M. Sickenberg

Photodynamic Therapy With Verteporfin for Choroidal Neovascularization Caused by Age-related Macular Degeneration: Results of a Single Treatment in a Phase 1 and 2 Study

OBJECTIVE To evaluate the safety and short-term visual and fluorescein angiographic effects of a single photodynamic therapy treatment with verteporfin with the use of different dosage regimens in patients with choroidal neovascularization (CNV) from age-related macular degeneration. DESIGN Nonrandomized, multicenter, open-label, clinical trial using 5 dosage regimens. SETTING Four ophthalmic centers in North America and Europe providing retinal care. PARTICIPANTS Patients with subfoveal CNV caused by age-related macular degeneration. METHODS Standardized protocol refraction, visual acuity testing, ophthalmic examination, color photographs, and fluorescein angiograms were used to evaluate the effects of a single treatment of photodynamic therapy with verteporfin. Follow-up was planned through 3 months in 97 patients and for less than 3 months in 31 other patients. RESULTS The mean visual acuity change (and range of change) from baseline at the follow-up examination at week 12 after a single treatment with regimens 1 through 5 was -0.2 (-3 to +2), -0.9 (-9 to +5), -1.6 (-9 to +2), +0.4 (-8 to +7), and +0.1 (-8 to +9) lines, respectively. Only the highest light dose (150 J/cm2) in regimens 2 and 3, which produced angiographic nonperfusion of neurosensory retinal vessels, caused marked vision loss. Some cessation of fluorescein leakage from CNV was achieved without loss of vision when the light dose used was less than 150 J/cm2. Systemic adverse events were rare. Cessation of fluorescein leakage from CNV was noted in all regimens by 1 week after photodynamic therapy. Fluorescein leakage from at least a portion of the CNV reappeared by 4 to 12 weeks after treatment in almost all cases. Progression of classic CNV beyond the area of CNV identified before treatment was noted in 42 (51%) of the 83 eyes with classic CNV followed up for 3 months after a single treatment. Eyes in which the area of any CNV leakage at 12 weeks was less than at baseline had a significantly better visual acuity outcome (+0.8 line) than eyes in which CNV leakage progressed (-0.8 line). CONCLUSIONS Photodynamic therapy with verteporfin achieved short-term cessation of fluorescein leakage from CNV without loss of vision or growth of classic CNV in some patients with age-related macular degeneration. Except for nonperfusion of neurosensory retinal vessels at a light dose of 150 J/cm2, no other adverse events were of concern. Randomized clinical trials to investigate whether this new modality can preserve vision in patients with CNV secondary to age-related macular degeneration are justified.

Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-Year results of a randomized clinical trial - VIP report no. 3

PURPOSE To report 24-month vision and fluorescein angiographic outcomes from trials evaluating photodynamic therapy with verteporfin in patients with subfoveal choroidal neovascularization (CNV) caused by pathologic myopia. DESIGN AND SETTING Multicenter, double-masked, placebo-controlled, randomized clinical trial at 28 ophthalmology practices in Europe and North America. PARTICIPANTS Patients with subfoveal choroidal neovascular lesions caused by pathologic myopia measuring no more than 5400 micro m and best-corrected visual acuity (approximate Snellen equivalent) of 20/100 or better. METHODS Similar to methods described for 1-year results with follow-up examinations beyond 1 year, continuing every 3 months (except Photograph Reading Center evaluations only at the month 24 examination). During the second year, the same regimen (with verteporfin or placebo as applied at baseline) was used if angiography showed fluorescein leakage from CNV. MAIN OUTCOME MEASURES The primary outcome was the proportion of eyes with fewer than 8 letters (approximately 1.5 lines) of visual acuity loss at the month 24 examination, adhering to an intent-to-treat analysis and using the last observation carried forward method to impute for any missing data. RESULTS Seventy-seven of 81 patients (95%) in the verteporfin group, compared with 36 of 39 patients (92%) in the placebo group, completed the month 24 examination. At this time point, 29 of 81 verteporfin-treated patients (36%) compared with 20 of 39 placebo-treated patients (51%) lost at least 8 letters (P = 0.11). The distribution of change in visual acuity at the month 24 examination was in favor of a benefit for the cases assigned to verteporfin (P = 0.05). This included improvement by at least 5 letters (equivalent to at least 1 line) in 32 verteporfin-treated cases [40%] vs. five placebo-treated cases (13%) and improvement by at least 15 letters (equivalent to at least 3 lines) in 10 verteporfin-treated cases (12%) vs. zero placebo-treated cases. No additional photosensitivity adverse reactions or injection site adverse events were associated with verteporfin therapy in the second year of follow-up. CONCLUSIONS Verteporfin therapy for subfoveal CNV caused by pathologic myopia safely maintained a visual benefit compared with a placebo therapy through 2 years of follow-up. Although the primary outcome was not statistically significantly in favor of verteporfin therapy at 2 years as it had been at 1 year of follow-up, the distribution of change in visual acuity at the month 24 examination was in favor of the verteporfin-treated group and showed that this group was more likely to have improved visual acuity through the month 24 examination. The VIP Study Group recommends verteporfin therapy for subfoveal CNV resulting from pathologic myopia based on both the 1- and 2-year results of this randomized clinical trial.

Verteporfin therapy for subfoveal choroidal neovascularization in age-related macular degeneration: three-year results of an open-label extension of 2 randomized clinical trials--TAP Report no. 5

OBJECTIVE To report vision and safety outcomes from an extension of a 2-year investigation evaluating verteporfin photodynamic therapy in patients with age-related macular degeneration with subfoveal choroidal neovascularization (CNV). DESIGN AND SETTING Open-label extension of selected patients from 2 multicenter, double-masked, placebo-controlled, randomized clinical trials, the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Investigation, at 22 ophthalmology practices in Europe and North America. PARTICIPANTS Patients enrolled in the TAP Investigation and followed up for at least 24 months in whom verteporfin therapy to CNV might reduce the risk of further vision loss. METHODS Before receiving verteporfin therapy in the extension, eligible patients signed a written informed consent form accompanied by an oral consent process approved by local institutional review boards. Methods were similar to those described for 1- and 2-year results, with follow-up examinations beyond 2 years continuing at 3-month intervals with a few exceptions, including that extension patients with fluorescein leakage from CNV were to receive open-label verteporfin therapy irrespective of their original treatment assignment. RESULTS Of 402 patients in the verteporfin group, 351 (87.3%) completed the month 24 examination; 320 (91.2%) of these enrolled in the extension study. The enrolled participants included 124 (78.0%) of the 159 verteporfin-treated patients with lesions composed of predominantly classic CNV at baseline, of whom 105 (84.7%) completed the month 36 examination. Verteporfin-treated patients with this lesion composition at baseline who participated in the extension study, with or without a month 36 examination, appeared more likely to have a younger age, better level of visual acuity, absence of fluorescein leakage from classic CNV, or no progression of classic CNV beyond the baseline boundaries of the lesion at the month 24 examination compared with those who did not enroll in the extension. For the 105 patients with a predominantly classic baseline lesion composition who completed the month 36 examination, an average of 1.3 treatments were given from the month 24 examination up to, but not including, the month 36 examination. A letter score loss in the study eye of at least 15 from baseline for these patients occurred in 39 (37.5%) at the month 24 examination compared with 44 (41.9%) of these patients at the month 36 examination. Visual acuity changed little from the month 24 examination (mean, -1.9 lines) to the month 36 examination (mean, -2.0 lines) for these eyes. Verteporfin-treated patients had little change in the mean visual acuity lost and few or no additional instances of infusion-related back pain or photosensitivity reactions from month 24 to month 36. Two patients originally assigned to placebo had acute severe vision decrease within 7 days after verteporfin treatment during the extension. One patient originally assigned to verteporfin had acute severe vision decrease after verteporfin treatment of the fellow eye during the extension. CONCLUSIONS Vision outcomes for verteporfin-treated patients with predominantly classic lesions at baseline remained relatively stable from month 24 to month 36, although only approximately one third of the verteporfin-treated patients originally enrolled with this lesion composition had a month 36 examination. From these results, the TAP Study Group identified no safety concerns to preclude repeating photodynamic therapy with verteporfin. Additional treatment was judged likely to reduce the risk of further vision loss. Caution appears warranted in the absence of comparison with an untreated group during the extension and since not all patients in the TAP Investigation participated in the TAP Extension.

Photodynamic therapy of subfoveal choroidal neovascularization: clinical and angiographic examples

Abstract · Background: Conventional photocoagulation of subfoveal choroidal neovascularization (CNV) is often accompanied by visual loss due to thermal damage to adjacent retinal structures. Photodynamic therapy (PDT) allows vascular occlusion by selective photochemical destruction of vascular endothelial cells only. In a pilot study we evaluated the use of PDT in CNV. · Methods: In a clinical phase I/II trial, patients with subfoveal CNV were treated with PDT. Benzoporphyrin derivative monoacid ring A (BPD) was used as sensitizer at a drug dose of 6 mg/m2 or 12 mg/m2. Irradiation was performed via a diode laser emitting at 690 nm coupled into a slit lamp. Safe and maximum tolerated light doses were defined by dose escalation from 25 to 150 J/cm2. Photodynamic effects were documented ophthalmoscopically and angiographically. · Results: Sixty-one patients received a single course of BPD-PDT. Preliminary results suggest no damage to retinal structures within the treated area clinically. Retinal perfusion was not altered, while CNV demonstrated immediate absence of fluorescein leakage in the majority of lesions subsequent to PDT. At optimized parameters (6 mg/m2 and 50 J/cm2) complete cessation of leakage from classic CNV occurred in 100% of cases at 1 week and in 50% at week 4. In 70–80% of classic CNV, leakage reappeared at week 12, but markedly less than before treatment. · Conclusion: PDT allows temporary absence of leakage from CNV with preservation of visual acuity. The long-term prognosis of CNV secondary to age-related macular degeneration treated with repeated courses of PDT is being evaluated in a phase III trial.

Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin in the ocular histoplasmosis syndrome: One-year results of an uncontrolled, prospective case series

OBJECTIVE To evaluate the safety and effect on visual acuity of photodynamic therapy with verteporfin (Visudyne, Novartis AG) in patients with subfoveal choroidal neovascularization (CNV) secondary to the ocular histoplasmosis syndrome (OHS). DESIGN Open-label, three-center, noncomparative prospective case series. PARTICIPANTS OHS patients with subfoveal CNV lesions no larger than 5400 micro m in greatest linear dimension (GLD) with classic or occult CNV extending under the geometric center of the foveal avascular zone and best-corrected visual acuity letter score of 73 to 34 (approximate Snellen equivalent 20/40-20/200). METHODS Twenty-six patients received verteporfin (6 mg/m(2)) infused IV over 10 minutes. Fifteen minutes after the start of infusion, a laser light at 689 nm delivered 50 J/cm(2) at an intensity of 600 mW/cm(2) over 83 seconds using a spot size with a diameter 1000 micro m larger than the GLD of the lesion. At 3-month follow-up examinations, retreatment with the same regimen was applied if angiography showed fluorescein leakage. Safety assessments were also made. MAIN OUTCOME MEASURES Visual function measurements were the changes from baseline in visual acuity and contrast sensitivity scores and the proportion of patients who, based on best-corrected visual acuity scores, (1) gained 7 or more letters, (2) lost 8 or more letters, and (3) lost 15 or more letters. RESULTS One patient was omitted from the study at the month 3 examination for not meeting the visual acuity eligibility requirements at baseline. By the month 12 examination, but excluding any retreatment at that visit, patients had received an average of 2.9 treatments of a maximum of 4 possible treatments. The month 12 median improvement from baseline in visual acuity of the remaining 25 patients was 7 letters, and median contrast sensitivity improved by 2 letters. Median visual acuity improvement was also 7 letters when three patients, who failed to meet all photographic eligibility requirements at baseline, were excluded. At the month 12 examination, 14 (56%) patients gained 7 or more letters of visual acuity from baseline, whereas 4 (16%) patients lost 8 or more letters, of which 2 (8%) lost 15 or more letters. No serious systemic or ocular adverse events were reported. CONCLUSIONS Median visual acuity improved after verteporfin therapy for at least 1 year in a small uncontrolled prospective case series of patients with subfoveal CNV caused by OHS. Verteporfin therapy seemed to be safe and well tolerated in these patients. Two-year data from this study will provide important, additional information on the safety and effect of verteporfin therapy for the treatment of subfoveal CNV secondary to OHS.

Photodynamic Therapy With Verteporfin for Choroidal Neovascularization Caused by Age-related Macular Degeneration

OBJECTIVES To evaluate safety and short-term visual acuity and fluorescein angiographic effects of photodynamic therapy (PDT) after retreatments with verteporfin for choroidal neovascularization (CNV) in age-related macular degeneration (AMD) that demonstrated fluorescein leakage after at least 1 course of PDT. DESIGN Nonrandomized, multicenter, open-label phase 1 and 2 clinical trial using 2 different retreatment dosage regimens. SETTING Four ophthalmic centers in Europe and North America providing retinal care. METHODS Standardized protocol refraction, visual acuity testing, ophthalmic examinations, color photographs, and fluorescein angiograms were used to evaluate the results of multiple PDT treatments. Two regimens (regimens 2 and 4) for treatment and retreatment were chosen from 5 used in a single-treatment study. Both regimens used a verteporfin dose of 6 mg/m2 infused for 10 minutes. However, regimen 2 used a light dose of 100 J/cm2 applied 20 minutes after the start of the verteporfin infusion, whereas regimen 4 used a light dose of 50, 75, or 100 J/cm2 applied 15 minutes after infusion commenced. Posttreatment evaluations were planned in 31 participants up to 3 months after up to 2 retreatments given at 2- or 4-week intervals after initial PDT treatment. Similar posttreatment evaluations were planned after retreatments in 5 additional participants who were reenrolled some time more than 12 weeks after an initial PDT treatment. RESULTS The average visual acuity change for the 31 participants who had retreatment within 2 to 4 weeks after the initial treatment and a follow-up examination 16 to 20 weeks after the initial treatment was 0.2 lines (range, -4 to 4 lines) in regimen 2 and -1.0 line (range, -5 to 3 lines) in regimen 4. Similar outcomes were noted in the 5 reenrolled participants. Cessation of fluorescein leakage from classic CNV for at least 1 to 4 weeks could be achieved without loss of visual acuity after at least 2 treatments in 2 (6.5%) of 31 patients. Similar to single-treatment effects, the disappearance of leakage was documented regularly at 1 week after each retreatment. Fluorescein leakage reappeared by 4 to 12 weeks after a retreatment in almost all cases. However, compared with baseline, leakage activity appeared to be reduced after multiple PDT courses. For the 31 patients who had follow-up for 3 months after the last retreatment and had received retreatment 2 to 4 weeks after the initial treatment, progression of CNV beyond the area identified before the retreatment was noted in 10 (48%) of the 21 eyes with classic CNV in regimen 2 and 9 (90%) of 10 eyes in regimen 4. The rate and severity of ocular or systemic adverse events were not increased by multiple applications. CONCLUSIONS Multiple applications of PDT with verteporfin achieve repetitive, short-term cessation of fluorescein leakage from CNV secondary to AMD, without loss of visual acuity. This strategy can be used in randomized clinical trials investigating the efficacy of verteporfin in PDT for recurrent fluorescein dye leakage from persistent or recurrent CNV, following an initial or subsequent PDT treatment, with maintenance of visual acuity. Retreatments may achieve progressive cessation of leakage and prevent further growth of CNV and subsequent visual loss.

Photodynamic therapy for polypoidal choroidal vasculopathy

The first effective therapy for exudative macular degeneration (AMD) was Photodynamic Therapy (PDT). Diagnosis of the disease was to a large extent by fluorescein angiography (FA). Distinguishing between the leaky choroidal neovessels (CNV) associated with exudative AMD, and the polypoidal structures associated with Polypoidal Choroidal Vasculopathy (PCV) is not always easy using FA alone. The switch to Indocyanine Green angiography helped to pinpoint PCV, and thus to study the efficacy of photodynamic therapy of this particular form of retinal disease, which is more frequently encountered among pigmented individuals. The results appear to be quite promising, and in the year following treatment only a small fraction of the patients had to be retreated. Alternatively, treating PCV with repeated intravitreal VEGF blocking agents was not as successful as it was in the treatment of wet AMD. However, combining PDT-induced angio-occlusion of the polypoidal lesions with anti-vascular endothelial growth factor therapy was shown to be quite effective, and the combination of PDT with an anti-angiogenic agent as well as a steroid, in a triple therapy, was recently also shown to be a quite promising option. In the present article we review the data on PDT of PCV, including combination therapies and alternative treatments. We also report on similarities and differences between AMD and PCV.

MORPHOMETRIC CHARACTERISTICS OF TRAUMATIC CHOROIDAL RUPTURES ASSOCIATED WITH NEOVASCULARIZATION

Purpose: To define the morphometric characteristics of indirect choroidal ruptures associated with choroidal neovascularization (CNV). Methods: A total of 79 eyes that had sustained traumatic indirect choroidal ruptures was studied retrospectively. Color pictures of the fundus and fluorescein angiograms were available in all cases, and patients were followed for at least 1 year. Eyes that were free of CNV constituted Group I; eyes that developed CNV constituted Group II. Baseline characteristics of both groups, including age, sex, and visual acuity, were recorded. Distance of indirect choroidal ruptures from the center of the fovea and morphometric characteristics of the ruptures were calculated using image analysis software (Image 1.60; National Institutes of Health, Bethesda, MD). Results: A total of 63 eyes (79.7%) free of CNV was included in Group I and 16 eyes (20.3%) that developed CNV were included in Group II. Morphometric analysis showed a greater distance between the indirect choroidal rupture and the center of the fovea in Group I than in Group II (median, 1480 μm versus 612 μm; P = 0.009). In addition, the length of the rupture was shorter in Group I than in Group II (median, 3054 μm versus 4504 (μm; P = 0.03). Conclusions: Two significant factors associated with the presence of CNV in case of traumatic choroidal rupture were identified and quantified: the proximity of the rupture to the center of the fovea and the length of the rupture. Both should be considered as risk factors for the development of CNV and monitoring should take them into account.

A computer-based method to quantify the classic pattern of choroidal neovascularization in order to monitor photodynamic therapy

Abstract · Background: Photodynamic therapy (PDT) is a new treatment modality which relies on a nonthermal light exposure of choroidal neovascularization (CNV) which has accumulated a photosensitizer, to produce a photochemical thrombosis. The aim of the present study was to develop a more quantitative outcome parameter that can be used to optimize a number of treatment parameters which in PDT are larger than many other modalities. · Methods: Nine patients underwent up to four standardized fluorescein angiography (FA) examinations on a Zeiss 30° retinograph using Kodak Trimax film. The 35-mm pictures were digitized. The CNV size was evaluated using the NIH Image 1.60 software, comparing the CNV surface to the disk area. The fluorescence intensity was measured comparing the grayscale fluorescence levels of the CNV classic pattern with the mean grayscale level of control areas. A combination of the CNV size parameter with the fluorescence contrast parameter was called “integrated contrast” (IC). The IC amplitude was then used to describe and compare the fluorescence before and after PDT. · Results: FAs on three normal patients defined the normal range of the IC. IC measurements on two patients with a classic CNV who underwent FA examinations respectively 1 and 3 months apart demonstrated the robustness and the reproducibility of the method. IC measurements on three patients who underwent PDT with three different treatment parameters demonstrated the feasibility of using this IC measurement as a PDT outcome criteria. · Conclusion: We have developed a method to transform a qualitative clinical evaluation of CNV leakage into a more quantitative grading.

The Role of Photodynamic Therapy in Non-malignant and Malignant Eye Disorders

Photodynamic therapy (PDT) has represented an important treatment modality in many ocular disorders for more than a decade. The introduction of verteporfin-PDT to the treatment of neovascular age-related macular degeneration and polypoidal choroidal vasculopathy has rescued millions of patients from vision loss and blindness around the world. The most well-known vascular tumors in the eye treated with PDT include retinal capillary hemangioma, choroidal hemangioma, retinal vasoproliferative tumor or Wyburn-Mason syndrome. The discovery of the role of vascular endothelial cell growth factor in age-related macular degeneration and the revolution of its treatment by anti-vascular endothelial cell growth factor agents reduced the need for PDT in age-related macular degeneration; however, the use of PDT in the treatment of PCV is dramatically increasing. Furthermore, clinical results obtained with PDT, in combination with angiogenesis inhibitors, vascular disrupting agents, or/and anti-inflammatory compounds as adjuvant therapies, may well keep PDT as one the main treatment options. This review summarizes the present role and future possible improvements of ocular PDT.