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Impact on Ophthalmology and Visual Sciences

Neil M. Bressler and Susan B. Bressler

R

ecently, the Treatment of Age-Related Macular Degen-eration with Photodynamic Therapy (TAP) Study Group reported that photodynamic therapy with verteporfin (Visudyne; Ciba Vision, Bu¨lach, Switzerland) can reduce the risk of vision loss in patients with subfoveal choroidal neovas-cularization (CNV) due to age-related macular degeneration (AMD).1

This is a review of the circumstances leading to the design of the TAP Investigation, the findings of that investiga-tion, and the impact of those findings on clinicians and re-searchers in ophthalmology and vision sciences.

L

IMITATIONS OF

T

REATMENT FOR

CNV

IN

AMD

THROUGH THE

1990

S

The TAP Investigation was designed to determine whether photodynamic therapy with verteporfin could reduce the risk of vision loss in patients who have subfoveal CNV in AMD. The investigation was initiated because of the many limitations of treatment for CNV in AMD through the 1990s. Specifically, CNV, or the ingrowth of new vessels from the choriocapillaris with subsequent fibrosis and destruction of the outer retina and inner choroid, which usually extends under the center of the foveal avascular zone (i.e., is subfoveal) in patients with AMD, is the leading cause of severe central vision loss in people more than 65 years of age in the United States and throughout the Western world.2,3

Occasionally, laser photoco-agulation of subfoveal CNV can reduce the risk of severe visual acuity loss, compared with no photocoagulation, by confining the lesion to a small area of damaged retina using thermal laser. In comparing this laser treatment with observation 2 years after entry into randomized clinical trials, the Macular Photocoagu-lation Study Group reported that the proportion of patients in whom severe vision loss developed (approximately 20%) was approximately half the proportion of those in whom such loss developed without treatment.4

However, this treatment is ben-eficial only for relatively small lesions, because the photocoag-ulation damages viable neurosensory retina overlying the treated CNV.5

Unfortunately, most patients with subfoveal CNV do not benefit from laser photocoagulation, because the lesions are too large or have poorly demarcated boundaries

that require treatment of a relatively large area of the macula to ensure that treatment covers the entire area of the lesion.6,7 The risk of severe visual acuity loss after laser treatment of such a large area of subfoveal CNV in AMD (in an eye that has had no prior laser photocoagulation) is as great or greater than the risk without treatment.

P

OTENTIAL OF

P

HOTODYNAMIC

T

HERAPY IN THE

T

REATMENT OF

CNV

IN

AMD

Because of the limitations of laser photocoagulation for subfo-veal CNV and because CNV in AMD is an important public health problem, other treatments that may be less destructive but are still able to slow down visual loss from CNV are under evaluation in an effort to improve the visual outcome in this condition. One such treatment is photodynamic therapy with verteporfin, a benzoporphyrin derivative monoacid ring A,8 the only drug, to date, to have a therapeutic benefit in large-scale randomized clinical trials, although other photosensitiz-ers are under investigation. Photodynamic therapy is a two-step process. The first two-step requires the intravenous infusion of a photosensitive drug, in this case, verteporfin. The second step is activation of the drug by nonthermal light at the wave-length absorbed by the photosensitizer used and in the pres-ence of oxygen.9The activation probably results in the forma-tion of cytotoxic oxygen species such as singlet oxygen and free radicals, which can damage cellular structures. This dam-age may lead to platelet activation and subsequent thrombosis and occlusion of choroidal neovasculature within the treated area. After studies reported that photosensitizers could be retained preferentially in tumors10 and that photodynamic therapy could lead to tumor death by occlusion of the tumor vasculature and direct cytotoxic effects,11 investigators hy-pothesized that photodynamic therapy may be particularly useful in the selective destruction of CNV to confine the lesion from growing and thereby reduce the risk of progressive visual damage without causing significant destruction to viable neu-rosensory retina overlying the CNV.12,13

Verteporfin was be-lieved to be a good photosensitizer for treatment of CNV, not only because of its potential selectivity for neovasculature lesions, but also because of its pharmacokinetics, which in-clude rapid clearance within the first 24 hours after infusion to reduce the chance of generalized photosensitivity of a patient after treatment.14

Based on preclinical studies,13,15,16a phase I and II inves-tigation was designed to evaluate the safety of verteporfin therapy for the treatment of patients with CNV and to deter-mine the effects of this therapy on fluorescein leakage from CNV.17–19This investigation showed that an initial treatment of photodynamic therapy with verteporfin could cause short-term cessation of fluorescein leakage from CNV without angio-From the Retinal Vascular Center, Wilmer Ophthalmological

Insti-tute, Johns Hopkins University School of Medicine, Baltimore, Mary-land.

Supported by Wilmer Macular-Retinal Research Fund and the Research to Prevent Blindness Olga Keith Wiess Scholar Award (SBB). Submitted for publication September 24, 1999; accepted Novem-ber 2, 1999.

Commercial relationships policy: C2, C3, C7, C8 (NMB); C7 (SBB). Corresponding author: Neil M. Bressler, Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, 550 North Broadway, Ninth Floor, Baltimore, MD 21205-2010. pstaflin@jhmi.edu

Investigative Ophthalmology & Visual Science, March 2000, Vol. 41, No. 3

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graphic damage to retinal blood vessels (Fig. 1 and Fig. 2) or loss of vision.17

In most cases, fluorescein leakage from CNV became apparent by 12 weeks after this initial treatment, even in subjects who had received the maximum tolerated light dose (in which nonselective damage to sensory retinal blood vessels with visual loss had occurred). The investigators sus-pected that this reappearance of leakage probably would be accompanied by subsequent growth of the neovascular lesion with progressive vision loss. Therefore, the investigators sidered evaluating a treatment strategy that would try to con-fine the neovascular lesion and reduce the chance of vision loss by periodically applying photodynamic therapy with verte-porfin to an eye with subfoveal CNV. Subsequently, the

safety and fluorescein angiographic effects of multiple treat-ments of verteporfin therapy were evaluated.18

These stud-ies suggested that repeated treatments could consistently cause short-term cessation of fluorescein leakage from CNV without angiographic damage to the overlying retinal blood vessels and without short-term visual acuity loss after each treatment. However, because fluorescein leakage from CNV typically was noted by 12 weeks after a retreatment, al-though often involving an area smaller than was noted before treatment, investigators believed that periodic re-treatments for an unknown length of time might be required if verteporfin therapy were to be beneficial in reducing vision loss from CNV.

FIGURE1. Pretreatment late phase flu-orescein angiogram frame shows leak-age from classic and occult CNV ex-tending under the center of the foveal avascular zone. (Reprinted from Miller JW, Schmidt–Erfurth U, Sickenberg M, et al. Photodynamic therapy for choroi-dal neovascularization due to age-re-lated macular degeneration with verte-porfin: results of a single treatment in a phase I and II study. Arch Ophthalmol. 1999;117:1161–1173, with permission of the American Medical Association.)

FIGURE 2. One week following pho-todynamic therapy of patient shown in Figure 1, early phase fluorescein angio-gram frame shows circular area of hy-pofluorescence corresponding to spot size used to illuminate retina following infusion of verteporfin. Fluorescein leakage from CNV no longer is appar-ent. (Reprinted from Miller JW, Schmidt–Erfurth U, Sickenberg M, et al. Photodynamic therapy for choroidal neovascularization due to age-related macular degeneration with vertepor-fin: results of a single treatment in a phase I and II study. Arch Ophthalmol. 1999;117:1161–1173, with permission of the American Medical Association.)

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R

ESULTS OF

R

ANDOMIZED

C

LINICAL

T

RIALS

E

VALUATING

V

ERTEPORFIN

T

HERAPY

Based on the phase I and II investigation, two identically designed phase III randomized clinical trials (the TAP Investi-gation), sponsored by CibaVision and QLT PhotoTherapeutics (Vancouver, British Columbia, Canada), were initiated at 22 clinical centers in Europe and North America in December 1996.1

The study objective was to determine whether photo-dynamic therapy with verteporfin could safely reduce the risk of vision loss in patients with subfoveal CNV in AMD. Partici-pants included patients with fluorescein angiographic evi-dence of subfoveal CNV lesions due to AMD measuring 5400 ␮m or less in greatest linear dimension (because of spot size limitations of the laser devices used to activate the verteporfin) and classic CNV. Classic CNV is defined by a fluorescein an-giographic pattern consisting of an area of bright fluorescence in the early phase of the angiogram with fluorescein leakage at the periphery of that area in the mid- and late-phase frames. Investigators believed that this pattern probably would be associated with a relatively high risk of losing vision without treatment within 1 to 2 years after study entry. Other patterns of fluorescein leakage from CNV noted at the level of the retinal pigment epithelium are termed occult CNV. The best-corrected visual acuity was to be approximately 20/40 to 20/200 measured on a retroilluminated distance visual acuity test chart (Lighthouse, Long Island, NY).

Six-hundred nine patients were enrolled through Septem-ber 1997 and were randomly assigned (2:1) to verteporfin (6 mg/m2body surface area) or placebo (5% dextrose in water) administered by intravenous infusion of 30 ml during 10 min-utes. Fifteen minutes after the start of the infusion, a laser light (Coherent, Palo Alto, CA or Zeiss, Jena, Germany) at 689 nm delivered 50 J/cm2at an intensity of 600 mW/cm2during 83 seconds using a spot size with a diameter 1000␮m larger than the greatest linear dimension of the CNV lesion. This choice of a spot size 1000␮m larger than the largest linear dimension was chosen to increase the chance that the lesion would be treated in its entirety and to compensate for any slight move-ments of the study eye during the light application under topical anesthesia. Follow-up examinations were scheduled every 3 months (⫾2 weeks), and retreatment with the same regimen used at baseline was to be applied if fluorescein leakage from classic CNV, occult CNV, or both was identified by the treating ophthalmologist on the follow-up angiogram. The spot size at follow-up was to be 1000␮m larger than the largest linear dimension of any areas of CNV leakage on the follow-up fluorescein angiogram (even if those areas were noncontiguous or did not involve the foveal center) and any blood or serous detachment of the retinal pigment epithelium contiguous to that leakage. All patients, treating ophthalmolo-gists, vision examiners, and fundus photograph graders were masked to the treatment assignment. Although the TAP Inves-tigation consisted of two trials (to comply with regulatory agency requirements that two randomized clinical trials con-firm a statistically significant benefit for a primary outcome), because the two trials ran concurrently (except that 10 of the clinical centers from Europe and North America were assigned to one trial and the other 12 clinical centers to the other trial), and because baseline characteristics, completeness of follow-up, and outcomes were similar for the two studies, the TAP Data and Safety Monitoring Committee recommended, with

agreement by the TAP Study Group, that the scientific presen-tation of the results combine the data sets from both studies.

Main Outcomes

Ninety-four percent of each group completed the month 12 examination. Visual acuity, contrast sensitivity, and fluorescein angiographic outcomes were better in the verteporfin-treated patients than in the placebo-treated group at every follow-up visit through the month 12 examination. At the month 12 examination, 156 (39%) of 402 eyes assigned to verteporfin compared with 111 (54%) of 207 eyes assigned to placebo (P⬍ 0.001) had moderate vision loss or worse (loss ofⱖ15 letters or approximately three or more lines on an eye chart compared with baseline). At this follow-up, verteporfin-treated eyes had a low mean number of contrast sensitivity letters lost compared with patients given placebo (1.3 versus 4.5, P⬍ 0.001). These treated eyes also were less likely to show progression (growth) of classic CNV beyond the area of the lesion at baseline (46% versus 71%, P⬍ 0.001), have fluorescein leakage from classic CNV (77% versus 88%, P⫽ 0.002), and have a lesion size more than six disc areas (41% versus 73%, P⬍ 0.001), even though most lesions in both groups were less than this size at the time of study entry for the participant.

Subgroup Analyses

In subgroup analyses, the visual acuity benefit was clearly demonstrated when the area of classic CNV occupied 50% or more of the area of the entire lesion (termed predominantly classic CNV lesions), especially when there was no occult CNV. Specifically for the predominantly classic CNV lesions, 33% of the 159 verteporfin-treated eyes compared with 61% of the 84 placebo-treated eyes (P⬍ 0.001) had moderate vision loss or worse at the month 12 examination. These benefits were even greater in predominantly classic CNV lesions with-out occult CNV.

No difference in visual acuity between verteporfin-treated patients and controls was noted when the area of classic CNV was more than 0% but less than 50% of the area of the entire lesion (termed minimally classic CNV lesions). However, min-imally classic CNV lesions receiving verteporfin therapy were less likely to show progression of classic CNV beyond the area of the lesion at baseline, to have fluorescein leakage from classic CNV, and to have a lesion size more than six disc areas compared to those receiving placebo. These positive outcomes using angiographic surrogate end points did not correspond to a visual acuity benefit at the month 12 examination.

Safety

Few ocular or other systemic adverse events associated with verteporfin treatment were judged to be clinically relevant. The results suggested that treated patients should be warned of the possibility of adverse events at the injection site, infusion-related back pain, photosensitivity reactions, and transient visual disturbances. Adverse events at the injection site (such as pain, edema, hemorrhage, or inflammation) were noted in 13.4% of verteporfin-treated patients compared with 3.4% of patients given placebo. Infusion-related back pain was noted only in verteporfin-treated patients (2%). Photosensitivity reac-tions, noted only in verteporfin-treated patients (3%) were generally transient mild to moderate sunburns due to direct sunlight exposure shortly after drug administration, usually

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within 24 hours of administration. Transient visual distur-bances in 18% of verteporfin-treated patients compared with 12% of placebo-treated patients included reports of abnormal vision, decreased vision, and visual field defects that the treat-ing ophthalmologist judged were not due to the impact of the natural course of CNV in AMD on vision. Two percent of patients assigned to verteporfin and 2% of those given placebo had died by the month 12 examination; no deaths were judged to be related to treatment. Verteporfin-treated patients did not experience development of more subretinal hemorrhage, fi-brosis, or atrophy of the retinal pigment epithelium than did placebo-treated patients.

I

MPACT ON

O

PHTHALMOLOGY AND

V

ISUAL

S

CIENCES

Thus, the TAP Investigation provides strong evidence that photodynamic therapy with verteporfin can safely reduce the risk of vision loss for at least 1 year in patients with subfoveal lesions in AMD that are predominantly classic CNV, especially in the absence of occult CNV. This vision benefit, which probably represents a potential improvement on the quality of life for patients who should be considered to receive this therapy, represents the culmination of basic scientists working on compounds for photodynamic therapy,8 vision scientists providing preclinical data essential to designing clinical tri-als,9 –16clinical researchers evaluating the safety and potential efficacy of various treatment regimens,17–19

investigators in clinical trials determining the precise risks and benefits of verteporfin therapy1

using methods adapted from prior well-designed clinical trials,4,5sponsors willing to provide the sup-port for these investigations, and patients willing to volunteer to participate in these clinical trials. Given the public health impact of CNV in AMD, these results probably will have a large impact on ophthalmology and visual sciences.

For ophthalmologists, this therapy will add a technique to their treatment armamentarium for some lesions for which there has been no other proven treatment. Because the therapy reduces the risk of vision loss rather than restoring vision, all eye care providers now should have an additional impetus to identify the development of CNV in AMD patients as soon as possible in an attempt to treat patients in whom therapy is beneficial when visual acuity is relatively good. Furthermore, reviewing the therapy with patients will require careful edu-cation regarding the risks and benefits, to try to avoid overen-thusiastic expectations in patients for whom verteporfin ther-apy is indicated. Because the lesion components have an impact on the treatment benefit, the ability to identify classic CNV on fluorescein angiography is critical for ophthalmolo-gists using this therapy. In addition, identification of the area of the entire lesion (including recognition of the entire area of any occult CNV, if present) is important to determine whether the lesion is predominantly classic CNV. It is unknown at this time how successful ophthalmologists will be in determining whether a lesion is predominantly classic CNV. However, the TAP Investigation demonstrated that ophthalmologists who were certified through training to identify eligible lesions for the study identified lesions that the Photograph Reading Center graders agreed had some classic CNV 90% of the time and were composed of CNV that comprised 50% or more of the lesion 98% of the time.1Thus, it seems likely that similarly trained

ophthalmologists should be able to identify cases that would benefit from therapy most of the time.

Those conducting clinical trials must consider the impact of the 1-year results of photodynamic therapy on investigations evaluating other therapies for subfoveal lesions due to AMD with predominantly classic CNV. If the beneficial outcomes reported by the month 12 examination in the TAP Investiga-tion remain the same or increase with longer follow-up, then clinical trials evaluating new treatments for predominantly classic CNV lesions that are subfoveal in AMD could be de-signed to compare the new treatment to verteporfin therapy and only compare to observation if such a patient refused verteporfin therapy.

Clinical research projects that may be relevant to patient management issues and health policy because of the TAP Investigation results may include determining what proportion of AMD patients are seen by an ophthalmologist with a pre-dominantly classic CNV lesion that is subfoveal and would benefit from verteporfin therapy. Ophthalmologists and health policy experts also may want to know how often and when patients, who initially had a minimally classic or no classic CNV lesion develop lesions that would benefit from verteporfin therapy. These data are unknown at this time; before the TAP Investigation results, there was no reason for investigators to determine this information.

Improvements in this therapeutic approach may be made possible by future clinical trials that determine whether other treatment regimens or other photosensitizers20,21

may result in better vision outcomes for predominantly classic CNV lesions or lesions that are not predominantly classic CNV. Although a small proportion of patients enrolled in the TAP Investigation with no evidence of classic CNV (as judged by Photograph Reading Center graders) may have had a treatment benefit, the beneficial effects for this subgroup are imprecise, because this subgroup included only 37 verteporfin-treated patients and 19 placebo-treated patients at study entry. It is not known whether these 56 cases represent the universe of occult CNV lesions without classic CNV, because the enrolling ophthalmol-ogist (but not the Reading Center grader) believed that these cases had some evidence of classic CNV. The Verteporfin In Photodynamic Therapy (VIP) Trial, a companion trial to the TAP Investigation, which includes a large proportion of subfo-veal lesions in AMD with occult CNV but no classic CNV, should provide additional information regarding the benefits of this therapy for AMD lesions with compositions different from those enrolled in TAP22

as well as for subfoveal CNV lesions due to pathologic myopia.23

Use of this therapy to limit vision loss from other retinal diseases, including vascular tumors such as choroidal hemangiomas, also might be explored further in the future.

The results of the TAP Investigation present additional questions for vision scientists to consider. For example, future investigations that determine why fluorescein angiography re-sults in a pattern of classic CNV versus occult CNV may be helpful in understanding how to improve on the therapeutic benefits and in determining why verteporfin therapy is bene-ficial for predominantly classic CNV lesions. Clinicopathologic correlation of verteporfin-treated eyes also may provide more information regarding how this therapy works. Clearly, the TAP Investigation results suggest that continued basic science investigations on other photosensitizers and their affects on

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ocular tissues may lead to new therapies that will continue to reduce the morbidity from AMD.

C

ONCLUSION

The results of a new treatment, photodynamic therapy with verteporfin for selected patients with subfoveal lesions in AMD with predominantly classic CNV, especially in the absence of occult CNV lesions AMD, show that verteporfin therapy can reduce the risk of moderate vision loss for at least 1 year. Although the therapy is not a magic bullet that can stop or reverse vision loss in all patients with AMD, the benefits are another step in the right direction (joining laser photocoagu-lation4,5

) for ophthalmologists and vision scientists pursuing investigations intended to reduce the magnitude of vision loss from AMD and its impact on the quality of life of people with this condition. The TAP Investigation should provide encour-agement and provide the foundation for future investigations of new treatments for AMD and related conditions by ophthal-mologists and vision scientists as the number of people at risk for AMD at least doubles during the next 30 years.

References

1. Treatment of Age-Related Macular Degeneration with Photody-namic Therapy (TAP) Study Group. Verteporfin (Visudyne) ther-apy of subfoveal choroidal neovascularization in age-related mac-ular degeneration: one year results of two randomized clinical trials—TAP Report #1. Arch Ophthalmol. 1999;117:1329 –1345. 2. Klein R, Klein BEK, Linton KLP. Prevalence of age-related

maculopathy: The Beaver Dam Eye Study. Ophthalmology. 192; 99:933–943.

3. Vingerling JR, Dielemans I, Hofma A, et al. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology. 1995;102:205–210.

4. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration: updated findings from clinical trials. Arch Ophthalmol. 1993;111: 1200 –1209.

5. Macular Photocoagulation Study Group. Visual outcome after laser photocoagulation for subfoveal choroidal neovascularization second-ary to age-related macular degeneration: the influence of initial lesion size and initial visual acuity. Arch Ophthalmol. 1994;112:480 – 488. 6. Bressler NM, Bressler SB, Gragoudas ES. Clinical characteristics of

choroidal neovascular membranes. Arch Ophthalmol. 1987;105: 209 –213.

7. Freund KB, Yannuzzi LA, Sorenson JA. Age-related macular degen-eration and choroidal neovascularization. Am J Ophthalmol. 1993; 115:786 –791.

8. Aveline B, Hasan T, Redmond RW. Photophysical and photosensi-tizing properties of benzoporphyrin derivative monoacid ring A (BPD-MA). Photochem Photobiol. 1994;59:328 –335.

9. Manyak MJ, Russo A, Smith PD, Glatstein E. Photodynamic therapy. J Clin Oncol.1988;6:380 –391.

10. Roberts WG, Hasan T. Role of neovasculature and vascular perme-ability on the tumor retention of photodynamic agents. Cancer Res.1992;52:924 –930.

11. Zhou C. Mechanisms of tumor necrosis induced by photodynamic therapy. J Photochem Photobiol B. 1989;3:299 –318.

12. Schmidt–Erfurth U, Hasan T, Gragoudas E, Michaud N, Flotte TJ, Birngruber R. Vascular targeting in photodynamic occlusion of subretinal vessels. Ophthalmology. 1994;101:1953–1961. 13. Miller JW, Walsh AW, Kramer M, et al. Photodynamic therapy of

experimental choroidal neovascularization using lipoprotein-deliv-ered benzoporphyrin. Arch Ophthalmol. 1995;113:810 – 818. 14. Richter AM, Cerruti–Sola S, Sternberg ED, Dolphin D, Levy JG.

Biodistribution of tritiated benzoporphyrin derivative (3H-BPD-MA), a new potent photosensitizer, in normal and tumor-bearing mice. J Photochem Photobiol B. 1990;5:231–244.

15. Kramer M, Miller JW, Michaud N, et al. Liposomal benzoporphyrin derivative verteporfin in photodynamic therapy: selective treat-ment of choroidal neovascularization in monkeys. Ophthalmol-ogy.1996;103:427– 438.

16. Husain D, Miller JW, Michaud N, et al. Intravenous infusion using liposomal BPD for photodynamic therapy. Arch Ophthalmol. 1996;114:978 –985.

17. Miller JW, Schmidt–Erfurth U, Sickenberg M, et al. Photodynamic therapy for choroidal neovascularization due to age-related macu-lar degeneration with verteporfin: results of a single treatment in a phase I and II study. Arch Ophthalmol. 1999;117:1161–1173. 18. Schmidt–Erfurth U, Miller JW, Sickenberg M, et al. Photodynamic

therapy of choroidal neovascularization due to age-related macular degeneration using verteporfin: results of retreatments in a phase I and II study. Arch Ophthalmol. 1999;117:1177–1187.

19. Sickenberg M, Schimdt–Erfurth U, Miller JW, et al. A preliminary study of photodynamic therapy using verteporfin for choroidal neovascularization in pathologic myopia, ocular histoplasmosis syndrome and idiopathic causes. Arch Ophthalmol. 2000;118. In press.

20. Thomas EL, Rosen R, Murphy R, Puliafito C, Jonsson P. Visual acuity stabilizes after a single treatment with SnET2-photodynamic therapy in patients with subfoveal choroidal neovascularization [ARVO Abstract]. Invest Ophthalmol Vis Sci. 1999;40(4):S401.

Abstract nr 2112.

21. Arbour JD, Connolly EJ, Graham K, et al. Photodynamic therapy of experimental choroidal neovascularization in a monkey model using intravenous infusion of lutetium texaphyrin [ARVO Ab-stract]. Invest Ophthalmol Vis Sci. 1999;40(4):S401. Abstract nr

2111.

22. Mones J, VIP Research Study Group. Photodynamic therapy (PDT) with verteporfin of subfoveal choroidal neovascularization in age-related macular degeneration: study design and baseline character-istics in the VIP randomized clinical trial [ARVO Abstract]. Invest Ophthalmol Vis Sci.1999;40(4):S321. Abstract nr 1704.

23. Slakter J, VIP Research Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin: study design and baseline characteristics in the VIP randomized clinical trial [ARVO Abstract]. Invest Ophthalmol Vis Sci.1999;40(4):S401. Abstract nr 2114.

References

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