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Natural History of Minimally Classic Subfoveal Choroidal Neovascular Lesions in the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Investigation
Outcomes Potentially Relevant to Management—TAP Report No. 6
Susan B. Bressler, MD;
Dante J. Pieramici, MD;
John M. Koester, MS;
Neil M. Bressler, MD; for the TAP Study Group
Arch Ophthalmol. 2004;122:325-329.
ABSTRACT
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Objective To determine if there is a rationale for monitoring patients with age-related macular degeneration who have a minimally classic subfoveal choroidal neovascular lesion and do not receive treatment at initial examination.
Methods Participants assigned to placebo who had a minimally classic lesion composition at baseline were identified from the TAP Investigation. Fluorescein angiograms at baseline and follow-up examinations from these participants were reviewed by photograph reading center graders to determine if any follow-up angiograms had converted from a minimally classic lesion composition to a predominantly classic lesion composition.
Main Outcome Measures Proportion of minimally classic lesions at baseline that converted to a predominantly classic lesion composition, time of this conversion, and visual acuity and lesion size at the time of conversion.
Results Of the 207 patients assigned to placebo in the TAP Investigation, 98 were judged to have a minimally classic lesion at baseline in the study eye when the fluorescein angiograms were reviewed in 2001. Of these 98 patients, 39 (40%) had lesions that converted to a predominantly classic lesion composition, including 21 by the month 3 examination. At the time of conversion, 32 (82%) lesions were no greater than 9 disc areas, including 20 (51%) with visual acuity of 20/200 or better.
Conclusions These data would suggest that patients with minimally classic lesions, in whom no therapy is recommended initially, should be monitored so that potential conversion to a predominantly classic lesion can be identified promptly and verteporfin therapy considered.
INTRODUCTION
The Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Investigation showed that photodynamic therapy with verteporfin (Visudyne; Novartis AG, Basel, Switzerland) could reduce the risk of moderate ( 3 lines) and severe (6 lines) visual acuity loss compared with a sham treatment in selected patients with age-related macular degeneration (AMD). These patients had subfoveal choroidal neovascularization (CNV) judged by photograph reading center graders to have a predominantly classic lesion composition (area of classic CNV 50% area of entire lesion).1-3 In the subgroup analysis of minimally classic lesions (area of classic CNV >0% to <50% area of entire lesion) in the TAP Investigation, the therapy did not reduce the risk of vision loss. This latter finding seemingly was inconsistent when the results in predominantly classic lesions from the TAP Investigation were coupled with results from the Verteporfin in Photodynamic Therapy Trial, in which the therapy reduced the risk of vision loss in selected cases with an occult with no classic composition and presumed recent disease progression.4 Subsequent exploratory analyses made some sense of this apparent inconsistency, suggesting that the benefits of verteporfin therapy might be dependent not only on the lesion composition but also on lesion size.4-5 Recent results reported from the Visudyne in Minimally Classic CNV Trial also suggest that verteporfin therapy might reduce the risk of moderate and severe vision loss through at least 1 year of follow-up in selected eyes with minimally classic lesions.6 Current expert opinion suggests that verteporfin therapy could be considered for patients with minimally classic lesions with smaller lesions ( 4 Macular Photocoagulation Study [MPS] disc areas) and lower levels of visual acuity (20/50-1).7 However, verteporfin therapy is not widely used for minimally classic CNV lesions because evidence of effectiveness in these lesions is not considered conclusive.
In this setting, investigators participating in the TAP Investigation questioned if data from the verteporfin randomized clinical trials could provide a rationale for monitoring patients with AMD who have subfoveal minimally classic lesions if verteporfin therapy was not applied at initial examination. Specifically, for minimally classic lesions assigned to placebo in the TAP Investigation, the investigators wanted to determine how often a predominantly classic lesion developed. To answer this question, the investigators determined the proportion of placebo-treated minimally classic lesions that converted to a predominantly classic lesion, as well as the lesion size and visual acuity at the time of this conversion.
METHODS
The methods of the TAP Investigation have been reported previously.1-2 In brief, study participants were enrolled into 1 of 2 identically designed randomized clinical trials between December 1996, and September 1997, at 1 of 22 clinical centers throughout North America and Europe after an informed consent process and form were approved by the respective center's institutional review board. Principal eligibility criteria included the following: (1) presence of subfoveal CNV due to AMD in which the lesion on fluorescein angiography had evidence of some classic CNV, (2) a greatest linear dimension on the retina no greater than 5400 µm, and (3) a lesion in which at least 50% of the lesion components were CNV (including any classic and any occult CNV) following specific definitions for these terms as previously described.7-9 At study entry, patients were assigned randomly to verteporfin therapy or a sham treatment using a placebo in a double-masked fashion.1 Patients were to be observed as often as every 3 months for at least 2 years with baseline and follow-up examinations that included best-corrected visual acuity following a standardized protocol refraction and visual acuity determination, as well as stereoscopic color fundus photographs and fluorescein angiograms.
At baseline, 2 independent photograph reading center graders categorized lesions with evidence of classic CNV as predominantly classic (area of classic CNV 50% area of entire lesion) or minimally classic (>0% to <50% area of entire lesion) without knowledge of treatment assignment, followed by open adjudication of any discrepancies between graders and review by a reading center ophthalmologist. At each scheduled follow-up examination (every 3 months through the 12-month examination, then every 6 months through the 24-month examination) for initial studies reported,1-2 photograph reading center graders identified whether any classic CNV was present and measured the size of the entire lesion within specific disc area categories; however, the graders did not determine whether the lesion was predominantly classic or minimally classic when classic CNV was identified at follow-up. These baseline and follow-up assessments were completed in the late 1990s.
In 2001, follow-up angiograms were reanalyzed to determine whether lesions were predominantly classic (Figure 1) or minimally classic (Figure 2) when classic CNV was identified at follow-up. Because follow-up angiograms were reanalyzed, baseline angiograms also were reanalyzed to minimize temporal variability in the grading process, described previously.9 This reanalysis of baseline angiograms resulted in slight changes in the total number of placebo-treated lesions originally categorized as minimally classic (n = 104) from the TAP Investigation.2 This subgroup of 104 patients originally included 98 lesions confirmed as minimally classic and 6 lesions graded as questionably having evidence of classic CNV by the reading center graders. These 6 lesions graded as questionably classic originally were included in the minimally classic subgroup before outcome assessment based on the enrolling ophthalmologist's assessment that classic CNV was present to meet the eligibility criteria. Of the 6 lesions originally graded as questionably classic, 2 were judged to be minimally classic and 4 subsequently were judged to have no classic CNV in the 2001 rereview; these latter 4 lesions were not analyzed further. Of the remaining 98 lesions originally graded as minimally classic, 2 subsequently were judged to be predominantly classic in the 2001 rereview and were not analyzed further. Therefore, 98 minimally classic lesions assigned to placebo were analyzed for this article. The 2001 reevaluation of angiograms to determine lesion composition was done according to the same procedures as for initial evaluations (ie, 2 independent graders, open adjudication, and review by a reading center ophthalmologist). For those lesions that converted to a predominantly classic composition, no further follow-up angiograms were evaluated, but the visual acuity and lesion size at the time of conversion were obtained from the TAP Investigation's database.
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Figure 1. A, Late-phase fluorescein angiogram of study participant judged to have a minimally classic lesion at baseline in which the area of classic choroidal neovascularization (CNV) is less than 50% the area of the entire lesion (visual acuity, 20/100). B, Subsequent grading of the lesion composition at the 3-month examination indicates conversion to a predominantly classic lesion in which the area of classic CNV is at least 50% the area of the entire lesion (visual acuity, 20/80).
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Figure 2. A, Early-phase fluorescein angiogram of study participant judged to have a minimally classic lesion at baseline in which the area of classic choroidal neovascularization (CNV) is less than 50% the area of the entire lesion (visual acuity, 20/40). B, Subsequent grading of the lesion composition at the 3-month examination indicates a minimally classic lesion in which the area of classic CNV, while larger than the area of classic CNV at baseline, remains less than 50% the area of the entire lesion (visual acuity, 20/100).
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RESULTS
Of the 104 study eyes of 104 study participants assigned to placebo that were originally included in the minimally classic subgroup from the TAP Investigation, 98 study eyes in 98 participants were confirmed in 2001 by photograph reading center graders to have a minimally classic lesion composition at baseline. Of these 98 cases, 39 (40%) had a lesion composition judged by the graders to become predominantly classic at a follow-up examination between 3 and 24 months after study entry. For the 39 lesions that converted to a predominantly classic lesion, the size of the minimally classic lesion at baseline was no greater than 4 MPS disc areas in 16 (41%), including 15 eyes with a visual acuity (approximate Snellen equivalent) no better than 20/50-1. The size of the minimally classic lesion at baseline was greater than 4 MPS disc areas in 22 cases (56%). The lesion size at baseline could not be determined in 1 case (3%), although the lesion composition could be graded as minimally classic.
Figure 3 shows that most of these conversions (21/39 [54%]) were first noted at the 3-month examination, with most conversions (34/39 [87%]) noted by the 9-month examination and only 2 (5%) noted at the 24-month examination. For the 16 conversions among lesions no greater than 4 MPS disc areas at baseline, 10 converted at the 3-month examination, 4 at 6 months, 1 at 9 months, and 1 at 18 months. For the 22 conversions among lesions greater than 4 MPS disc areas, 11 converted at the 3-month examination, 3 at 6 months, 4 at 9 months, 2 at 18 months, and 2 at 24 months. One patient with a lesion size that could not be determined at baseline converted at 9 months.
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Figure 3. Left, Number of eyes with a minimally classic lesion at baseline that converted to a predominantly classic lesion (n = 98) at follow-up examination when conversion was first noted. Right, Percentage of conversions by the 24-month examination by follow-up examination when conversion was first noted.
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Figure 4 shows the lesion size and visual acuity at the time of conversion for those study eyes that converted to a predominantly classic lesion. For 7 (18%) of the 39 eyes, the lesion size was greater than 9 MPS disc areas with a visual acuity (approximate Snellen equivalent) ranging from 20/160 to 20/800. For the remaining 32 (82%) of the 39 eyes, the lesion size was no greater than 9 MPS disc areas, including 20 (51%) of the 39 eyes with this lesion size that had a visual acuity of 20/200 or better at the time of conversion.
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Figure 4. Flow diagram for 39 of 98 minimally classic lesions (among 207 patients assigned to placebo in the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy Investigation) that converted to predominantly classic lesions by the 24-month examination by lesion size and visual acuity when conversion was first noted. MPS indicates Macular Photocoagulation Study.
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COMMENT
Of 98 placebo-treated lesions identified as having a minimally classic composition at study entry, 39 (40%) converted to a predominantly classic lesion, including 21 by the 3-month examination and 34 by the 9-month examination, although some conversions were noted for the first time at the 24-month examination. These results were similar whether or not at baseline the minimally classic lesion was small (4 MPS disc areas). At the time that the conversion was first noted, about half of the patients had lesion sizes no greater than 9 MPS disc areas accompanied by visual acuities of 20/200 or better, such that verteporfin therapy likely would be considered based on the inclusion criteria and results from the TAP Investigation.
Several caveats to this analysis should be recognized when considering using this information to manage patients with AMD who have subfoveal CNV with a minimally classic lesion composition. First, while verteporfin therapy has been shown to be beneficial for lesions with predominantly classic lesion compositions, one does not know how many of the predominantly classic lesions at initial examination had converted from a minimally classic lesion. Therefore, one does not know if results from the TAP Investigation regarding predominantly classic lesions apply to lesions that had converted from minimally classic, or those that did not convert from minimally classic lesions, or both. Nevertheless, there is no biologic rationale, in our opinion, to suggest that the TAP Investigation results on predominantly classic lesions would not apply to minimally classic lesions that convert to predominantly classic lesions.
Second, recent information suggests that lesion size is a strong factor in determining if verteporfin therapy is likely to reduce the risk of vision loss. Specifically, smaller minimally classic lesions and smaller occult with no classic lesions (4 MPS disc areas) had a greater treatment benefit than larger lesions within these lesion compositions.3-5 Based on this recent information, as well as reports from the Visudyne in Minimally Classic CNV Trial,6 some ophthalmologists might consider recommending verteporfin therapy for minimally classic lesions that are small, without waiting for conversion to a predominantly classic lesion, perhaps making the findings of this report less relevant for minimally classic lesions that are small at initial examination.
Third, this analysis may underestimate the number of lesions that may convert to a lesion composition for which therapy might be beneficial. Specifically, the Verteporfin in Photodynamic Therapy Trial4 results in patients with AMD showed that verteporfin therapy could reduce the risk of moderate and severe visual acuity loss in selected patients with presumed recent disease progression who have subfoveal CNV with a lesion composition that has occult CNV with no classic CNV. The methods for this study did not allow one to determine how many minimally classic lesions converted to a lesion composition that had occult CNV with no classic CNV. If conversion to a lesion composed of occult with no classic CNV occurred in the setting of presumed recent disease progression, verteporfin therapy also might reduce the risk of vision loss, especially if the lesion was smaller (as noted when using a cutoff of 4 MPS disc areas) or associated with lower levels of visual acuity (as noted when using a cutoff of 20/50-1). Underestimation also is possible if one considers that more cases might have been identified if follow-up fluorescein angiograms were done more frequently.
Fourth, this study does not differentiate among cases that developed a small amount of increased classic CNV (eg, from 45%-55% of the lesion) from those developing a large amount (eg, from 10%-90%). Both examples would be labeled as progressing to a predominantly classic lesion. The reliability of grading areas of classic CNV within categories smaller than predominantly or minimally classic has not been evaluated, and such information was not collected in this trial, as it was judged to be difficult to make finer differentiations than predominantly and minimally classic. Nevertheless, this study suggests that some minimally classic cases will be considered predominantly classic at follow-up with a visual acuity and lesion size for which verteporfin therapy likely would be considered to reduce the risk of additional moderate and severe visual acuity loss.
Fifth, as only 20 eyes (20% of the cases available for this study) converted to a predominantly classic lesion composition with a lesion size no greater than 9 MPS disc areas and a visual acuity of 20/200 or better, this number is too small to identify factors associated with this conversion. Even if one were to treat minimally classic lesions with a small size, this study suggests a rationale to observe those with a larger size. Some of these larger minimally classic lesions will convert to a predominantly classic lesion with a size no greater than 9 MPS disc areas and a visual acuity of 20/200 or better, a situation in which many experts would consider recommending verteporfin therapy.7 Unfortunately, the number of cases evaluated in this study is too small to determine which minimally classic lesions will convert if monitored, necessitating that one consider observing all minimally classic lesions that do not receive treatment at initial examination.
CONCLUSIONS
In conclusion, this analysis suggests that ophthalmologists who identify patients with subfoveal CNV with a minimally classic composition for whom no verteporfin therapy is recommended should consider continued follow-up rather than discharging the patient from continued monitoring. Prudent follow-up would provide an opportunity to identify cases that may convert to a predominantly classic composition for which verteporfin therapy likely would reduce the risk of moderate and severe visual acuity loss compared with no therapy. As many of these conversions may occur within the first 3 months after a patient is initially seen with a minimally classic lesion, frequent monitoring of such patients within the first 3 months of examination seems warranted to try to identify these conversions while the lesion is still small enough and the visual acuity is still good enough to potentially benefit from verteporfin therapy. Because conversions may occur at least up to 24 months after initial examination, monitoring may be indicated as long as the lesion has not become too large or the visual acuity too poor before the conversion to suggest that reducing the risk of moderate and severe visual acuity loss with verteporfin therapy no longer would be helpful to the patient. Because few conversions occurred beyond the 9-month examination, the frequency of monitoring beyond 9 to 12 months probably can be based on whether the situation (eg, considering the visual acuity, lesion size, and lesion composition) appears stable from one examination to the next. These recommendations may change as new data relevant to the management of minimally classic lesions in patients with AMD are obtained.
AUTHOR INFORMATION
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Corresponding author: Neil M. Bressler, MD, The Retinal Vascular Center, The Wilmer Ophthalmological Institute and Department of Ophthalmology, The Johns Hopkins University School of Medicine and The Johns Hopkins Hospital, 550 N Broadway, Suite 115, Baltimore, MD 21205-2002 (e-mail: nmboffice{at}jhmi.edu).
Reprints: Novartis Ophthalmics Medical Affairs, One Health Plaza, Building 118, East Hanover, NJ 07936.
Submitted for publication May 28, 2003; final revision received October 22, 2003; accepted November 6, 2003.
This study was sponsored by Novartis AG and QLT Inc.
The authors had complete access to the raw data needed for this article.
From The Retinal Vascular Center, The Wilmer Ophthalmological Institute and Department of Ophthalmology, The Johns Hopkins University School of Medicine and The Johns Hopkins Hospital, Baltimore, Md (Drs S. Bressler, Pieramici, and N. Bressler); and Novartis AG, Duluth, Ga (Mr Koester). Funding for the study described herein was provided by Novartis AG and QLT Inc, Vancouver, British Columbia. The Johns Hopkins University is paid for consulting services provided by Dr N. Bressler to Novartis AG and QLT Inc. The terms of this institutional consulting arrangement are being managed by The Johns Hopkins University in accord with its conflict of interest policies. A complete list of the participants in the TAP Study Group is available in Arch Ophthalmol. 1999;117:1329-1345. Revisions to this list, as of January 11, 2000, are available in Arch Ophthalmol. 2001;119:198-207.
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2. 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.
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4. 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;131:541-560.
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6. Bressler NM, Rosenfeld PJ, Lim JI, VIM Study Group. A phase II placebo-controlled, double-masked randomized trial: Verteporfin in Minimally Classic CNV due to AMD (VIM) [abstract]. In: 2003 Annual Meeting Abstract and Program Planner of the Association for Research in Vision and Ophthalmology; May 5, 2003; Fort Lauderdale, Fla. Abstract 1100. Available at: http://www.arvo.org. Accessed May 22, 2003.
7. Verteporfin Roundtable 2000 and 2001 Participants, Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Study Group Principal Investigators, Verteporfin in Photodynamic Therapy (VIP) Study Group Principal Investigators. Guidelines for using verteporfin (Visudyne®) in photodynamic therapy to treat choroidal neovascularization due to age-related macular degeneration and other causes. Retina. 2002;22:6-18.
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