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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
Arch Ophthalmol. 2002;120:1029-1038.
ABSTRACT
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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 measure 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 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 support the routine clinical
use of external beam radiation therapy in subjects with subfoveal choroidal
neovascularization in age-related macular degeneration.
INTRODUCTION
CHOROIDAL 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 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 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 age-related 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 fractions) 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.
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-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 stereo-pair
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 ( 50% 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 MPS-certified 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.
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Figure 1. Flowchart depicting participation
in the Subfoveal Radiotherapy Study.
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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 x
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 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
RESULTS
PATIENTS ANALYZED
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.
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Table 1. No. of Participants From Each Center*
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BASELINE CHARACTERISTICS
Randomization achieved prior similarity between the treated and control
groups (Table 2). Most patients
in the study (72.9%) had wholly or predominantly classic CNV.
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Table 2. Baseline Characteristics*
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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.
VISUAL OUTCOMES
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.
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Table 3. Estimated Treatment Benefit to Distance Visual Acuity (DVA)*
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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 the treatment and control
groups (Figure 2 and Figure 3).
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Table 4. Lines of DVA Lost by 3, 6, 12, and 24 Months of Follow-up*
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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.
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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).
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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.
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Table 5. Estimated Treatment Benefit to Near Visual Acuity (NVA)*
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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.
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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).
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Table 6. Lines of NVA Lost by 3, 6, 12, and 24 Months of Follow-up*
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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).
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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).
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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 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).
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Table 7. Estimated Treatment Benefit to Contrast Sensitivity (CS)*
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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).
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Table 8. Log Units of CS Lost by 3, 6, 12, and 24 Months of Follow-up*
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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).
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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).
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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 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 additional 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.
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.
AUTHOR INFORMATION
Submitted for publication July 12, 2001; final revision received April
17, 2002; accepted April 24, 2002.
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{at}qub.ac.uk).
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.
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