Visual Outcomes in the Subfoveal Radiotherapy Study for Age-Related Macular Degeneration

Transcription

CLINICAL SCIENCES
Visual Outcomes in the Subfoveal
Radiotherapy Study
A Randomized Controlled Trial of Teletherapy
for Age-Related Macular Degeneration
P. M. Hart, FRCOphth; U. Chakravarthy, FRCOphth, PhD; G. Mackenzie, PhD; I. H. Chisholm, FRCOphth;
A. C. Bird, FRCOphth; M. R. Stevenson, MSc; S. L. Owens, MD; V. Hall, FRCR; R. F. Houston, FRCR;
D. W. McCulloch, PhD; N. Plowman, FRCR
Objective: To determine whether teletherapy with 6-mV
photons can reduce visual loss in patients with subfoveal
choroidal neovascularization in age-related macular
degeneration.
Design: A multicenter, single-masked, randomized controlled trial of 12 Gy of external beam radiation therapy delivered to the macula of an affected eye vs observation only.
Setting: Three United Kingdom–based hospital units.
Participants: Patients with age-related macular degeneration, aged 60 years and older, who had subfoveal choroidal neovascularization and a visual acuity of 20/200
(logMAR 1.0) or better.
Methods: Two hundred three patients were randomly
assigned to radiotherapy or observation. Treatment was
undertaken at designated radiotherapy centers, and patients assigned to the treatment group received a total dosage of 12 Gy of 6-mV photons in 6 fractions. Follow-up
was scheduled at 3, 6, 12, and 24 months. After excluding protocol violators, the data from 199 patients were
analyzed.
Main Outcome Measures: The primary outcome mea-
sure was mean loss of distance visual acuity in the study
eye at 12 and 24 months. Other outcome variables analyzed were near visual acuity and contrast sensitivity. The
C
Author affiliations are listed
at the end of this article.
proportions of patients losing 3 or more or 6 or more lines
of distance and near acuity and 0.3 or more or 0.6 or more
log units of contrast sensitivity at each follow-up were
also analyzed.
Results: At all time points, mean distance visual acuity
was better in the radiotherapy-treated group than in the
control group, but the differences did not reach statistical significance. At 24 months, analysis of the proportions of patients with loss of 3 or more (moderate) (P=.08)
or 6 or more (severe) (P = .29) lines of distance vision
showed that fewer treated patients had severe losses, but
there was no statistically significant difference between
groups. For near visual acuity, although there was no evidence of treatment benefit at 12 and 24 months, a significant difference in favor of treatment was present at 6
months (P=.048). When analyzed by the proportions of
patients losing 3 lines of contrast sensitivity, there was a
significant difference in favor of treatment at 24 months
(P=.02). No adverse retinal effects were observed during the study, but transient disturbance of the precorneal tear film was noted in treated patients.
Conclusion: The results of the present trial do not sup-
port the routine clinical use of external beam radiation
therapy in subjects with subfoveal choroidal neovascularization in age-related macular degeneration.
Arch Ophthalmol. 2002;120:1029-1038
HOROIDAL neovascularization (CNV) as a complication of age-related
macular disease has a
poor visual outcome, with
60% of affected patients becoming severely visually impaired within 3 years.1
Reports2-5 from randomized controlled
clinical trials, starting in the 1980s, indicated that photocoagulation benefited the
small proportion of patients found to have
(REPRINTED) ARCH OPHTHALMOL / VOL 120, AUG 2002
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extrafoveal or juxtafoveal classic CNV. Unfortunately, because recurrence of new vessel growth occurred in most cases, treatment served only to delay visual loss in
most.5,6 In patients who have occult CNV7
or a mixture of classic and occult disease,
there is no evidence of benefit by argon laser therapy.8 One study9 implied that laser photocoagulation treatment confers
benefit even when the neovascular complex is subfoveal. In this study, 24 months
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PATIENTS AND METHODS
DESIGN AND INCLUSION
AND EXCLUSION CRITERIA
This trial was conducted in accord with the tenets of the
Declaration of Helsinki, 1996, for studies on human subjects. The SFRADS was undertaken in 3 ophthalmic units
in major National Health Service hospitals located in Belfast, Northern Ireland, and in London and Southampton,
England. The trial design was developed by the steering committee and approved by the local ethics committee at each
center before commencement of the study. Patients with a
presumptive diagnosis of subfoveal CNV due to ARMD were
screened in special study clinics. A full medical history was
obtained for each subject. This included current medications, history of hypertension, respiratory and cardiovascular status, prior major surgery, malignant disease, and
smoking status.
After giving informed consent, suitable patients were
recruited into the study and were randomized to the treated
(EBRT) or control (observation only) group. Patients in the
treated group were scheduled to receive radiotherapy within
14 days of entry, and both groups were examined at 3, 6,
12, and 24 months after randomization, when standard efficacy and safety variables were recorded. The optometrists who undertook visual assessments were unaware of
the treatment status of the patients; however, neither the
treating physicians nor the patients were masked.
Enrollment commenced November 1995, and was
completed July 1998. Patients were required to be aged 60
years or older and have evidence of subfoveal CNV (some
classic CNV or a vascularized pigment epithelial detachment) on a fundus fluorescein angiogram performed within
1 week of randomization. Visual acuity at baseline was required to be 20/200 or better in the study eye.
Exclusion criteria were (1) inability to give informed
consent; (2) angiographic evidence of late leakage of indeterminate origin only; (3) presence of blood under the
geometric center of the fovea; (4) presence of additional
ocular disease, including high myopia in excess of −6.0 diopter in any axis; (5) diabetes mellitus, uncontrolled hypertension, or any life-threatening disorder at the initial visit;
(6) concurrent enrollment in any other ophthalmic clinical trial; and (7) prior radiotherapy to either eye.
Patients who might benefit from foveal ablation according to the Macular Photocoagulation Study (MPS) criteria25 were made aware of this option and were invited to
participate in the SFRADS only if they declined photocoagulation.
MEASURES OF VISUAL FUNCTION
All patients underwent assessment of visual function by a
trained optometrist, using a protocol adapted from the MPS
Manual of Procedures.26 All measurements were performed
on each eye. Following refraction, best-corrected DVA was
measured on the logMAR scale, using the backlit Early Treatment of Diabetic Retinopathy Study charts. The line with
the smallest letters in which at least 3 of the letters were
correctly identified was entered as the line acuity for that
eye. The number of letters read was also recorded to give a
letter score for that eye. Best corrected near visual acuity
(NVA) in each eye at 25 cm was obtained using the Bailey-
1030
Lovie near-reading chart. Contrast sensitivity was measured for each eye using the Pelli Robson chart, with the
patient seated at the recommended distance of 1 m.
Slitlamp biomicroscopy of anterior and posterior segments and intraocular pressure measurement were carried out on both eyes of every patient. High-dose radiotherapy is known to have adverse effects on the conjunctiva,
lens, and retina. Detailed monitoring of these tissues was
carried out at baseline and each subsequent visit. The conjunctiva was examined for vascular changes, such as microaneurysms and telangiectasia. The lacrimal system was
evaluated as follows: The state of the precorneal tear film
and the cornea were examined by slitlamp biomicroscopy. The tear film breakup time was measured and the
Schirmer test was performed. Lens clarity was monitored
using a clinical grading system and red-reflex anterior segment photography. The retina and its vasculature were
monitored for radiation retinopathy by biomicroscopic examination, electrophysiological assessment, and scrutiny
of fundus photographs and fluorescein angiograms. The
presence of retinal vessel microaneurysms or hemorrhage
remote to the CNV was recorded.
ANGIOGRAPHY
Most patients referred to the study clinic had been previously assessed angiographically by their referring physician.
A routine angiogram was usually sufficient to assess eligibility. On entry into the study, if not already performed for eligibility purposes, a study angiogram was undertaken. The photographic protocol specified the taking of bilateral color stereopair and red-free photographs centered on the macula. During
angiography, stereo-pair photographs of the macula of the
study eye were taken throughout the transit phase. Stereo pairs
of the study eye and the fellow eye were captured during the
later phases of the angiographic procedure, defined as 2 to 5
minutes after injection.
Angiograms were scrutinized by the principal investigators (U.C., P.M.H., A.C.B., and I.H.C.) at each center,
who ascertained eligibility using a checklist of inclusion
and exclusion criteria. The CNV was classified based on
the fluorescein angiographic appearance of a lesion by the
reading center based in Belfast. The size of the lesion (defined as any abnormal fluorescence, elevated blocked fluorescence, or contiguous blood) and the area of classic hyperfluorescence were measured in disc areas according to
MPS criteria. Lesions were classified as wholly or predominantly classic (ⱖ50% of the lesion), minimally classic (1%49% of the lesion), occult (0%), or vascularized pigment
epithelial detachment. Of the 203 baseline angiograms, 110
were read by a senior MPS-certified grader from The Scheie
Eye Institute Photographic Reading Center, Philadelphia,
Pa. Agreement between Belfast graders and the MPScertified grader was high, with a ␬ value of 0.89. Discordance was primarily because of differences in the grading
of mixed lesions, with Belfast graders classifying more cases
as minimally classic than the MPS grader. There was no disagreement between graders in lesions classified as either
purely classic or purely occult.
RANDOMIZATION
Eligible subjects were counseled and informed consent
was obtained. The randomization code was kept at the
coordinating center (Belfast) and released by telephone on
receipt of patient details. To ensure balance within each of
the 3 centers, the randomization was blocked. Two hundred three patients were recruited from 477 screened, and
the detailed flowchart depicting study participation is shown
in Figure 1.
RADIOTHERAPY TECHNIQUE
Patients in the treatment arm were assessed in the radiotherapy unit in each center by the designated radiotherapist.
All centers used a 6-mV photon beam from a linear accelerator, and the dosage of radiotherapy selected for this study was
12 Gy given as 6 equal fractions on consecutive working days.
The treatment plan was based on a high-definition computed axial tomographic scan, taken with the patient’s head
immobilized using a custom-made bexoid beam direction
shell. Fine radiopaque tubing was placed on the beam direction shell marking the sagittal and coronal planes to establish reference points for the treatment port. The tomogram selected for treatment planning was one that clearly
showed the lens, medial and lateral recti, and optic nerve
of the ipsilateral eye in the same slice and included a clear
view of the lens and optic nerve of the contralateral eye.
The whole length of the optic nerve may be demonstrated
in 1 slice when the chin is raised to bring the orbitomeatal
line to an angle of 16° to the vertical. The patient was instructed to keep his or her eyes closed while the scan was
performed. The treatment plan was constructed using a computer-based software program (Theraplan 500 series;
Theratronics, Ottawa, Ontario) for 6-mV photons prescribed to the 90% isodose. In the generation of the treatment plan, care was taken to minimize exposure to the optic nerves of both eyes and the ipsilateral lens. The 90%
isodose curve included the macula and optic disc, with less
than 50% of the maximum dose falling on the posterior lens
capsule.
The eye was irradiated through a single lateral port
measuring 3⫻3 cm. The beam was angled 10° posteriorly
to avoid the lens of the contralateral eye. Cursor measurements were made from the surface reference marks on the
beam direction shell to localize the lateral beam entry port.
This port was marked on the beam direction shell using a
treatment simulator. Before treatment, or following the first
treatment session, a monitoring computed axial tomographic scan was performed to confirm the accuracy of beam
placement. Eighty-eight percent of patients received radiotherapy within 3 weeks of randomization and the remainder within 4 weeks.
OUTCOME MEASURES
The primary outcome measure, change in DVA in the
study eye, was chosen because of its traditionally accepted
role as a marker for visual function. We also measured
NVA and CS as a set of secondary outcomes. With respect
to patient-centered outcomes, we collected information
on self-reported visual functioning and health-related
quality of life; these measures are reported elsewhere
(M.R.S., P.M.H., A.C.B., I.H.C., and U.C., unpublished
data, 2002).
The null hypotheses of primary interest were that there
was no difference in change in DVA between treated and control groups at 12 and 24 months. As this is a longitudinal
1031
study, we also routinely report outcome at 3 and 6 months
and the group trajectories over time after randomization for
each of the outcome measures.
As a means of comparing the results with those of previous studies, we also analyzed the number of lines of acuity lost from baseline to the 12- and 24-month examinations in the 2 groups. Losses of 3 or more or 6 or more lines
of DVA and NVA (which reflects a doubling or a quadrupling of the visual angle) were used as binary outcomes.
Similarly, for CS, losses of 0.3 log units (2 triplets) or 0.6
log units (4 triplets) were used as binary outcomes. A decrease of 0.3 log units or 2 triplets on the Pelli Robson chart
represents a halving of the contrast threshold from the baseline value. Therefore, these latter measures may be regarded formally as comprising a second set of secondary
outcomes of interest.
STATISTICAL METHODS
Design
The study was designed to be 95% confident in detecting
a minimum mean difference in DVA of 2 lines on the logMAR scale between treated and control groups with 90%
power. Initial power calculations were made using data
from the pilot study,14 and the sample size was determined to be 240 observations (120 per arm). Revised calculations based on the generalized Laird-Ware model27
allowed a subsequent reduction in sample size to 200
without loss of power. The study was not powered to
investigate NVA, CS, or the second set of secondary outcomes.
Analysis
Standard univariate methods (␹2 and t tests and parametric and nonparametric analyses of variance) were used to
analyze the data. The 5% level of statistical significance was
adopted throughout to construct tests of hypotheses and
confidence intervals (CIs). In relation to the outcomes of
DVA, NVA, and CS, longitudinal multiple linear regression modeling was used, which allowed us to adjust the
treatment effect for factors measured at baseline and the
trend over time. In longitudinal studies, repeated measurements made on each individual are correlated, and alternative models are required that allow for this correlation.
Accordingly, we adopted a specially modified Laird-Ware
model27 that allows for correlation between the repeated
measures when the individual follow-up examinations are
irregularly spaced in time.28 The effects of the following factors were considered in these analyses: (1) treatment indicator, (2) time trend after randomization, (3) treatment
by time interaction, (4) baseline value of the outcome measure, (5) CNV composition (classic or predominantly classic vs other), (6) center, and (7) whether both eyes were
affected.
Scheduled follow-up examinations necessitate that information accruing over time is interval-censored and does
not accurately reflect time to event. In the Kaplan-Meier–
based presentations of the cumulative proportions of patients losing 3 or more or 6 or more lines of visual acuity,
we used the scheduled, rather than the observed, visit times,
and this is in accord with most previously published randomized clinical trials in this field.4-11
Screened (N = 477)
Table 1. No. of Participants From Each Center*
Did Not Meet Angiographic Criteria (n = 126)
Did Not Meet Visual Acuity Criteria (n = 54)
Refused Consent (n = 24)
Age-Related Macular Degeneration Not
Confirmed (n = 21)
Systemic Disease (n = 20)
Prior Laser Therapy (n = 16)
Other Eye Disease (n = 13)
Study Group
Center
Treatment
Control
Belfast
Southampton
London
Total
42 (50.6)
23 (48.9)
34 (49.3)
99 (49.7)
41 (49.4)
24 (51.1)
35 (50.7)
100 (50.3)
Total
83
47
69
199
(100)
(100)
(100)
(100)
*Data are given as number (percentage).
Randomized (n = 203)
Allocated to Treatment (n = 101)
Received External Beam Radiation
Therapy as Allocated (n = 101)
Reallocated From Observation (n = 1)
Protocol Violations (n = 3)
(age <60 y = 1; Visual Acuity Worse
Than 20/200 = 2)
Allocated to Observation (n = 102)
Inadvertently Received Radiotherapy
(n = 1) (Analyzed as Treated)
Other Protocol Violations (n = 1)
(Visual Acuity Worse Than 20/200)
Treatment (n = 99)
Control (n = 100)
Follow-up, mo
3 = 91
6 = 93
12 = 93
24 = 87
Complete Visual Outcome Data Were
Obtained at Every Time Point
Follow-up, mo
3 = 95
6 = 87
12 = 91
24 = 88
Complete Visual Outcome Data Were
Obtained at Every Time Point
tions) of 6-mV photons delivered as external beam radiotherapy (EBRT) to the macula of eyes with CNV resulted in benefit of maintained DVA in the treated group.22
More recently, 2 additional randomized controlled trials of EBRT vs sham irradiation demonstrated no visual
benefit in subjects observed for up to 1 year.23,24
We commenced a prospective, longitudinal, multicenter, randomized controlled trial November 1995, to
investigate the hypothesis that 12 Gy of EBRT would limit
the loss of visual function in patients with ARMD in whom
CNV involved the fovea. The acronym used to designate the Subfoveal Radiotherapy Study is SFRADS. Patients were observed for 24 months, and the visual outcomes are reported herein.
RESULTS
Figure 1. Flowchart depicting participation in the Subfoveal
Radiotherapy Study.
PATIENTS ANALYZED
after enrollment, mean losses of 3.0 and 4.4 lines of distance visual acuity (DVA) were recorded in treated and
control eyes, respectively. Greater benefit was seen with
maintained contrast sensitivity (CS) and reading speed
at the same time point. As central vision is substantially
reduced immediately after foveal ablation, any benefit is
therefore only detectable in the longer term.
Because of the disappointing outcome with or without intervention in this common ophthalmic condition,
several novel therapeutic approaches have been proposed for the treatment of subfoveal CNV during the past
decade. Recent studies10,11 showed that photodynamic
therapy with verteporfin reduces the risk of moderate and
severe vision loss in patients with subfoveal CNV in agerelated macular degeneration (ARMD). This treatment
exploits the property of verteporfin uptake by the endothelia of the CNV, and targeted activation of the dye, using an infrared laser, results in occlusion of the neovascular complex, with minimal or no initial damage to the
adjacent retinal neuropile.
The use of ionizing radiation to cause involution of
the CNV is another possible therapeutic approach.
Clinical studies have been undertaken, with some identifying a visual benefit,12-19 and others20,21 suggesting a
lack of benefit and adverse outcome due to teletherapy.
However, none of these studies incorporated a concurrently recruited control group with visual and angiographic baseline characteristics similar to those of the
treated group.
A small randomized controlled trial consisting of 74
patients showed that a total dose of 24 Gy (in 4 frac(REPRINTED) ARCH OPHTHALMOL / VOL 120, AUG 2002
1032
Two hundred three patients were randomized into this
study, and the numbers from each center are shown in
Table 1. Of the 203, 4 were subsequently found not to
satisfy all study entry criteria. One patient was aged 56,
and 3 patients had baseline DVAs of 1.1 logMAR or
worse. Three of these 4 were allocated to the treatment
group. These 4 patients were excluded from the analysis. One other patient was randomized to the control
group but subsequently received treatment according to
protocol. This patient was analyzed as if she had been
allocated to the treatment group. The baseline angiograms of the study eyes were graded for CNV composition, and the lesions were classified as purely or predominantly classic (145 [72.9%]), minimally classic (45
[22.6%]), occult with no classic (3 [1.5%]), or fibrovascular pigment epithelial detachment (6 [3.0%]).
Although the reading center classified the study eyes of
3 patients as having no classic CNV at baseline, these
subjects were not excluded from the analysis, as this
was not considered a protocol violation. This is because
the criterion specifying the presence of at least some
classic CNV is subjective, and arbitration may be used
in the event of disagreements between reading center
staff and investigators. The flow chart (Figure 1) shows
the route to the final numbers of participants analyzed
within the treatment and control groups.
BASELINE CHARACTERISTICS
Randomization achieved prior similarity between the
treated and control groups (Table 2). Most patients in
Table 2. Baseline Characteristics*
Table 3. Estimated Treatment Benefit
to Distance Visual Acuity (DVA)*
Group
Factors
Treatment
Control
Categorical
Sex
Male
43 (43.4)
43 (43.0)
Female
56 (56.6)
57 (57.0)
Index
Right
53 (53.5)
54 (54.0)
Left
46 (46.5)
46 (46.0)
Fellow eye
Unaffected
38 (38.4)
51 (52.0)
Affected
61 (61.6)
47 (48.0)†
CNV morphologic structure
Classic
49 (49.5)
55 (55.0)
Predominantly classic
21 (21.2)
20 (20.0)
Minimally classic
25 (25.3)
20 (20.0)
Occult
2 (2.0)
1 (1.0)
Vascularized pigment
2 (2.0)
4 (4.0)
epithelial detachment
Continuous‡
Age, y
75.31 (0.64) 75.23 (0.64)
Duration of symptoms, wk 13.01 (1.05) 14.24 (1.01)
Initial DVA
0.59 (0.02) 0.58 (0.02)
Initial NVA
0.87 (0.03) 0.86 (0.04)
Initial CS
1.13 (0.03) 1.08 (0.03)
Total
86 (43.2)
113 (56.8)
107 (53.8)
92 (46.2)
89 (45.2)
108 (54.8)
104 (52.3)
41 (20.6)
45 (22.6)
3 (1.5)
6 (3.0)
Follow-up, mo
Benefit
SE
No. of
Participants
P
Value
3
6
12
24
−0.051
−0.085
−0.060
−0.091
0.039
0.052
0.055
0.056
185
179
183
174
.19
.11
.28
.11
*Data are given as logMAR acuity. Multiply times 10 to obtain the number
of lines of distance visual acuity. Benefit indicates the difference in group
averages (treatment minus controls) in change in DVA from baseline. The
number of participants varies according to the number of completed visits.
Table 4. Lines of DVA Lost by 3, 6, 12, and
24 Months of Follow-up*
Group
Lines of DVA Lost
75.27 (0.45)
13.63 (0.73)
0.59 (0.02)
0.86 (0.02)
1.10 (0.02)
*Data are given as number (percentage) unless otherwise indicated.
CNV indicates choroidal neovascularization; DVA, distance visual acuity;
NVA, near visual acuity; and CS, contrast sensitivity.
†Two fellow eyes did not have acuity recorded.
‡Continuous data are given as mean (SE).
the study (72.9%) had wholly or predominantly classic
CNV.
COMPLETENESS OF FOLLOW-UP
During the study, 48 visits were missed, and the numbers of missed visits and withdrawals were similar among
treatment groups and centers.
By 3 mo
ⱖ3†
ⱖ6‡
By 6 mo
ⱖ3§
ⱖ6㛳
By 12 mo
ⱖ3¶
ⱖ6#
By 24 mo
ⱖ3**
ⱖ6††
Treatment
Control
Total
24 (26.4)
5 (5.5)
31 (33.0)
9 (9.6)
55 (29.7)
14 (7.6)
38 (40.9)
18 (19.4)
43 (50.0)
20 (23.3)
81 (45.3)
38 (21.2)
53 (57.0)
26 (28.0)
52 (57.8)
37 (41.1)
105 (57.4)
63 (34.4)
61 (70.1)
37 (42.5)
71 (81.6)
44 (50.6)
132 (75.9)
81 (46.6)
*Data are given as number (percentage) of participants. The number
of participants varies according to the number of completed visits.
DVA indicates distance visual acuity.
†␹21 = 0.97, P = .34.
‡␹21 = 1.10, P = .29.
§␹21 = 1.51, P = .22.
㛳␹21 = 0.41, P = .52.
¶␹21 = 0.01, P = .91.
#␹21 = 3.51, P = .06.
**␹21 = 3.13, P = .08.
††␹21 = 1.13, P = .29.
VISUAL OUTCOMES
the treatment and control groups ( Figure 2 and
Distance Visual Acuity
Table 3 shows that the primary null hypotheses could
not be rejected at 12 and 24 months. Although the difference between the groups at 12 and 24 months favored treated patients, the magnitude of the difference,
less than 1 line of DVA, was small and did not reach statistical significance. The findings were similar at 3 and 6
months. The longitudinal regression analysis was conducted by systematically removing redundant terms from
the model, and this showed that the treatment indicator
remained nonsignificant throughout.
Analysis of the data on the basis of lines of acuity
lost showed that a greater proportion of patients in the
control group lost 3 or more or 6 or more lines at each
follow-up visit, but the differences did not reach statistical significance (Table 4). These findings are corroborated by examination of the cumulative proportions of
patients losing 3 or more or 6 or more lines of DVA in
1033
Figure 3).
Near Visual Acuity
At the primary follow-up visits, at 12 and 24 months, no
statistically significant difference between the groups was
detected. However, the difference between treated and
control groups was statistically significant at 6 months
(t test, P=.048) (Table 5), when the magnitude of the
change was −0.102, which is equal to 1 line of NVA (95%
CI, 0.001-0.203). As noted previously with DVA, the direction of the mean change from baseline in NVA always favored treated patients during the study, and this
is shown in Figure 4. When the data were analyzed by
longitudinal regression, no treatment benefit was found.
In only one regression analysis did the treatment effect
(␤) approach statistical significance (␤=−0.07, SE=0.04,
t=−1.94, P value is between .05 and ⬍.10), when adjusting for time and baseline NVA.
1.0
Table 5. Estimated Treatment Benefit to Near Visual
Acuity (NVA)*
Follow-up, mo
Benefit
SE
No. of
Participants
P
Value
3
6
12
24
−0.066
−0.102
−0.061
−0.076
0.042
0.051
0.052
0.057
186
179
181
172
.12
.048†
.25
.19
Cumulative Proportion
0.8
0.6
0.4
Group
Treatment
Treatment-Censored
Control
Control-Censored
0.2
0
0.0
0.5
1.0
1.5
2.0
*Data are given as logMAR near acuity. Benefit indicates the difference
between group averages (treatment minus controls) in change in NVA from
baseline. The number of participants varies according to the number of
completed visits.
†P⬍.03 in nonparametric testing.
1.5
2.5
Time, y
1.0
0.8
Change in NVA (LogMAR)
1.0
Figure 2. Kaplan-Meier–based graph of proportions of eyes losing 3 logMAR
lines of distance acuity. At all time points, fewer eyes assigned to treatment
lost 3 lines of acuity compared with the control group. No statistically
significant differences were seen at any of the time points.
0.5
0.0
– 0.5
–1.0
0.6
–1.5
0.0
0.4
Group
Trend for Treatment Group
Treatment Group
0.5
1.5
1.0
Trend for Control Group
Control Group
2.0
2.5
3.0
Time, y
Group
Treatment
Treatment-Censored
Control
Control-Censored
0.2
0
0.0
0.5
1.0
1.5
2.0
Figure 4. Change in near visual acuity (NVA) over time. Nonparametric trend
lines fitted to the data show separation between treatment and control
groups, which is maximum in the first 6 months of the study. Although
treatment and control groups lost acuity during the study, the loss is less in
the former.
2.5
Time, y
Figure 3. Kaplan-Meier–based graph of proportions of eyes having severe
vision loss (loss of 6 logMAR lines of distance acuity). Maximum divergence
between treatment and control groups is seen from 12 months onward, but
the difference did not reach statistical significance (P=.12).
When the proportions of patients losing 3 or more
or 6 or more lines of NVA were examined, statistically
significant differences were detected at 3 and 6 months
but not at 12 or 24 months (Table 6). Kaplan-Meier–
based graphs show the cumulative proportions of patients losing 3 or more or 6 or more lines of NVA over
time (Figure 5 and Figure 6).
Contrast Sensitivity
Table 7 shows that the primary null hypotheses
could not be rejected at 12 and 24 months. As before,
mean changes in CS from baseline favored treated
1034
patients throughout the study but did not reach statistical significance. The longitudinal regression analysis
revealed a marginally significant treatment effect when
time and baseline CS were entered into the model:
(␤ = 0.09, SE = 0.04, t = 2.0, P value is between .02 and
⬍.05).
At all time points, the proportion of patients losing
0.3 or more or 0.6 or more log units of CS was lower in
the treatment group than in controls (Table 8). At 12
months, the difference was not significant; 34 patients
(37.4%) had lost 0.3 or more log units of CS in the treatment group, compared with 45 patients (49.5%) in the
control group (difference, 12.1%; 95% CI, −1.9% to
26.1%). At 24 months, there was evidence of a significant difference in the loss of 0.3 log units of CS in favor
of treatment (treated, 43.5%, vs controls, 60.9%; difference, 17.4%; 95% CI, 3.4%-31.4%) (Figure 7 and
Figure 8).
Group
Lines of NVA Lost
By 3 mo
ⱖ3†
ⱖ6‡
By 6 mo
ⱖ3§
ⱖ6㛳
By 12 mo
ⱖ3¶
ⱖ6#
By 24 mo
ⱖ3**
ⱖ6††
Treatment
Control
Total
19 (20.9)
5 (5.5)
35 (36.8)
15 (15.8)
54 (29.0)
20 (10.8)
43 (46.2)
12 (12.9)
54 (62.8)
21 (24.4)
97 (54.2)
33 (18.4)
53 (57.0)
22 (23.7)
55 (62.5)
28 (31.8)
108 (59.7)
50 (27.6)
58 (66.7)
27 (31.0)
61 (71.8)
36 (42.4)
119 (69.2)
63 (36.6)
0.5
Table 6. Lines of NVA Lost by 3, 6, 12, and 24 Months
of Follow-up*
0.4
0.3
Group
Treatment
Treatment-Censored
Control
Control-Censored
0.2
0.1
0.0
0.0
0.5
1.0
1.5
2.0
2.5
Time, y
Figure 6. Kaplan-Meier–based graph of proportions of eyes losing 6 or more
lines of near acuity. At all time points, fewer eyes assigned to treatment lost
6 or more lines of acuity compared with the control group, although the
difference did not reach significance (P = .17).
Table 7. Estimated Treatment Benefit to Contrast
Sensitivity (CS)*
*Data are given as number (percentage) of participants. The number
of participants varies according to the number of completed visits.
NVA indicates near visual acuity.
†␹21 = 5.75, P = 0.02.
‡␹21 = 5.13, P = 0.02.
§␹21 = 4.93, P = 0.03.
㛳␹21 = 3.94, P = 0.05.
¶␹21 = 0.57, P = 0.45.
#␹21 = 1.51, P = .22.
**␹21 = 0.52, P = .47.
††␹21 = 2.37, P = .12.
Follow-up, mo
Benefit
SE
No. of
Participants
P
Value
3
6
12
24
+0.082
+0.056
+0.102
+0.052
0.046
0.062
0.065
0.067
184
178
182
172
.08†
.36
.12‡
.44
*Data are given as log contrast threshold. Benefit indicates the difference
between group averages (treatment minus controls) in change in CS from
baseline. The number of participants varies according to the number of
completed visits.
†Nonsignificant on nonparametric testing (P = .10).
‡P=.06 in nonparametric testing.
1.0
0.8
0.6
0.4
Group
Treatment
Treatment-Censored
Control
Control-Censored
0.2
0.0
0.0
0.5
1.0
1.5
2.0
2.5
Time, y
Figure 5. Kaplan-Meier–based graph of proportions of eyes losing 3 or more
lines of near acuity. Maximum separation between groups is seen between
3 and 6 months. This difference reached significance (P=.048).
SAFETY OUTCOMES
The analysis of the angiographic outcomes will be the
subject of a detailed further report. No patients were found
to develop features of radiation retinopathy in the 24
months after trial entry. As we did not carry out indocyanine green angiography, we could not rule out radiation-induced choroidopathy.
Treatment and control groups had similar tear
film breakup times at baseline (mean, 11.6 and 11.3
1035
seconds, respectively). At 3 months, this decreased in
the treatment group by a mean (SD) of 1.7 (0.8) seconds, compared with an increase of 0.6 (0.8) seconds
in the control group (P = .03). A similar finding was
noted at 6 months (P =.04) but not at subsequent time
points. Statistically significant differences in Schirmer
test results were also noted between treatment and
control groups at 6 and 12 months. At baseline, mean
Schirmer test values were 11.84 and 12.74 mm,
respectively, but at 6 months, the mean (SD) in the
treatment group had decreased by 0.83 (0.94) mm,
whereas in the control group the mean increased by
1.98 (0.94) mm (P = .04). By 12 months, the mean in
the treated group had decreased by 2.27 mm from
baseline, compared with an increase in the control
group of 0.92 mm (P =.02).
COMMENT
The present study and most other clinical trials in
ophthalmology have used DVA as a principal outcome
measure.1-10 This measure of vision is based on the
ability of the eye to resolve targets at a distance, and it
is generally accepted that threshold visual acuity,
when measured using the logMAR chart to standardized protocols, provides a useful yardstick for monitoring outcome for research purposes. However, the
validity of using DVA alone has been questioned in
assessing the benefits of treatment for ocular disorders, including ARMD.29-32 For this reason, 2 addiWWW.ARCHOPHTHALMOL.COM
Group
Log Units CS Lost
By 3 mo
ⱖ0.3†
ⱖ0.6‡
By 6 mo
ⱖ0.3§
ⱖ0.6㛳
By 12 mo
ⱖ0.3¶
ⱖ0.6#
By 24 mo
ⱖ0.3**
ⱖ0.6††
Treatment
Control
Total
21 (23.6)
6 (6.7)
34 (35.8)
15 (15.8)
55 (29.9)
21 (11.4)
30 (33.0)
15 (16.5)
36 (41.4)
19 (21.8)
66 (37.1)
34 (19.1)
34 (37.4)
18 (19.8)
45 (49.5)
27 (29.7)
79 (43.4)
45 (24.7)
37 (43.5)
24 (28.2)
53 (60.9)
26 (29.9)
90 (52.3)
50 (29.1)
*Data are given as number (percentage) of participants. The number of
participants varies according to the number of completed visits. CS indicates
contrast sensitivity.
†␹21 = 3.26, P = .07.
‡␹21 = 3.72, P = .05.
§␹21 = 1.35, P = .24.
㛳␹21 = 0.83, P = .35.
¶␹21 = 2.71, P = .10.
#␹21 = 2.39, P = .12.
**␹21 = 5.21, P = .02.
††␹21 = 0.06, P = .81.
1.0
0.8
0.6
0.4
Group
Treatment
Treatment-Censored
Control
Control-Censored
0.2
0.0
0.0
0.5
1.0
1.5
2.0
2.5
Time, y
Figure 7. Kaplan-Meier–based graph of proportions of eyes losing 0.3 or
more log units of contrast sensitivity. At all time points, proportionately
fewer eyes assigned to treatment lost 0.3 or more log units of contrast
compared with the control group. The differences between treatment and
control groups was highly significant (P =.005).
tional variables of visual function, NVA and CS, are
also presented in this study.
The study was designed to detect an average difference of 2 logMAR lines of DVA with 90% power and 95%
confidence. The magnitude of the detectable difference
was based on the results of a pilot study,12,14 which suggested a potential 2-line benefit likely to have an effect
on visual function in the study population.
1036
0.5
Table 8. Log Units of CS Lost by 3, 6, 12, and 24 Months
of Follow-up*
0.4
0.3
0.2
Group
Treatment
TreatmentCensored
0.1
0.0
0.0
0.5
1.0
1.5
Control
ControlCensored
2.0
2.5
Time, y
Figure 8. Kaplan-Meier–based graph of proportions of eyes losing 0.6 or
more log units of contrast sensitivity. Proportionately fewer eyes assigned to
treatment lost 0.6 or more log units of contrast compared with the control
group, but the difference was not statistically significant (P = .11).
In the SFRADS, DVA was not statistically significantly different between the study groups at 12 or 24
months, when we believe a benefit would have been
clinically useful. During the study, visual outcome was
better on average in treated patients, but the differences
observed were smaller than those considered likely to
be clinically relevant, and most were not statistically
significant. When considering mean differences
between the groups, the only single measure of outcome that was significantly different was mean NVA at
6 months, and the magnitude of this difference was 1
logMAR line, the 95% CI being consistent with an effect
size ranging from just above zero to 2 logMAR lines.
The analysis of dichotomous variables in relation to
NVA suggests the presence of an early therapeutic effect
(not sustained beyond 6 months). This finding is more
persuasive given that these differences were detected
despite the fact that the SFRADS was not powered to
investigate these aspects of visual outcome. However,
the significant findings in relation to CS at 3 and 24
months are more difficult to explain and accordingly
are less convincing.
Therefore, when all outcome measures were considered, the data suggest that visual outcome was better
in treated patients. That the data imply, but do not
establish beyond doubt, that a therapeutic effect exists
is consistent with the mixed conclusions of other
studies22-24 using low-dose radiotherapy. Bergink et al22
concluded that 24 Gy of radiation given as 4 fractions of
6 Gy was effective in reducing moderate and severe
visual loss in eyes with CNV in ARMD. However, more
recent studies23,24 did not find any evidence of benefit
from EBRT. The absence of a therapeutic effect in the
latter studies is unlikely to be related to variation in
dosage, as similar dosages were used (16 Gy23 and 14
Gy24 vs 12 Gy in the SFRADS). However, there are
other factors that could account for the variation in outcome. In one study,23 most subjects (55.6%) had purely
occult CNV, and in the other,24 fewer than 14% of subjects were graded at baseline as having classic CNV
only. In comparison, most subjects in the SFRADS
(72.9%) belonged to the wholly classic or predominantly classic subgroups. Furthermore, the studies with
negative findings were based on 12 months of data
alone. Other small randomized controlled studies33,34
have used sources of radiotherapy that are more capable
of precisely delineating the target area, including proton
beam and plaque radiotherapy. Although the data
from these studies are encouraging, the high dosages of
radiation to the choroidal vasculature may result in
greater damage to the choroid and retinal pigment epithelium, with the prospect of a worse visual outcome
than that associated with the natural history. In this
regard, several reports20,21,35 suggest that EBRT to CNV
may cause abnormal vascular proliferations in the retinal and choroidal circulations.
The results of the present study indicate that radiotherapy to a subfoveal CNV given as 6 fractions to a
total dosage of 12 Gy is not inimical and does not result
in a worse visual outcome compared with the natural
history. To our knowledge, none of the controlled trials
thus far have reported radiation retinopathy or optic
neuropathy, 22-24 and similarly we found no serious
adverse effects, although some temporary abnormality
of tear film was recorded. Also, the value of the small
differences noted in acuity and contrast between treatment and control groups may not translate into
improvements in visual functioning.32 The magnitude
of benefit detected indicates that EBRT will not resolve
the problem of blindness from age-related macular disease. Whether the magnitude of the detected benefit
warrants the use of this treatment is questionable. Most
subjects enrolled in the SFRADS had wholly or predominantly classic CNV and thus fall into the category
of patients who would benefit from photodynamic
therapy with verteporfin. 10,11 With photodynamic
therapy, the need for successive treatments and the
accompanying investigations have important implications for the patient. Also, there are health, economic,
and cost-benefit issues to be considered when comparing treatments. 36 However, the smaller proportion
(28%) of eyes losing 3 lines of acuity in a predominantly classic subgroup treated with photodynamic
therapy10,11 is considerably better than that achieved by
EBRT in this study (58%). It is therefore our opinion
that the present study has not identified a specific clinical role for 12 Gy of photon radiotherapy given as a
series of 6 fractions in the management of CNV in
ARMD.
Submitted for publication July 12, 2001; final revision received April 17, 2002; accepted April 24, 2002.
From the Departments of Ophthalmology and Visual
Science (Drs Hart and Chakravarthy) and Epidemiology
(Dr Stevenson), Queen’s University of Belfast and Northern Ireland Radiotherapy Centre, Belvoir Park Hospital
(Dr Houston), Belfast, Northern Ireland; School of Public
Policy, Economics and Law, University of Ulster, Antrim,
Northern Ireland (Dr McCulloch); and Centre for Medical Statistics, Keele University, Keele (Dr Mackenzie);
Eye Unit, Southampton University Hospitals (Dr Chisholm) and Wessex Radiotherapy Centre, Royal South
Hants Hospital, Southampton (Dr Hall), England; and
Institute of Ophthalmology, University College (Dr Bird),
Moorfields Eye Hospital (Dr Owens), and Department of
Radiotherapy and Oncology, St Bartholomew’s Hospital
(Dr Plowman), London, England.
1037
This study was supported by strategic project grant
G9404235 from the Medical Research Council of the United
Kingdom, London, International Standardized Random Control Trial Number (ISRCTN 84737434).
The SFRADS group members thank the following:
Judy Alexander, The Scheie Eye Institute; John Reeves,
PhD, GD Searle, Inc, Chicago, Ill; M. Broadbery, MSc, and
M. McClure, MSc, Royal Victoria Hospital, P. McEvoy,
G. McGoldrick, and Kay Andrews, Queen’s University, and
M. Burns, Green Park Hospitals Trust, Belfast; K. Grigg
and A. Brannon, Moorfields Eye Hospital, London;
and B. Ashleigh, K. Parrish, Sheila Davis, and Sheila
Bryant, Southampton University Hospitals Trust, Southampton.
Corresponding author and reprints: Usha Chakravarthy, FRCOphth, PhD, Department of Ophthalmology and
Vision Science, The Royal Victoria Hospital, Queen’s University of Belfast, Grosvenor Road, Belfast BT12 6BA, Northern Ireland (e-mail: g.mcgoldrick@qub.ac.uk).
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Visual Outcomes in the Subfoveal Radiotherapy Study for Age-Related Macular Degeneration

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