneration (AMD) is not advantageous. A pilot project [in German]. Ophthalmologe 2003;100:314 –7.
Appendix: Participating Study Centers University Eye Hospital Lübeck: U. Schmidt-Erfurth, S. Michels, A. Beckendorf, C. Kusserow, F. Hansmann. University Eye Hospital Charité, Campus Benjamin Franklin, Berlin: J. Wachtlin, A. Gabel, H. Heimann. University Eye Hospital Regensburg: M.-A. Gamulescu, A. Bunse, C. Brückner, W. Ahr. University Eye Hospital Leipzig: U. Schnurrbusch, S. Wolf. University Eye Hospital Essen: B. Jurklies, U. Orthmanns. University Eye Hospital Hamburg: A. Hassenstein. Eye Hospital Karlsruhe: A. Augustin, S. Puls. University Eye Hospital Tübingen: W. Inhoffen, U. Schneider. University Eye Hospital Basel: C. Prünte. University Eye Hospital Aachen: A. Weinberger. Eye Hospital Rudolfstiftung Vienna: I. Krebs, S. Binder. University Eye Hospital Freiburg: M. Becker, H. Hansen. University Eye Hospital Homburg: A. M. PalmowskiWolfe. St. Franziskus Eye Hospital Münster: D. Pauleikhoff, M. Radermacher, G. Spital.
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Exudative age-related macular degeneration (AMD) is one of the leading causes of legal blindness in industrialized countries.1,2 Photodynamic therapy (PDT) using verteporfin (Visudyne, Novartis Pharma AG, Basel, Switzerland) has Originally received: January 31, 2005. Accepted: June 24, 2005. Manuscript no. 2005-98. 1 Klinik für Augenheilkunde und Optometrie, Medizinische Universität Wien, Vienna, Austria. 2 Augenklinik der Charité–Universitätsmedizin Berlin, Berlin, Germany. 3 Klinikum der Universität Regensburg, Klinik und Poliklinik für Augenheilkunde, Regensburg, Germany. 4 St. Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool, United Kingdom. 5 Universitäts-Augenklinik Basel, Basel, Switzerland. 6 Universitäts-Augenklinik Tübingen, Tübingen, Germany. 7 Augenklinik Rudolfstiftung, Vienna, Austria.
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© 2005 by the American Academy of Ophthalmology Published by Elsevier Inc.
been shown to be an effective, relatively selective, and safe treatment of neovascular AMD in large multicenter, randomized, placebo-controlled trials.3–5 Predominantly classic lesions as defined by fluorescein angiography, which are the
Supported by the German Research Foundation (Bonn, Germany) Priority Program (grant no.: DFG Schm 835-2). Medication (verteporfin) was provided in part by Novartis Pharma AG, Basel, Switzerland. Dr Schmidt-Erfurth is an owner of the patent on the use of green porphyrins in neovasculature of the eye under the guidelines of the Wellman Laboratories of Photomedicine, Harvard Medical School, Boston, Massachusetts. The remaining authors do not have any conflict of interest in the material presented in the article. Correspondence to Ursula Schmidt-Erfurth, MD, Klinik für Augenheilkunde und Optometrie, Medizinische Universität Wien, Währinger Gürtel 18-20, 1090 Wien, Austria. ISSN 0161-6420/05/$–see front matter doi:10.1016/j.ophtha.2005.06.034
Michels et al 䡠 Early Retreatment in Verteporfin Therapy most aggressive subtype, appear to benefit most from treatment with PDT.6 In the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) study, a significant visual benefit after PDT compared with placebo was sustained over 24 months. However, despite a significant treatment benefit, patients still lost an average of 2.2 lines of vision at 12 months and of 2.7 lines at 24 months.4 In patients treated with repeated PDT every 3 months over the course of 2 years, 75% and 82% of visual loss occurred within the first 6 and 12 months, respectively. Despite repeated PDT with verteporfin 6 months after initial treatment, no significant change in visual acuity was seen during continued follow-up, and only 18.8% of patients had complete absence of leakage from classic choroidal neovascularization (CNV) at the 12-month follow-up.6 Earlier retreatment with PDT offers the potential to inhibit progressive CNV growth and to provide better visual outcomes. Several studies have indicated that primary CNV closure after PDT is transient and that CNV recanalization and progressive growth occurs as early as 4 to 6 weeks after PDT.7,8 Early retreatment with PDT, however, also may have adverse effects limiting visual recovery. For example, despite the relative selectivity of PDT, transient choriocapillaris closure occurs 1 week after PDT.9,10 Immunohistochemistry performed 1 week after verteporfin therapy exhibited an enhanced angiogenic response to verteporfin therapy.11 Repeating PDT as late as 2 months after initial treatment may offer the choriocapillaris time to reperfuse and may still limit CNV recanalization and regrowth after PDT-induced occlusion more effectively than the extended intervals of 3 months recommended by the standard regimen. This study was designed to compare earlier retreatment every 8 weeks within the sensitive first 6 months after initiation of verteporfin treatment with standard therapy. In comparison, the Verteporfin Early Retreatment Study was designed after the presented study to evaluate retreatment every 6 weeks and larger, predominantly classic CNV, up to 5400 m in greatest linear dimension (GLD). The primary outcome of the presented study was mean visual acuity. The secondary outcomes were percentage of patients losing at least 3 lines of vision, the percentage of patients gaining at least 1 line of vision, CNV growth, and retreatment rate as well as safety.
Patients and Methods The study was a randomized, controlled, multicenter, phase IIIb study. Fourteen clinical centers (see “Appendix”) participated throughout Europe. The study design was reviewed and approved by an independent study advisory group as well as by the institutional review boards of each participating clinical center. The study was approved and supported by the German Research Council Priority Program (Deutsche Forschungsgemeinschaft DFG Schm 835-2). The protocol adhered to the Helsinki Declaration.
Patient Selection Two hundred three patients with subfoveal, predominantly classic choroidal neovascularization (CNV) secondary to AMD were en-
rolled in the study between August 2000 and May 2002. Before enrollment of each patient into the study, a central angiographic reading center (University Eye Hospital, Luebeck, Germany) assessed fluorescein angiograms and fundus photographs to confirm that all eligibility criteria were met. Inclusion criteria included: CNV secondary to AMD; CNV under the geometric center of the foveal avascular zone; evidence of at least 50% classic CNV as defined by fluorescein angiography; greatest linear dimension ⬍4400 m (6 disc areas); best-corrected visual acuity from 20/40 to 20/200; age 50 years or older; willing and able to provide written informed consent. Exclusion criteria included: any significant ocular disease that could compromise vision in the study eye; concurrent use of any investigational drug; active hepatitis or other clinically significant liver disease; porphyria or porphyrin sensitivity; intraocular surgery within 1 month before study enrollment; previous laser or verteporfin therapy in the study eye; uncontrolled hypertension (⬎140/90 mmHg).
Evaluation At every visit, best-corrected visual acuity was assessed at 2 m distance using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity protocol. In addition, a complete ophthalmologic examination, fundus photographs, and fluorescein angiography were performed. Fundus photography included digital color photos taken at a 30° field. Fluorescein angiography was performed using intravenous application of 5 ml of a 10% sodium fluorescein solution and the regimen used by the TAP study protocol.4 The Heidelberg Retina Angiograph (Heidelberg Instruments, Dossenheim, Germany) and the Zeiss FF 450 System (Carl Zeiss, Oberkochen, Germany) were approved to be used in the study. Patients were seen for follow-up visits according to their treatment group within 1 week before the first treatment and every 2 months (group A) or 3 months (group B) for the first 6 months. Thereafter, all patients were seen at 3-month intervals up to month 12.
Treatment Protocol All patients defined as eligible by the central reading center were randomized (1:1) to either the 2-month (group A) or the 3-month (group B) treatment group. Patients in the 2-month treatment group (group A) received verteporfin therapy at 2-month intervals during the first 6 months and retreatment beyond month 6 at 3-month intervals. Patients randomized to the 3-month treatment group (group B) were treated with verteporfin therapy according to the TAP criteria with retreatment at 3-month intervals. Patients in both treatment arms received retreatment only if leakage was present angiographically. Verteporfin treatment was given to all study patients according to the TAP study.4 Briefly, verteporfin was infused at a dose of 6 mg/m2 of body surface area for 10 minutes. Five minutes after the end of the infusion, a nonthermal laser light (689 nm) of 50 J/cm2 irradiating at an intensity of 600 mW/cm2 was applied for 83 seconds. Before treatment, the GLD of the lesion was determined by the treating investigator at each study center using the Heidelberg Eye Explorer or the Zeiss Visupac software. A 500-m circular security margin was added to the GLD of the lesion to obtain the adequate coverage of the entire lesion during photosensitization.
Statistical Analysis The primary efficacy analysis was based on an intent-to-treat analysis. Patients were analyzed within the group to which they were randomized. All 203 randomized patients were included in
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Ophthalmology Volume 112, Number 12, December 2005 was less frequent in the early retreatment than in the standard treatment group (20% vs. 31.6% retreatment rate; P ⫽ 0.073).
Vision Outcomes
Figure 1. Graph showing mean visual acuity of early versus standard verteporfin therapy. P values refer to change from baseline. SEM ⫽ standard error of mean.
the statistical analysis. Mean visual acuity and lesion size were evaluated using a paired t test for change from baseline. The Pearson chi-square test was used to compare proportions of patients losing at least 15 or 30 letters and gaining at least 5 letters. Analysis of variance was used for between-treatment difference evaluation and for subgroup analysis based on baseline GLD. Statistical significance was defined as P⬍0.05.
Results Baseline Characteristics Of the 203 patients included in this study, 103 were randomized to receive the standard treatment and 100 to early treatment. All 203 patients were included into the intent-to-treat population. The mean age was 75.1 years in the standard treatment and 72.7 years in the early treatment group. Visual acuity was balanced at baseline. Mean visual acuity in the standard treatment group was 48.9 letters versus 49.3 letters (approximately 20/100⫺1) in the early treatment group. Nine patients evaluated at the angiographic reading center did not meet the inclusion criteria; 7 patients had a baseline visual acuity of ⬍34 letters (⬍20/200) and 2 patients had baseline lesion sizes of ⬎6 macular photocoagulation study disc areas (GLD ⬎ 4400 m).
Follow-up and Number of Retreatments In both treatment groups, at least 90% of patients completed the 12-month follow-up. The mean number of retreatments over the first year was 3.81 treatments (maximum possible treatments, 5) in group A compared with 3.25 treatments (maximum possible treatments, 4) in group B. At the month 12 follow-up visit, retreatment
In both groups, mean visual acuity decreased by approximately 1 line at 6 months. Patients in the early treatment group (group A) had a mean loss of 4.3 to 44.7 letters (approximately 20/125) compared with a loss of 6.1 to 42.6 letters (approximately 20/125⫺2) in the standard treatment group (group B) at month 6 (Fig 1). The between-treatment group difference was 1.9 letters (P ⫽ 0.427) in favor of the early retreatment. At 6 months, 26.9% of patients in group A and 29.7 % of patients in group B had lost at least 15 letters (3 lines; Table 1). Improvement of vision of at least 5 letters (1 line) at 6 months was seen in 39.8% of patients in group A and in 23.8% of patients in group B (Table 1). At month 9, patients in the standard treatment group lost 3.9 letters more compared with those in the early retreatment group (P ⫽ 0.161). Mean visual acuity was 39.8 letters (approximately 20/160) versus 43.7 letters (approximately 20/125⫺1) in the standard and early treatment groups, respectively. However, at month 12 the between-treatment difference in favor of the early treatment group decreased to 1.5 letters (P ⫽ 0.589). Mean visual acuity was 39.1 letters (approximately 20/160⫺1) in the standard treatment group and 40.8 letters (approximately 20/160⫹1) in the early retreatment group. In the standard treatment group, 48.3% of patients lost at least 15 letters (3 lines) compared with 39.0% in the early retreatment group. A gain in vision of at least 1 line was seen in 27% of the standard treatment group and 24.7% in the early treatment group. Despite an overall favorable trend for the early retreatment group, none of the visual acuity data within the 1-year follow-up showed a statistically significant benefit for either group. Further analysis combining the early and standard treatment regimen indicated a change in visual acuity from baseline to be associated with change in GLD from baseline (Fig 2). Patients with a loss of more than 15 letters (3 lines) showed a mean increase in GLD of at least 1002 m at 6 and 12 months of follow-up. Patients gaining at least 5 letters at 6 and 12 months of follow-up had, in comparison, a mean increase in GLD of less than 261 m.
Fluorescein Angiography Outcomes This study used an angiographic eligibility review at study entry, and all patients included in the study had a predominantly classic CNV resulting from AMD. The mean GLD of the lesion, 2104 m in the early treatment group (group A) and 2179 m in the standard treatment group (group B), was comparable between the 2 treatment groups at baseline. Progressive lesion growth was seen in both groups. At 6 months, mean lesion diameters increased to 2842 m in the standard treatment and to 2512 m in the early treatment group. Lesion growth was generally slower between 6and 12-month follow-up. The GLD increased to 2871 m and 2546 m at 9 months and to 2996 m and 2790 m at 12 months in the standard treatment and early treatment groups, respectively (Fig 3). The between-treatment group differences were not statis-
Table 1. Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Outcomes 6 Months
Mean change Loss ⱖ15 letters Gain ⱖ5 letters
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12 Months
Early Retreatment
Standard
P Value
Early Retreatment
Standard
P Value
⫺4.3 26.9% 39.8%
⫺6.1 29.7% 23.8%
0.427 0.663 0.016
⫺8.5 39% 24.7%
⫺9.9 48.3% 27%
0.589 0.226 0.737
Michels et al 䡠 Early Retreatment in Verteporfin Therapy
Figure 2. Graph showing the increase in greatest linear diameter (GLD) from baseline compared with change in visual acuity at 6 and 12 months. The figure indicates an association of lesion growth and loss in visual acuity.
tically significant at any point (Pⱖ0.059). However, there was a trend toward less intensive lesion growth in group A.
Subgroup Analysis Visual acuity scores were analyzed for 2 subgroups: patients with a baseline GLD ⱕ2000 m and patients with a baseline GLD ⬎2000 m. The mean visual acuity letter scores at follow-up are shown in Figure 4. In the subgroup of patients with small lesions (ⱕ2000 m), patients who received early retreatment had a more favorable outcome than those who received standard treatment at all follow-up visits. However, only at 9 months of follow-up was
Figure 4. Graph showing the subgroup analysis for mean visual acuity. GLD ⫽ greatest linear dimension; SEM ⫽ standard error of mean.
the difference in mean visual acuity of 7.7 letters between these 2 treatment groups statistically significant (P ⫽ 0.046). Accordingly, patients with large lesions (⬎2000 m) at baseline receiving early retreatment had the least favorable visual outcome, as shown in Figure 4. These patients lost a mean of 14 letters during the next 12 months compared with patients with large lesions at baseline in the standard treatment group who lost a mean of 11 letters. Patients in the early retreatment group with small lesions (ⱕ2000 m) at baseline had significantly better mean visual acuity outcomes than patients with larger lesions (⬎2000 m) at month 6 (P ⫽ 0.002), 9 (P ⫽ 0.004), and 12 (P ⫽ 0.002). Within the standard treatment group (group B), a difference in mean visual acuity between initially small lesions (ⱕ2000 m) and large lesions (⬎2000 m) also was seen; however, the difference did not become statistically significant at any follow-up visit (Pⱖ0.282; Fig 4). Figures 5 and 6 demonstrate the impact of baseline lesion size on change in visual acuity from baseline at 6 and 12 months of follow-up for patients with early treatment and standard treatment. Very small lesions (ⱕ1000 m) had overall the best vision outcome in both treatment groups, losing a mean of 1.4 letters in the early treatment group and 1 letter in the standard treatment group at month 12. Figure 5 indicates more vision loss with increasing lesion size at baseline for patients receiving early treatment. Very small lesions in the standard treatment group also benefitted most; however, with increasing baseline lesion size, progressive vision loss is not seen as clearly as in the early treatment group.
Safety
Figure 3. Graph showing the mean greatest linear dimension (GLD) of choroidal neovascularization (CNV). All changes in GLD were statistically significant from baseline (Pⱕ0.002). SEM ⫽ standard error of mean.
Severe loss of vision of at least 30 letters (6 lines) was seen less frequently in the early treatment group (group A). At 12 months of follow-up, there was severe vision loss in 21.3% of patients in the standard group and 10.4% of patients in the early retreatment group (P ⫽ 0.056). Within the first 12 months of follow-up, there were no severe ocular or systemic side effects related to early retreatment. None of the patients showed retinal ischemia, nor
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Figure 5. Graph showing the baseline greatest linear dimension (GLD) compared with mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity at 6 and 12 months of follow-up in the early retreatment group.
were there any reports of early, severe vision decrease defined as vision loss of at least 20 letters (4 lines) within 7 days of verteporfin therapy. The risk of subretinal hemorrhage and intravitreal hemorrhage was not increased in either group.
that most significant mean visual outcome differences were dependent on initial lesion size for minimally classic and occult-only lesions.12 A recent prospective study on verteporfin therapy supported this hypothesis also for predominantly classic CNV in AMD, and a smaller initial lesion size also was discussed as a base for improved outcomes in a verteporfin trial in Japanese patients.13,14 However, an impact of lesion size was not shown for predominantly classic CNV in the TAP study. Our study presents a group of 203 individuals exclusively with predominantly classic features. For this well-defined group, lesion size plays an important role. Interestingly, small lesions with typically better initial visual acuity responded better to verteporfin therapy, despite their higher potential for progressive growth and severe vision loss. This difference from the TAP study could be explained by the smaller mean lesion size at baseline in the presented study. However, the most important prognostic factor may be the associated treatment spot size used in verteporfin therapy, and not baseline lesion size. Verteporfin therapy, using standard parameters, induces transient choriocapillaris closure, resulting in an angiogenic response.9 –11 The treatment of small lesions with PDT needs a small treatment spot exposing a limited area of adjacent choriocapillaris to damage. The beneficial effect of verteporfin therapy-induced CNV closure of small lesions may outweigh the limited angiogenic stimulus using a small treatment spot. This may explain why there was a benefit in mean visual acuity for small lesions (ⱕ2000 m) retreated early versus small lesions (ⱕ2000 m) treated with standard therapy (Fig 4). Adding a 1000-m security margin to the GLD— especially in the verteporfin
Discussion The 12-month follow-up of a comparison trial between early verteporfin retreatment and standard verteporfin treatment did not show a statistically significant benefit in primary or secondary outcomes for either treatment protocol (Pⱖ0.161). However, at all follow-up visits, the early retreatment group lost less mean vision, fewer patients lost at least 3 lines of visual acuity, more patients gained at least 1 line of vision, and CNV growth was less progressive (Figs 1, 3, 4; Table 1). This study presents the largest treated study population with the uniform feature of a predominantly classic lesion and a prospective study protocol for verteporfin therapy. This subtype was seen in the TAP study group as a subgroup in 160 patients treated with verteporfin therapy and thus allows some comparison. The mean change in visual acuity over 12 months in the presented study was a loss of 1.7 and 2 lines, which is consistent with the 2.2-line difference observed in the TAP study group. The TAP and the Verteporfin in Photodynamic Therapy studies indicated that lesion size is the most important prognostic factor in verteporfin therapy. This conclusion was reached using a multiple linear regression model of TAP and Verteporfin in Photodynamic Therapy subgroup data. One study reported
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Figure 6. Graph showing the baseline greatest linear dimension (GLD) compared with mean change in Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity at 6 and 12 months of follow-up in the standard retreatment group.
Michels et al 䡠 Early Retreatment in Verteporfin Therapy treatment of large CNV—leads to a much larger area of physiological choriocapillaris affected. Hypoperfusion of a larger area of choriocapillaris possibly evokes a stronger angiogenic stimulus and consequently a more progressive regrowth of CNV with increased leakage. This may play an even more important role in early retreatment of large versus small CNV and in an early versus a standard retreatment regimen. The results of this study correlate with other studies with shortened retreatment intervals.7,15 They all showed no significant benefit for the overall group of patients using early retreatment. However, early retreatment was not associated with any additional side effects or safety compromise. Patients retreated earlier had a lower risk of severe vision loss, and the rate of hemorrhages was not increased. The standard regimen as identified by the TAP study seems to be a useful recommendation, and treatment protocols should not be modified arbitrarily. However, the recommendation of a treatment spot larger than the lesion size exposing more physiologic choroid to photodynamic effects should be discussed again. Biological tissue effects can explain why baseline lesion size associated with treatment spot size seems to be a prognostic factor and why more frequent occlusive effects may not provide any overall advantage in verteporfin therapy.
References 1. Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 1992;99:933– 43. 2. Vingerling JR, Dielemans I, Hofman A, et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 1995;102:205–10. 3. Verteporfin in Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—Verteporfin in Photodynamic Therapy report 2. Am J Ophthalmol 2001;131:541– 60. 4. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-TAP report 2. Arch Ophthalmol 2001; 119:198 –207. 5. Visudyne in Minimally Classic Choroidal Neovascularization Study Group. Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial. Arch Ophthalmol 2005;123:448 –57. 6. Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report 1. Arch Ophthalmol 1999; 117:1329 – 45. 7. Schmidt-Erfurth U, Miller JW, Sickenberg M, et al. Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: results of retreatments in a phase 1 and 2 study. Arch Ophthalmol 1999;117:1177– 87.
8. Schmidt-Erfurth U, Michels S, Barbazetto I, Laqua H. Photodynamic effects on choroidal neovascularization and physiological choroid. Invest Ophthalmol Vis Sci 2002;43:830 – 41. 9. Michels S, Schmidt-Erfurth U. Sequence of early vascular events after photodynamic therapy. Invest Ophthalmol Vis Sci 2003;44:2147–54. 10. Schlotzer-Schrehardt U, Viestenz A, Naumann GO, et al. Dose-related structural effects of photodynamic therapy on choroidal and retinal structures of human eyes. Graefes Arch Clin Exp Ophthalmol 2002;240:748 –57. 11. Schmidt-Erfurth U, Schlotzer-Schrehard U, Cursiefen C, et al. Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 2003;44:4473– 80. 12. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Group, Verteporfin in Photodynamic Therapy Study Group. Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1. Am J Ophthalmol 2003;136:407–18. 13. Arias L, Pujol O, Berniell J, et al. Impact of lesion size on photodynamic therapy with verteporfin of predominantly classic lesions in age related macular degeneration. Br J Ophthalmol 2005;89:312–5. 14. Japanese Age-Related Macular Degeneration Trial (JAT) Study Group. Japanese Age-Related Macular Degeneration Trial: 1-year results of photodynamic therapy with verteporfin in Japanese patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Am J Ophthalmol 2003;136:1049 – 61. 15. Eter N, Vogel A, Inhetvin-Hutter C, Spitznas M. Interval reduction of photodynamic therapy (PDT) in age-related macular degeneration (AMD) is not advantageous. A pilot project [in German]. Ophthalmologe 2003;100:314 –7.
Appendix: Participating Study Centers University Eye Hospital Lübeck: U. Schmidt-Erfurth, S. Michels, A. Beckendorf, C. Kusserow, F. Hansmann. University Eye Hospital Charité, Campus Benjamin Franklin, Berlin: J. Wachtlin, A. Gabel, H. Heimann. University Eye Hospital Regensburg: M.-A. Gamulescu, A. Bunse, C. Brückner, W. Ahr. University Eye Hospital Leipzig: U. Schnurrbusch, S. Wolf. University Eye Hospital Essen: B. Jurklies, U. Orthmanns. University Eye Hospital Hamburg: A. Hassenstein. Eye Hospital Karlsruhe: A. Augustin, S. Puls. University Eye Hospital Tübingen: W. Inhoffen, U. Schneider. University Eye Hospital Basel: C. Prünte. University Eye Hospital Aachen: A. Weinberger. Eye Hospital Rudolfstiftung Vienna: I. Krebs, S. Binder. University Eye Hospital Freiburg: M. Becker, H. Hansen. University Eye Hospital Homburg: A. M. PalmowskiWolfe. St. Franziskus Eye Hospital Münster: D. Pauleikhoff, M. Radermacher, G. Spital.
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